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REVIEW ARTICLE OPEN

The mechanism underlying extrapulmonary complications of

the coronavirus disease 2019 and its therapeutic implication
Qin Ning1 ✉, Di Wu1, Xiaojing Wang1, Dong Xi1, Tao Chen1, Guang Chen1, Hongwu Wang1, Huiling Lu2, Ming Wang1, Lin Zhu1,
Junjian Hu1, Tingting Liu1, Ke Ma1, Meifang Han1 ✉ and Xiaoping Luo2 ✉

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory
system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple
extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial,
involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response.
Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease
progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19
from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the
management of COVID-19.
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Signal Transduction and Targeted Therapy (2022)7:57 ; https://doi.org/10.1038/s41392-022-00907-1

INTRODUCTION perspective on the extrapulmonary organ-specific pathophysiol-

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ogy and potential therapeutic strategies for COVID-19, in order to
is a highly contagious and pathogenic virus that was identified as help scientists and clinicians to identify and monitor the spectrum
a causative agent of the coronavirus disease 2019 (COVID-19).1 As of disease, and to establish research priorities within this field.
of January 6, 2022, SARS-CoV-2 has infected nearly 289 million
people and caused over 5.4 million deaths globally.2 Accumulating
evidence suggests that SARS-CoV-2 infection primarily attacks the PATHOGENESIS OF SARS-COV-2 INFECTION
lung and causes respiratory diseases ranging from mild cold to Key mechanisms underlying pathophysiology of extrapulmonary
more severe illness such as severe acute respiratory syndrome organ injury secondary to SARS-CoV-2 infection include direct viral
(ARDS), but it can also affect other organs and have systemic invasion, imbalance of renin–angiotensin-aldosterone system
consequences with multiple organ injury.3 The extrapulmonary (RAS), dysregulation of the immune response, endothelial cell
complications4 include a wide spectrum of disorders with damage, and thromboinflammation. These mechanisms respon-
cardiovascular,5 endothelial,6 coagulation,7 renal,8 hepatobiliary,9 sible for multiple organ involvement of COVID-19 has not yet been
gastrointestinal,10 endocrinological,11 neurological12 involvement, fully understood. ACE2-mediated virus entry and dysregulated
which may occur in severe and critically ill patients and are RAS may be unique to SARS-CoV-2 infection, while immune
associated with prolonged hospitalization and increasing mortality dysregulation characterized by excessive release of proinflamma-
risk. The extrapulmonary organ injury of COVID-19 may result from tory cytokines and microcirculation disorder may occur in other
direct injury mediated by SARS-CoV-2 invasion, endothelial cell critical conditions such as sepsis.
damage, or possible indirect mechanisms secondary to excessive
local and systemic inflammatory responses. Angiotensin- Direct mechanism of SARS-CoV-2 infection
converting enzyme 2 (ACE2)13 has been identified as the entry SARS-CoV-2 is an enveloped virus with a positive-sense single-
receptor for SARS-CoV-2. The widespread distribution of ACE2 stranded RNA (+ssRNA) genome of around 30-kb. A mature SARS-
across multiple organs and tissues makes the virus-mediated CoV-2 particle contains four main structural components, includ-
direct tissue damage a plausible mechanism of systematic injury.14 ing spike (S), envelope (E), membrane (M) glycoproteins, and
Moreover, dysregulated immune response, endothelial damage as nucleocapsid phosphoprotein (N). The S glycoprotein mediates
well as thromboinflammation may also account for the extra- virus entry into target cells. E protein is a small integral membrane
pulmonary complications of COVID-19.6,15 In this review, we protein acting on viral assembly, budding, envelope formation,
narratively summarized the published literature on extrapulmon- and pathogenesis.16 N protein is an abundantly expressed
ary consequences of COVID-19, and provided a comprehensive RNA-binding protein that plays a critical role in the replication,

1
National Medical Center for Major Public Health Events, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science
and Technology, Wuhan, China and 2National Medical Center for Major Public Health Events, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, China
Correspondence: Qin Ning ([email protected]) or Meifang Han ([email protected]) or Xiaoping Luo ([email protected])
These authors contributed equally: Qin Ning, Di Wu

Received: 4 October 2021 Revised: 10 January 2022 Accepted: 17 January 2022

© The Author(s) 2022

The mechanism underlying extrapulmonary complications of the coronavirus. . .
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transcription, and genome packaging of SARS-CoV-2. M protein is structural proteins (S, E, and M) traffic through the endoplasmic
key for the assembly of viral particles through interacting with all reticulum (ER) to ER–Golgi intermediate compartment (ERGIC).
other structural proteins. These interactions between structural The N protein package genomic RNA into helical structures in the
proteins help form replication-incompetent virus-like particles cytoplasm, and interact with hydrophobic M protein in the ERGIC
(VLPs), which resemble the morphological structure of SARS-CoV- that serve to direct assembly and budding of the mature virion.39
217 and are efficient platform for vaccine development. These virions are transported to the cell surface in vesicles and
SARS-CoV-2 can enter the host cells either via endocytosis or via then released through exocytosis into the extracellular
direct fusion with the plasma membrane. The S protein binding to region.33,34 The development of effective therapeutic strategies
ACE2 represents the initial step of SARS-CoV-2 infection, thus it is for COVID-19 relies on the knowledge of molecular mechanisms
the main target for the design of vaccines and inhibitors of viral of SARS-CoV-2 infection.
entry. S protein includes S1 and S2 subunits. The S1 subunit
comprises an N-terminal domain (NTD) and the receptor-binding Emerging SARS-CoV-2 variants. Like other RNA viruses, SARS-CoV-
domain (RBD).18 The RBD contains a conserved core and receptor- 2 tends to evolve rapidly, producing mutants that differed
binding motif (RBM), which is a variable region of S protein significantly from its ancestral strains. A classification system was
responsible for direct binding to ACE2 and the key target of established to distinguish the emerging SARS-CoV-2 variants into
neutralizing antibodies.19,20 The S2 subunit mediates fusion of the variants of concern (VOCs) and variants of interest (VOIs). There
viral envelope with host cellular membrane. It consists of a highly are currently five main designated VOCs, including Alpha, Beta,
conserved fusion peptide (FP) domain, two heptad-repeat Gamma, Delta, and Omicron variants. Alpha, Beta, Gamma, and
domains (HR1 and HR2), a central helix (CH), a connector domain Delta variants were first identified in the UK, South Africa, Brazil,
(CD), transmembrane domain (TM), and cytoplasmic tail (CT).21 and India, respectively.40 VOCs have been associated with
ACE2 was identified as the binding receptor of both SARS-CoV increased transmissibility and viral virulence, decreased diagnostic
and SARS-CoV-2. The RBD of SARS-CoV-2 has a higher ACE2- sensitivity, and potential influence on vaccination.41 All VOCs carry
binding affinity compared to that of SARS-CoV, supporting mutation D614G that may enhance infectivity of SARS-CoV-2 by
efficient cell entry.22 The enhanced affinity may increase the assembling more functional S protein into the virion.42 N501Y
infectivity of SARS-CoV-2. The ACE2 gene expression was initially mutation located within the RBD is common to all variants except
established in the heart, kidneys, and testes,23 while further the Delta variant that contributes to increased affinity of the S
studies showed a much broader distribution, such as the upper protein to ACE2, promoting the viral attachment and its
respiratory tract, lungs, intestine, liver, and pancreas.24–26 More- subsequent entry into the host cells.43,44
over, neuropilin-1 (NRP1), expressed in the respiratory and Alpha variant is also known as lineage B.1.1.7. Three B.1.1.7 S
olfactory epithelium, may be an additional cellular facilitator of protein mutations are of particular concern: a two-amino-acid
SARS-CoV-2 cell entry and infectivity.27 In addition, an RNA deletion at position 69–70 of the NTD; N501Y; and P681H,
sequencing analysis shows that although immune cells do not proximal to the furin cleavage site.45 Mutation P681H is a known
express ACE2 or TMPRSS2, another receptor for SARS-CoV-2, a region of importance for infection and transmission.28,46 The
transmembrane protein of the immunoglobulin cluster of ΔH69/ΔV70 deletion results in increased infectivity and evasion of
differentiation (CD)147 provides a potential route for viral the immune response.20 Beta variant known as multiple
entry.28,29 SARS-CoV-2 can also exploit receptor-mediated endo- B.1.351 sublineages, includes nine mutations in S protein.
cytosis through interaction between its S protein with soluble K417N, E484K, and N501Y are located in the RBD.19 These
ACE2 or soluble ACE2-vasopressin via angiotensin (Ang) II type changes confer enhanced affinity for ACE244 and help to escape
receptor 1(AT1R) or arginine vasopressin receptor 1B (AVPR1B).30 from neutralization and reduce neutralization sensitivity to
After binding to the receptor, proteolytic cleavage of SARS- convalescent plasma.47 Gamma variant, also known as lineage
CoV-2 S protein enables the S2 subunit-assisted fusion of viral P.1, harbors ten mutations in the S protein. Three mutations
and cellular membranes. This process is mediated via certain (L18F, K417N, E484K) are located in the RBD.18,48 This variant may
host proteases including furin, cell surface transmembrane have reduced neutralization by monoclonal antibody therapies,
serine proteases 2 (TMPRSS2),31 cathepsins B and L, factor Xa convalescent sera, and postvaccination sera.49 Delta variant
and elastase. An insertion of four amino acids in the S1/S2 site of referred to as the B.1.617.2 lineage, has a highly mutated NTD
S protein provides a minimal cleavage motif (RRAR) recognized (T19R, G142D, Δ156-157, R158G, A222V). According to the
by proprotein convertase furin, which is a unique feature of reports,50,51 the Delta variant was resistant to neutralization by
SARS-CoV-2. S protein is cleaved at the S1/S2 site by furin and some anti-NTD and anti-RBD monoclonal antibodies.52 The Delta
subsequent at the S2’ site by TMPRSS2, triggering an irreversible Plus variant also known as B.1.617.2.1 or AY.1, is a sublineage of
and extensive conformational change to mediate membrane the Delta variant. Five key mutations (T95I, A222V, G142D, R158G,
fusion.32–34 Besides, inside the endosome, a pH-dependent and K417N) were significantly more prevalent in the Delta Plus
endosomal protease cathepsin L can facilitate the cleavage and than in the Delta variant.53 On 26 November 2021, WHO
proteolytical activation of S protein for fusion within the designated the newly emerging variant B.1.1.529 a VOC, named
endosomal membrane.35 Inhibition of these proteases, particu- Omicron, which has a total of 60 mutations.
larly TMPRSS2,36 might constitute a treatment option to treat
COVID-19. Indirect mechanisms of SARS-CoV-2 infection
The following SARS-CoV-2 life cycle inside the cell is similar to Dysregulation of the immune response. The pathogenesis of
that of other coronaviruses.37 SARS-CoV-2 releases viral genome COVID-19 is triggered by SARS-CoV-2 infection and amplified by
into the cytoplasm to induce translation of open reading frame dysregulated immune responses. Impaired immune system and
(ORF)1a and ORF1b into the large replicase polyproteins 1a hyperinflammation induced by SARS-CoV-2, instead of the direct
(pp1a) and pp1ab. Subsequently, two viral proteases, a papain- detrimental toxicity of virus, may account for severe disease with
like protease (PLpro) and a 3C-like protease (3CLpro) cleave pp1a multiple organ involvement in severe and critically ill COVID-19
and pp1ab into 16 nonstructural proteins (nsps) that assemble patients.54 Patients with ARDS and extrapulmonary complications
into replication-transcription complexes (RTCs) for RNA synth- have increased levels of circulating proinflammatory cytokines,
esis.38 The RNA-dependent RNA polymerase (RdRp) is the central chemokines and systemic inflammatory markers such as ferritin,
enzyme of RTCs. The RTCs produce new genomic RNA by lactate dehydrogenase (LDH), c-reactive protein (CRP), D-dimer, and
continuous synthesis and a set of subgenomic RNA.33 These neutrophil-to-lymphocyte ratio.55 As summarized in Fig. 1, increased
further are translated into respective viral proteins. The viral proinflammatory of cytokines, lymphocytopenia, lymphocyte

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Fig. 1 The potential mechanisms of SARS-CoV-2-induced immunopathology. a Lymphopenia, b Exhaustion of cytotoxic T lymphocytes and
NK cells, c Cytokine storm, d Activation of other immune cells contribute to the pathogenesis and exacerbation of COVID-19

exhaustion, and upregulated antibodies may be involved in the The pattern-recognition receptors (PRRs) in/on the immune
immune pathogenesis of COVID-19.15 cells, involving toll-like receptors (TLRs) such as TLR3 or TLR7, and
retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) such as
Innate immune response: As a frontline of defense, the innate RIG-I and the melanoma differentiation-associated gene 5
immune response to SARS-CoV-2 infection triggers several (MDA5) recognize the pathogen-associated molecular patterns
signaling pathways to induce the production of IFN, proinflam- (PAMPs) derived from SARS-CoV-2, such as viral ssRNA genome,
matory cytokines and chemokines, and initiate adaptive immunity replication intermediates or double-stranded RNA (dsRNA),
against SARS-CoV-2. Epithelial cells in the respiratory tract acting thereby initiating the antiviral responses.61 Endosomal TLR7
as the first line of innate immune sensing of SARS-CoV-2 infection, expressed in monocytes, dendritic cells (DCs) and macrophages
are a major source of chemokine interleukin (IL)-8 that plays an recognizes viral genomic RNA and subsequently results in the
important role in regulating lung neutrophil recruitment and activation of Janus kinase (JAK)/signal transducer and activator of
survival. Alveolar neutrophils and macrophages subsequently transcription (STAT) signaling pathways, and its downstream
trigger the innate immune response to the virus.56 Neutrophils transcription factors, activator protein-1 (AP-1), nuclear factor
engulf and kill the viruses through the release of neutrophil kappa B (NF-κB), interferon response factor (IRF) 3, and IRF7.62
extracellular traps (NETs), reactive oxygen species (ROS), and These activated signaling pathways and transcription factors
antimicrobial peptides.57 The enhanced infiltration of granulocytes induce the rapid production of proinflammatory cytokines.63
and monocyte-macrophages is a common phenomenon in severe The immune hallmark of severe COVID-19 is exaggerated
COVID-19 cases. Monocytes and macrophages are involved in the secretion of cytokines, such as interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-
exacerbated and hypersensitive reactions contributing to the 10, granulocyte macrophage-colony stimulating factor (GM-CSF),
organ damage.58 Besides, multiple studies have shown decreased IFN-γ, and TNF-α, interferon-inducible protein-10 (IP10), macro-
numbers and functionally exhaustion of natural killer (NK) cells phage inflammatory protein (MIP)-1α, tumor necrosis factor (TNF)-
during SARS-CoV-2 infection.59 The diminished NK cell cytotoxicity α, etc. This life-threatening condition related to systemic
and immune regulation result in a critical inflammatory phenotype inflammation with sometimes lethal consequences is known as
in COVID-19.60 cytokine storm syndrome (CSS) or cytokine release syndrome

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(CRS), or just cytokine storm.64,65 Cytokine storm, an overwhelm- are more likely to carry mutations in genes involved in type I IFN
ing inflammatory response results in the pathophysiology and pathways or have autoantibodies against IFN that can neutralize
mortality of SARS-CoV-2 infection. Cytokine storm is closely high concentrations of type I IFN in vitro.83,84 However, increasing
associated with macrophage activation syndrome (MAS), which evidence also shows contradictory findings that severe COVID-19
is characterized by inflammatory systemic abnormality such as patients have a robust type I IFN response, contrary to a delayed
pancytopenia, hyperferritinemia, coagulopathy, hemodynamic and likely suppressed IFN response found in the early phase of
instability, liver failure, neurological disorder, and can lead to infection.85 Deeper understanding of the roles of IFNs response in
ARDS or even multiorgan damage associated with unfavorable SARS-CoV-2 infection is warrant further investigation.
prognosis of COVID-19.66 MAS is resulted from the excessive
proliferation of differentiated macrophages that cause hemopha- Adaptive immune response: The adaptive immune system is also
gocytosis and hypercytokinemia.67,68 called specific or acquired immunity, including cellular immunity
As an important pleiotropic proinflammatory mediator, IL-6 is carried out by T cells and humoral immunity mediated by B cells
the main driver of cytokine storm through promoting the that elicit protective immune response against pathogens in an
proliferation of myeloid progenitor cells and activation of antigen-specific manner.86 During viral infection, an effective
leukocytes, inducing pyrexia, and escalating the secretion of adaptive immune response plays a crucial role in eliminating the
acute-phase proteins in the severe cases of COVID-19.69 SARS- virus and preventing the disease progression.87 Induction of an
CoV-2 infection induces a wide range of immune cells including adaptive immune response against pathogens relies on the initial
macrophages, neutrophils, DCs and lymphocytes to secrete recognition and capture of antigens by antigen presenting cell
excessive amounts of IL-6.70,71 Excessive IL-6 promotes the (APC). The viral antigens are identified, processed, and presented
differentiation of Th17 cells and stimulates IL-17 production,72 by APCs to activate and guide the differentiation of CD4+ and
and further recruits neutrophils, monocytes, and macrophages to CD8+ T cells into effector and memory cells.88 After being
the site of infection and inflammation and triggers a cascade of activated, CD4+ T cells differentiate into Th1, Th2 effector cells,
inflammatory cytokines, such as IL-1β and IL-6, leading to an IL-6 and other subsets, characterized by distinct cytokine pattern.89 Th
burst in its amplification cycle.73 Increased levels of IL-6 are cells play critical roles in orchestrating the adaptive immune
significantly associated with the disease severity and adverse responses, through secretion of cytokines and chemokines that
clinical outcome of COVID-19.74 The IL-6 signaling cascade is recruit immune cells and stimulate B cell differentiation and
initiated by IL-6 binding to the membrane-bound or soluble IL-6 antibody production as well as activate CD8+ cytotoxic T
receptor (IL-6R) and a second transmembrane protein, glycopro- lymphocytes (CTLs). Th1 cells produce IFN-γ, IL-2, and lymphotoxin
tein 130 (gp130), which is referred to as classic signaling or trans- α (LTα), and mediate immune responses against intracellular
signaling, respectively.75 IL-6 classic signaling may have homeo- pathogens, whereas Th2 cells produce IL-4, IL-5, IL-9, IL-10, IL-13,
static and anti-inflammatory effects, whereas trans-signaling may and IL-25, and mediate host defense against extracellular
regulate proinflammatory response.76 Expression of IL-6R is parasites.90 CTLs can directly kill the virus-infected cells via
restricted to cells including hepatocytes and immune cells, but exocytosis of lytic granules that contain perforin and granzymes or
gp130 is ubiquitously expressed, possibly explaining the via the Fas pathway.91 T-follicular helper (Tfh) cells are a
pleiotropic functions of IL-6. Recombinant humanized mono- specialized subset of CD4+ T cells that can activate B cells to
clonal antibodies against IL-6R or IL-6 are drug candidates for produce antibodies. The neutralizing antibodies exert protective
managing the cytokine storm secondary to SARS-CoV-2 infec- activities through blocking SARS-CoV-2 infection in a later phase
tion77 through inhibiting the intercellular signaling pathway in and conferring protection against future infection.92
gp130 expressing cells. Lymphopenia, particularly in peripheral CD4+ and CD8+ T cells,
GM-CSF also has a critical role in mediating cytokine storm. is frequently found and an early immunologic indicator of
Because of its function as a proinflammatory cytokine and a impending severe COVID-19.93,94 This lymphocytes depletion
myeloid cell growth factor, GM-CSF may be another important could be a manifestation of imbalance in both arms of immune
driver of the immunopathological sequelae of SARS-CoV-2 responses, leading to dysregulated IFN production, hyperactivated
infection.69 Upon SARS-CoV-2 infection, CD4+ T lymphocytes neutrophils and macrophages, and delayed viral clearance. The
are rapidly differentiated into pathogenic T helper (Th) 1 cells prevalence of lymphopenia differed among the patients with
that produce IL-6 and GM-CSF, subsequently inducing different disease severities, with 72.7% developed in severe cases
CD14+CD16+ monocytes to secrete high levels of IL-6 and GM- and 10.0% in the moderate case.94 Patients with severe COVID-19
CSF and worsen the cytokine storm.78 Hence, a monoclonal showed considerably decrease in the counts of circulating
antibody against GM-CSF may be effective to attenuate the memory CD4+ T cells, CD8+ T cells and regulatory T cells (Tregs).94
immunopathogenesis of COVID-19. Despite reduced CD8+ T-cell counts, their histocompatibility
IFN is innate cytokine that functions as the first-line defense complex (MHC) II cell surface receptor (HLA-DR) expression was
against viral infection. Type I IFN, including IFN-α and IFN-β, higher in patients with severe COVID-19 than moderate cases.
triggers the expression of IFN-stimulated genes (ISGs), which HLA-DR is primarily recognized as a marker of T-cell activation, but
directly suppress viral replication by various mechanisms, invol- a recent study shows that CD8+HLA-DR+ T cells may constitute a
ving degradation of viral RNA or inhibition of viral transcription or Treg cell subset,95 and have immunosuppressive properties
translation.79,80 More than one-third of SARS-CoV proteins have involving the inhibitory molecule the cytotoxic T lymphocyte
inhibitory effects on type I IFN-mediated antiviral immune antigen 4 (CTLA-4). High expressions of perforin and granzyme B
responses.81 Given most of the SARS-CoV-2 proteins exhibit high in CD8+ T cells, low levels of TNF-α and IFN-γ in CD4+ T cells were
amino acid-sequence homology with those of SARS-CoV, it is related to disease severity of COVID-19.96 Moreover, CD8+ T cells
speculated that SARS-CoV-2 proteins may exhibit inhibitory effects more frequently displayed an exhausted phenotype in the severe
on IFN responses through similar mechanisms.80 SARS-CoV-2 have COVID-19 cases. Patients with overtly symptomatic COVID-19
evolved mechanisms to evade the antiviral function of type I and showed increased programmed cell death protein-1 (PD-1) and
III IFNs, including interference with the induction of IFN T-cell immunoglobulin domain and mucin domain-3 (TIM-3)
production or the downstream signaling pathways after IFN expressions on CD8+T cells.97 These results indicate that
binding to the IFN receptors (IFNRs).80 Patients with severe or functional impairment or exhaustion of T cells is correlated with
critically ill COVID-19 had highly impaired type I IFN response, disease severity and prognosis of patients with COVID-19.
characterized by low production and activity of type I IFN and Moreover, SARS-CoV-2 infection may induce the downregulation
ISGs.82 Compared to asymptomatic or mild COVID-19, severe cases of the MHC II expression on B cells, leading to decreased acquired

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immunity activation.98 An increased SARS-CoV-2-specific IgG Patients with COVID-19 have severe endothelial damage in
antibody responses are strongly correlated with disease severity,99 their lungs, including viral invasion and rupture of the endothelial
suggesting that activation of B cells in severe COVID-19 patients is cell membrane.109 Another study identified the co-presence of
associated with adverse outcome. SARS-CoV-2 N protein and ACE2 receptor on the pulmonary
Multiple underlying mechanisms may be responsible for vascular endothelium in postmortem COVID-19 patient sam-
lymphopenia and lymphocyte dysfunction. SARS-CoV-2 infects ples.110 Moreover, IFN-α or -β can promote SARS-CoV-2 pulmon-
primarily epithelial cells in the respiratory tract through binding ary vascular infection by inducing the expression of ACE2 in
of S protein to ACE2. It is hypothesized that SARS-CoV-2 may human primary lung endothelial cells.111 S1 and S2 subunits of S
suppress adaptive cellular immune response through infecting protein mediate attachment and membrane fusion, respectively.
certain immune cells. However, some studies have demonstrated In primary human pulmonary microvascular endothelial cells that
that only limited pulmonary macrophages or monocytes may naturally express ACE2, S1 subunits instead of intact S protein
express ACE2,100 which raises the possibility of the presence of reduces transendothelial resistance (TER) and barrier function.112
additional receptors or cellular entry route such as antibody- Plasma mediators of severe COVID-19 patients can cause lung
dependent enhancement (ADE), granting SARS-CoV-2 an oppor- endothelial barrier failure.113
tunity to infect host immune cells. The reduced T-cell numbers SARS-CoV-2 can not only cause lung endothelial cell damage,
were inversely associated with IL-6, IL-10, and TNF-α levels. This but also affect the endothelial cells in extrapulmonary organs. The
phenomenon indicates that increased production of inflamma- study found that the endothelial cells of the vascular bed of
tory cytokines may promote T-cell exhaustion and apoptosis that different organs are affected in patients with COVID-19.114
accompanies disease progression.101 Soluble IL-2 receptor can Besides the lungs, endothelial-related inflammatory cells and
negatively regulate CD8+ T cells and induce lymphopenia via apoptotic bodies clusters were found in the heart and small
inhibition of IL-2 signaling.102 Moreover, lymphoid organ intestine. Moreover, another patient with COVID-19 has also
atrophy, such as the spleen and lymph node leads to further found obvious endotheliitis in the heart, liver, kidney, and small
impairments of lymphocyte.103 Severe COVID-19 patients had an intestine. In the circulatory system, COVID-19-induced endoder-
elevated level of lactic acid in the blood, which can suppress the matitis is a small vasculitis and does not involve the major
proliferation of lymphocytes.104 Neutrophils with suppressive coronary arteries.115 Renal biopsy also revealed endothelial
properties such as granulocytic myeloid-derived suppressor cells abnormalities, ranging from mild injury with enlarged subcuta-
(G-MDSCs) and their possible role in suppressing CD4+ and CD8+ neous space and/or loss of endothelial cell windows in the
T lymphocytes expansion may also give rise to lymphopenia in glomeruli to severe injury with swollen endothelial cells in the
severe SARS-CoV-2 infection.105 glomerular portal arterioles and fibrin thrombus.116
Endothelial injury may occur through direct invasion of
Endothelial cell damage. Endothelial biomarkers including von endothelial cells or indirect effect of SARS-CoV-2 (Fig. 2). ACE2
Willebrand factor (vWF), soluble P-selectin, and soluble thrombor- on the surface of endothelial cells can be invaded by SARS-CoV-
egulatory protein were elevated in severe COVID-19 patients, 2.117 SARS-CoV-2 can also infect the endothelial cells of
highlighting the importance of endothelial injury in the patho- extrapulmonary organs. ACE2 was present in arterial and venous
genesis of COVID-19.106 Excessive matrix metalloproteinase-1 endothelial cells of all studied organs.24 The structure of the virus
(MMP-1) and endothelial cell overactivation as evidenced by inclusion body was found in the kidney endothelial cells of
elevated soluble CD146, vascular cell adhesion molecule-1 (VCAM- patients who died from COVID-19 through electron micro-
1) and intercellular adhesion molecule-1 (ICAM-1) are associated scopy.114 In addition, SARS-CoV-2 have been found in neural
with disease severity of patients with COVID-19.107 In addition, and capillary endothelial cells of frontal lobe in COVID-19
Ang II, soluble E-selectin (sE-sel), and soluble thrombomodulin patients.118 The S protein of SARS-CoV-2 can directly damage
were elevated only in critically ill patients, while only vWF antigen endothelial cells, manifested as impaired mitochondrial function
increased with disease severity. Therefore, as markers of and endothelial nitric oxide synthase (eNOS) activity, as well as
endothelial injury, circulating vWF and high molecular weight downregulation of ACE2, which may further aggravate endothe-
multimers are the best predictors of in-hospital mortality.108 lial dysfunction due to the disorders of RAS.119

Fig. 2 Mechanisms of SARS-CoV-2 induced to endotheliopathy in COVID-19. SARS-CoV-2 directly invades endothelial cells or indirectly
induces cytokine storm to cause endothelial cell damage. On the one hand, the SARS-CoV-2 receptor ACE2 expressed on the surface of
endothelial cells can be directly invaded by the virus. On the other hand, cytokine storm destroys endothelial cells by inducing the release of
PAI-1, promoting the degradation of endothelial glycocalyx to release HA fragments and destroying the endothelial barrier; downregulating
the expression of KLF2 to induce adhesion and infiltration of monocytes/macrophages, or by immune dysregulation such as increased NETS
generation and T-cell dysfunction. Finally, endothelial dysfunction could be further aggravated by complement activation, thrombosis,
coagulation disorders and activation of immune cells. Meanwhile, circulating endothelial injury markers including vWF and sCD146 were
elevated

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In addition to directly infecting endothelial cells, SARS-CoV-2- COVID-19 patients admitted to ICU, the frequency of thrombotic
related cytokine storm and invasive inflammation contribute to complications was 31% of 184, composed by 27% Venous
endothelial damage in extrapulmonary organs.114,120 The plasma thromboembolism (VTE) events and 3.7% arterial thrombotic
of patients with severe COVID-19 can induce endothelial events. Moreover, age and coagulopathy were independent
damage.113,121 The excessive inflammatory effect of cytokine predictors of thrombotic complications.136 In total, 32 (24%) cases
storm may lead to endothelial activation and dysfunction. High of PE were identified with computed tomography pulmonary
serum TNF-α and IL-1β levels in patients with COVID-19 may angiogram (CTPA) in 135 COVID-19 patients, and the rate
downregulate the Kruppel-like factor 2 (KLF2) expression in increased to 50% in ICU patients.137 Existing data of autopsies
human endothelial cells, and subsequently induce monocyte from COVID-19 patients showed that massive PE accounted for
adhesion, leading to endodermatitis characterized by endothelial one-third of causes of death, with an additional one fourth with
dysfunction and hypercoagulability, and lymphocytic monocyte recent DVT but without PE. Overall, 75% of them were male and
infiltration in patients with COVID-19.122 IL-6 trans-signaling two-thirds were noted to have recent thrombosis in prostatic
mediates the plasminogen activator inhibitor-1 (PAI-1) releasing venous plexus.138 In all, 8% of patients matched overt DIC
from vascular endothelial cells in CRS. Increased levels of PAI-1 according to the International Society on Thrombosis and
can result in endothelial dysfunction, induce cell senescence, Hemostasis diagnostic criteria (ISTH).7 DIC was developed in
thereby promoting local hypoxia.123 In the liver sinusoidal 71.4% of patients who died from COVID-19, while it only occurred
endothelial cells (LSEC), IL-6 trans-signaling leads to proinflam- in 0.6% of those who survived.7
matory and procoagulant states endothelial lesions, and liver SARS-CoV-2-induced excessive immune response and inflam-
injury in COVID-19.124 In addition, macrophage and complement matory injury lead to endothelial dysfunction, dysregulation of
activation125 play a crucial role in endothelial damage and coagulation factors and complement, platelet activation and
thrombosis in SARS-CoV-2 infection.126 Hyaluronic acid (HA) is a death, as well as release of NETs, thereby promoting thrombosis
ubiquitous glycosaminoglycan and main constituent of the (Fig. 2), and eventually resulting in an imbalance of the
glycocalyx that is anchored to the vascular lumen and regulates coagulation system, coagulation dysfunction, and a range of
a diverse repertoire of endothelial functions. SARS-CoV-2 pulmonary and extrapulmonary complications. These multiple
infection-induced cytokine storm leads to abnormal degradation factors eventually result in pathological angiogenesis, thrombosis,
of endodermis glycocalyx, resulting in HA fragments that may and clotting disorders.
cause dysfunction of endothelial barrier and vascular hyperper- Viral infection can lead to systemic hypoxia, which may cause
meability in a ROCK- and CD44-dependent manner.127,128 The coagulation protein imbalance and increased activation of the
circulating granulocyte-myeloid-derived suppressor cells (G- coagulation cascade.139 Meanwhile, proteomics showed that in
MDSC) expressing high levels of arginase-1(Arg1) increased deceased COVID-19 patients, several coagulation factors such as
significantly in COVID-19 patients, which can deplete arginine in prothrombin (F2), factor XI, XII, and XIIIa, etc. involved in the
the plasma and inhibit T-cell receptor signal transduction, thereby coagulation, anticoagulation, and fibrinolysis systems, were
leading to T-cell dysfunction, also impairing the production of dysregulated, which may lead to coagulopathy in COVID-19.140
nitric oxide and increasing endothelial cell dysfunction, and Elevated plasma levels of complement component 5 (C5)
promoting intravascular coagulation.129 Moreover, due to sus- activation products, C5a and C5b-9 in the patients with
tained immune activation during COVID-19 convalescence, COVID-19 indicated complement activation.141 S protein of
activated and infected endothelial cells may be susceptible to SARS-CoV-2 can interfere with the function of complement
direct T-cell-mediated cytotoxicity that may intensify endothelial factor H to activate complement bypass, and directly block the
dysfunction in patients with COVID-19.130 combination of complement factor H with heparin, leading to
Endothelial injury in COVID-19 patients can lead to dysregula- complement imbalance.142
tion of coagulation factors and complement, as well as excessive In the context of COVID-19, platelets and platelet activation
activation of platelets, resulting in thrombosis and eventually biomarkers are elevated in deceased patients.143,144 SARS-CoV-2
clotting disorders. Moreover, endothelial injury recruits and binds to platelets through S protein to promote platelet
activates immune cells including neutrophils and macrophages, activation,145 activated platelets drive monocytes aggregation
as well as promotes the release of cytokines and the formation of and increase the tissue factor (TF) expression, ultimately leading
NETs, etc., leading to proinflammatory reactions, which may to the deterioration of coagulation.146 Transcriptomic analysis
further aggravate endothelial injury. showed that SARS-CoV-2 infection markedly altered expression
of genes related to platelet and triggered strong platelet
Coagulopathy. Coagulopathy is another common feature of hyperreactivity, leading to increased platelet activation and
COVID-19, which is depicted with thrombocytopenia, prolonged aggregation by activating mitogen-activated protein kinase
prothrombin time (PT), increased D-dimer levels, and/or decreased (MAPK) pathway and subsequent thrombin production.147
fibrinogen levels. In COVID-19, there were elevated D-dimer levels SARS-CoV-2 particles were internalized by platelets in an
and fibrin degradation products accompanied by mild to ACE2-independent manner, resulting in rapid digestion, pro-
moderate increase in PT and activated partial thromboplastin grammed cell death, and release of extracellular vesicles.148
times (APTT).7 About 60% ICU patients had abnormally elevated NETs are a key factor for COVID-19-associated immunothrom-
D-dimer levels compared with a prevalence of 43% in non-severe bosis, and plasma of patients with COVID-19 can induce the
patients.131 Moreover, increased D-dimer levels were associated formation of NETs.149 Pulmonary autopsy also confirmed
with adverse prognosis.132 In severe COVID-19 patients, thrombo- infiltration of NETs.150 Overactivated platelets recruit neutro-
tic complications are common due to the prothrombotic state and phils, which increase the release of NETs.151 In addition, SARS-
contribute significantly to mortality and morbidity. CoV-2 triggered NETs dependent of ACE2, viral replication,
The hypercoagulable state is more frequent in elderly COVID‐19 serine proteases, and protein arginine deiminase 4 (PAD4).152
patients.133 COVID-19 patients with hypertension or diabetes NETs bind to the factor XII zymogen and induce coagulation in a
mellitus are more likely to suffer lower extremity complications,134 factor XII-dependent manner.153 The accumulation of NETs in
and coagulopathy is a major extrapulmonary risk factor for the vessels results in rapid occlusion of the affected vessels,
mortality in hospitalized COVID-19 with type 2 diabetes rather microcirculation disruption, and organ injury.154
than acute kidney injury (AKI) and acute cardiac injury.135 Dysregulation of immune thrombosis is a key indicator of the
The most common thrombotic complications include deep vein disease severity of COVID-19.151 Endothelial cell injury and
thrombosis (DVT), pulmonary embolism (PE), and DIC. In severe activation, thrombin activation, platelet activation and aggregation,

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as well as neutrophil recruitment and activation are involved in the response. Pyroptosis of infected airway endothelial cells may allow
complex processes of immunothrombosis. In addition, COVID-19 SARS-CoV-2 to leak out into the bloodstream and circulate to
patients showed excessive activation of non-phagocytic cell oxidase other organs and infect ACE2-expressing cells at local sites,
(Nox) 2, which induced oxidative stress to cause vascular occlusion, resulting in extrapulmonary organ injuries.114
platelet aggregation, and ultimately thrombosis.155 Airway epithelial cells are the first gateway for SARS-CoV-2
invasion. Initial infection site is the ciliated cells within proximal
Dysregulation of RAS system. Apart from acting as an entry airway epithelium, but in severe cases, infection or injures induced
receptor for SARS-CoV-2, ACE2 seems to be a protective molecule by SARS-CoV-2 occurs diffusely in the alveolar epithelium, leading
for the heart and kidneys, and viral binding may deregulate its to gas-exchange impairment and respiratory failure with a high
protective effect. RAS system is involved in the regulation of mortality rate. In the gas-exchange region of the distal lung, the
cardiac, renal, and vascular physiology.13 RAS dysfunction is alveolar facultative progenitors, alveolar type 2 (AT2) epithelial
related to the development of acute lung injury and ARDS, and cells are the main target of infection.167 AT2 cells are specialized to
associated with poor prognosis.156 ACE2 negatively regulates RAS synthesize and secrete surfactant, which is indispensable to
system and maintains physiological homeostasis, by converting reduce alveolar surface tension and prevent alveoli from collap-
Ang I to the nonapeptide Ang 1–9, an inactive form of Ang, and sing and is involved in pulmonary host defense. Infection in this
Ang II to the counter‑regulatory heptapeptide, Ang 1–7.157 These region induces progressive hypoxia and inflammatory cell
peptides have vasodilatory and antiproliferative effects, and have infiltrates, which drive ARDS in severe cases of COVID-19.168 AT2
protective functions by interacting with MAS1 receptor, which is cells also play a critical role in regulating alveolar hypercoagula-
a G protein-coupled receptor.158 As a potent vasoconstrictor, Ang tion and fibrinolysis inhibition by PAI-1 and urokinase production.
II mediates vasoconstriction via AT1R and vasodilatation through Infection of AT2 cells initiates the innate immune response that
Ang II type 2 receptor (AT2R). In the context of SARS-CoV-2 favors virus propagation to adjacent alveoli and perpetuates a
infection, cleavage of ACE2 by a disintegrin and metallopeptidase hyperinflammatory state, resulting in ARDS with diffuse alveolar
domain 17 (ADAM17) and TMPRSS2 facilitates cell entry.158 This damage (DAD), microvasculature injury, hyaline membranes,
process may lead to ACE2 shedding and loss of protective thrombosis, and fibrin deposition in the alveoli.169,170
function of ACE2, subsequently increase Ang II levels and finally The evolution of ARDS can be divided into three phases,
induce AT1R stimulation and AT2R inactivation.159 This process including acute exudative, proliferative, and fibrotic phases. In
triggers the secretion of aldosterone, vasopressin, and adreno- exudative phase, DAD and endothelial injury induce the formation
corticotropic hormone (ACTH), hypokalemia, sodium reabsorp- of intra-alveolar hyaline membrane, as well as widening and
tion, inflammation, cell proliferation, and lung injury. ACE2/Ang edema in the lung interstitium. In the proliferative and fibrotic
1–7/MAS axis counterbalances the deleterious effect of the ACE/ phases, AT2 cells hyperplasia, fibroblasts proliferation and chronic
Ang II/AT1R axis. ACE2 downregulation leads to pulmonary inflammation may lead to pulmonary fibrosis. Pulmonary fibrous
vascular hyperpermeability and coagulation, which in turn results strips and fibrosis were reported in 17% of COVID-19 patients.171
in multiple organ damage.160 The ACE2 downregulation pro- The hallmark in the pathophysiology of ARDS is the increase in
motes pathological changes in acute lung injury and participates permeability of the alveolar-capillary epithelial barrier that allows
in inflammatory and fibrotic responses,14,161 and aggravates protein-rich fluid to enter the alveoli leading to pulmonary edema,
disease progression of COVID-19.162 ACE2 deficiency in patients hypoxemia, and consequent release of proinflammatory cytokines
with advanced age, comorbidities such as cardiovascular disease, such as IL-1β, IL-6, IL-8, and TNF-α.172 Similar pathological changes
diabetes mellitus, or increased shedding of ACE2 due to the of DAD in the lung are identified in COVID‐19 associated ARDS and
infection, may result in overactivity of the ACE/Ang II/AT1R axis, the typical ARDS.173
contributing to enhanced inflammation and thrombosis.163 Alveolar macrophages are critical for pathogen recognition,
Therefore, ACE2 acts as a key mediator and a therapeutic target normal tissue homeostasis, the orchestration of lung inflamma-
for COVID-19. tion and resolution of ARDS.174 Upon stimulation, alveolar
macrophages can recruit neutrophils and monocytes via several
chemokines such as IL-8 to the injury site in the lung. These
ARDS AND ITS ASSOCIATION WITH EXTRAPULMONARY cells contribute to the production of inflammatory mediators,
COMPLICATIONS such as ROS, proteases, cytokines, etc., which subsequently
SARS-CoV-2 predominantly displays a respiratory tissue tropism induce distal cell death, specifically AT2 epithelial cells. More-
and commonly causes pulmonary complications such as pneu- over, alveolar macrophages can interact with lymphocytes,
monia and, in severe cases, ARDS or hypoxemic respiratory failure. epithelial cells and mesenchymal stem cells (MSCs) in a
Meta-analysis has shown that 18% of patients hospitalized with paracrine manner, thereby augmenting inflammatory response
COVID-19 had severe disease, with 15% developing ARDS.164 and accentuating tissue injury.
COVID‐19 associated ARDS is more likely to have worse outcomes ARDS is a progressive systemic inflammatory syndrome with
than ARDS secondary to other predisposing causes, with mortality lung involvement and extrapulmonary multi-organs damage.
ranging from 26 to 61.5% in patients admitted to intensive critical Elevated proinflammatory cytokines were observed in both
care unit (ICU) and from 65.7 to 94% in those receiving mechanical bronchoalveolar lavage fluid (BALF) and plasma from patients
ventilation.165 with ARDS.175 COVID-19 associated ARDS is a typical “pulmonary”
Although SARS-CoV-2 can affect various tissues and organs ARDS. The hallmark of severe ARDS secondary to COVID-19 is
through widely distributed ACE2 in cardiovascular, renal, and cytokine storm resulted from dysregulated inflammatory
gastrointestinal systems, etc. During the initial phases of infection, responses.176 In the meantime, the spillover of proinflammatory
SARS-CoV-2 may be restricted to the respiratory tract, thus mediators into the peripheral bloodstream can maintain and
currently the laboratory diagnosis of SARS-CoV-2 infection is augment the inflammatory response, causing extensive tissue
based on the detection of viral nucleic acid in the nasopharyngeal damage to other organs. Endothelial cells are involved in the
(NP) or oropharingeal (OP) swab. The intense intracellular pathogeneses of both ARDS and extrapulmonary organ dysfunc-
replication of SARS-CoV-2 causes programmed cell death includ- tion, possibly through mediating systemic endotheliitis with
ing apoptosis and pyroptosis induced by inflammasome, resulting marked infiltration of inflammatory cells and apoptotic bodies in
in capillary leakage and proinflammatory cytokines release and various tissues and organs.114 The widespread endothelial
tissue damage.166 The activation of inflammasome is triggered by inflammation alters integrity of vessel barrier and promotes
viroporins-induced ion influx or by endoplasmic reticulum stress procoagulant state and contributes to the tissue edema and organ

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Fig. 3 The extrapulmonary complications of COVID-19. SARS-CoV-2 infection has resulted in not only a pulmonary disease but also potentially
systematic disease, which may cause long-term multiple organ-system complications including hyperinflammatory syndrome, vascular
thrombosis, coagulopathy, cardiovascular, hepatobiliary, gastrointestinal, renal, neurologic, endocrinologic, ophthalmologic, nasal, oral, and
dermatologic systems. Proposed mechanisms of the involvement of different organs or systems for COVID-19 caused by infection with SARS-
CoV-2 include: direct viral toxicity through interaction of SARS-CoV-2 spike protein with the entry receptor ACE2; dysregulation of the immune
response, T-cell lymphodepletion and hyperinflammation; endothelial cell damage and thromboinflammation. COVID-19 coronavirus disease
2019, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, DIC disseminated intravascular coagulation, PE pulmonary, DVT deep
venous thrombosis, DKA diabetic ketoacidosis, PTSD post-traumatic stress disorder

ischemia, leading to histopathologic alterations and systemic disease. There are several potential mechanisms, involving
complications in severe COVID-19 patients.177 myocardial injury, exacerbation of the underlying cardiovascular
Current evidence suggests that COVID-19-associated extrapul- comorbidities, as well as cardiovascular adverse effects of the
monary organ injury can also be explained by cross-talk between drugs used in the treatment of COVID-19.
the organs.178 Pulmonary complication is a key driver of increased Myocardial injury defined as elevated serum cardiac troponin I
mortality in patients with AKI, highlighting a bidirectional relation- concentrations or abnormalities in electrocardiogram (ECG) or
ship. Recent studies confirmed the close relationship between echocardiogram, is a common complication in the development
alveolar and tubular damage, the lung–kidney cross-talk in ARDS.179 and exacerbation of COVID-19. The incidence of myocardial injury
Cytokine such as IL-6 overproduction is involved in lung–kidney differed among patients with different severities of COVID-19,
bidirectional damage.180 ARDS can induce renal medullary hypoxia, with 10% in mild cases, roughly 30% in hospitalized patients on
which is an additional insult to tubular cells.180 In addition, admission and ~50% during hospitalization.184 An early study of
lung–heart,181 gut–lung,182 and brain–lung interactions,183 etc., 138 patients hospitalized with COVID-19 in Wuhan showed that
have also been proposed as potential underlying mechanisms of myocardial injury was observed in 7.2% of hospitalized COVID-19
SARS-CoV-2-induced multiorgan dysfunction. patients and 22% of those in the ICU.185 A report from China
showed that during hospitalization roughly 12% of patients
without a history of cardiovascular diseases showed elevated
EXTRAPULMONARY COMPLICATIONS levels of troponin or cardiac arrest. It is worth noting that elevated
In addition to the respiratory system, many other important organ high-sensitivity troponin I was found in 46% of the deceased
systems are also vulnerable to the SARS-CoV-2 infection, resulting COVID-19 patients but only 1% of the survivors.186 COVID-19-
in several extrapulmonary manifestations and complications related myocarditis is characterized by myocardial injury without
(Fig. 3). The systemic manifestations of COVID-19 vary, but these an ischemic cause and inflammatory infiltrates.187,188 Acute and
complications are largely interwoven by certain shared mechan- delayed-onset myocarditis have been reported in previous
isms, involving direct viral cytotoxicity, immune disturbances, cohorts as well as the autopsy studies of COVID-19 deaths.189
endothelial damage and thromboinflammation, and ACE2- Fulminant myocarditis and cardiogenic shock were accompanied
associated RAS system dysregulation. by atrial and ventricular arrhythmias.190 Takotsubo cardiomyo-
pathy is a non-ischemic cardiomyopathy characterized by
Cardiovascular complications transient weakening of the cardiomyocytes and subsequent
Adverse cardiovascular events of COVID-19. Cardiovascular system ballooning of the apex.191,192 In all, 2–7.75% of COVID-19 patients
is frequently involved during the development and exacerbation presenting with acute coronary syndrome were diagnosed with
of COVID-19, particularly in patients with preexisting cardiovas- stress-induced cardiomyopathy. Nearly one-third of the COVID-19
cular diseases such as hypertension, heart failure or coronary heart patients with myocardial involvement were complicated by

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cardiogenic shock.191 COVID-19 may predispose patients to injury. Under certain cardiovascular conditions, the inflammatory
arterial and venous thrombosis.193 The critically ill patients with response triggered by the NOD-like receptor family pyrin domain
COVID-19 have high venous thromboembolism risk of 31–40%.136 containing 3 (NLRP3) inflammasome activation leads to hyperin-
The incidence of disseminated intravascular coagulation (DIC) flammation, which promotes cardiac injury and could be targeted
was 71.4% in COVID-19 deaths. Lung microvasculature fibrin for the treatment of COVID-19.209
deposition can result in ARDS in patients concomitantly The damage-associated molecular patterns (DAMP) ligands of
diagnosed with DIC.194 The COVID-19 associated myocardial the receptor for advanced glycation end products (RAGE) may
injury and subsequent cardiac dysfunction may cause cardiac exacerbate the local responses to infection in the heart, leading to
arrhythmias. Relative tachycardia and bradycardia frequently severe cell stress and death, which in turn result in endothelial
occurred in mild to critically ill patients with COVID-19.195 In all, dysfunction, immune cell activation, oxidative stress, and upregu-
16.7% of patients hospitalized with COVID-19 and 44% of those lation of distinct factors such as early growth response 1 (EGR1).
referred to ICU developed cardiac arrhythmia.192,196,197 Abnormal The inexorable accumulation of advanced glycation end products
PR interval behavior with increasing heart rate and QT prolonga- (AGEs) and other DAMP RAGE ligands relevant to cardiometabolic
tion are frequently observed in critically ill patients.196,198 it perturbation may prime the organs for amplification of inflam-
remains unclear whether high prevalence of heart failure in matory and tissue-damaging mechanisms upon SARS-CoV-2
patients hospitalized with COVID-19 with a known history of infection.210 Nox2 is upregulated in pneumonia and closely
cardiac disease, results from worsening of preexisting left associated with troponin elevation. Nox2-derived oxidative stress
ventricular dysfunction or newly developed cardiomyopathy. An may contribute to myocardial injury via production of ROS, and
early report on 113 COVID-19 deaths showed high incidence of thus inhibition of Nox2 may have therapeutic potential for COVID-
cardiac complications including heart failure and acute cardiac 19.211 Alteration in RAS after SARS-CoV-2 infection could predis-
injury.93 Cardiogenic shock was developed in one-third of COVID- pose bradykinin storm. Given that bradykinin and its metabolites
19 cases with myocardial involvement and carried a high are inducers of endothelium-dependent vasodilation, vascular
mortality of 26%.199 permeability, and pain via the activation of the G protein-coupled
Newborns and children are expected to be less susceptible to receptors B1 and B2, this signaling could be a new therapeutic
COVID-19 partly because of the reduced function of ACE2 target of cardiovascular dysfunction and thromboembolism
receptors. SARS-CoV-2 infection appears to be asymptomatic or induced by COVID-19.212
mild in most children, some may develop a severe inflammatory
syndrome with symptoms similar to Kawasaki disease or toxic Renal complication
shock syndrome. This Kawasaki-like illness have been called the Adverse renal events of COVID-19. AKI is a frequent complication
multisystem inflammatory syndrome in children (MIS-C).200 Of in inpatients with COVID-19, with an incidence ranging from 10
recovered 99 competitive athletes with asymptomatic or mild to 80%.213–217 A meta-analytic study including 49,692 COVID-
SARS-CoV-2 infection, 3.3% had myopericarditis or pericarditis, 19 patients demonstrated that AKI was a common and serious
which is associated with exercise-induced ventricular arrhythmias complication of COVID-19. The in-hospital mortality risk was
or cardiac symptoms.201 Myocardial injury and left ventricular significantly increased in COVID-19 patients complicated by
dysfunction in pregnant women had a high mortality rate of AKI.218 Elevated serum creatinine and proteinuria are the main
13.3%, which was attributed to malignant arrhythmias.202 clinical features of COVID-19 with kidney injury. Another meta-
analytic study219 including 4963 COVID-19 patients showed
Pathogenesis of cardiovascular complications of COVID-19. COVID- that 9.6% of patients had elevation of serum creatinine. Of
19 related myocardial injury is frequently observed and is these patients, 57.2% had proteinuria. Proteinuria was reported
associated with poor prognosis. The central pathophysiology of in COVID-19 patients who did not develop AKI, which may
COVID-19 related myocardial injury involves a complex interplay indicate subclinical renal damage. Proteinuria occurs in
between viral tropism, dysregulated host immune response, patients with nephropathy, and significant heterogeneity exists
alteration in ACE2 and RAS system homeostasis, the vascular between studies.220–222
dysfunction, myocardial oxygen supply–demand imbalance as
well as microvascular and macrovascular thrombosis.5,203,204 Pathogenesis of renal complications of COVID-19. Multiple possi-
The cardiovascular pathology of COVID-19 can result from a ble mechanisms may be involved in COVID-19 associated AKI,
direct SARS-CoV-2 cardiotoxicity. Human pluripotent stem cell- including SARS-CoV-2-mediated injury, inflammatory response,
derived cardiomyocytes (hPSC-CMs) expressing ACE2 are permis- cytokine storm SARS-CoV-2-induced, activation of the ACE/Ang II
sive to SARS-CoV-2 replication. Notably, SARS-CoV-2-infected pathway, dysregulation of complement, hypercoagulation, and
hPSC-CMs exhibit progressively impaired contractile and electro- microangiopathy.223 In an autopsy study of 63 COVID-19 patients,
physiological properties, and extensive cell death.205,206 Cardiac the viral RNA presence in the kidneys is correlated with older age
stromal cells can be infected by SARS-CoV-2, which could and increased comorbidities, as well as reduced survival time.
contribute to myocardial injury. Moreover, stromal cells exposed These results indicate a potential association between the renal
to SARS-CoV-2 can evolve into hyperinflammatory and pro-fibrotic tropism of SARS-CoV-2 and adverse clinical outcome.224 Renal
phenotypes via ACE2-independent mechanism. tubular epithelial cells and podocytes express ACE2,225 while the
Platelet activation plays an important role in the pathogenesis distal nephrons but not the proximal tubules express TMPRSS2.223
of thrombotic events and cardiovascular complications. S protein The hyperinflammatory state of COVID-19 can result in kidney
of SARS-CoV-2 induces platelet activation directly to facilitate injury. Previous studies have found that high levels of cytokine
leukocyte–platelet aggregate formation, the release of coagula- release and inflammatory response lead to microvascular dysfunc-
tion factors and inflammatory mediator, thereby resulting in tion, capillary hyperpermeability and insufficient perfusion, caus-
thrombosis formation. Furthermore, the MAPK cascade, consid- ing renal microcirculatory dysfunction.226 The critically ill COVID-
ered as a downstream signaling of ACE/Ang II, mediates the 19 patient had increased IL-6 levels that were associated with
activation effect of SARS-CoV-2 on platelet.145 kidney damage possibly due to lung–kidney cross-talk.180 The
Abundant expression of Th1 and Th2 cytokines lead to direct bidirectional relationship between alveolar and tubular damage,
cardiac immunological injury and chemotaxis of neutrophil and lung–kidney cross-talk in ARDS is confirmed by recent studies.179
macrophage.207,208 The inflammasome activation in the patients ARDS can induce hypoxia in the renal medulla, which may result in
with COVID-19 is strongly related to hypercoagulopathy and renal tubular epithelial cells injury, subsequently leading to the
cytokine storm, contributing to the COVID-19-associated cardiac upregulation of IL-6.180 Glomerular diseases have been found in

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COVID-19 patients with kidney involvement.227 The most common patients with gastrointestinal symptoms was longer than in those
pathological feature of glomerular disease is collapsing glomer- without gastrointestinal symptoms.246 The presence of gastro-
ulopathy.228–232 Collapsing glomerulopathy is a distinct pathology intestinal symptoms was associated with a high risk of ARDS, non-
related to COVID-19, which may affect patients carrying high-risk invasive mechanical ventilation and tracheal intubation, but not
APOL1 genotypes.233,234 Kidney biopsy of COVID-19 patients who with mortality in COVID-19 patients.253 Patients with gastrointest-
had APOL1 high-risk genotype showed collapsing glomerulo- inal symptoms had higher rates of positive results for a COVID-19
pathy, tubuloreticular inclusions in endothelial cells, and acute test than those without.254 Roughly 10% of COVID-19 patients
tubular injury, without evidence of SARS-CoV-2 infection or presented initially with only gastrointestinal complaints without
replication in kidney cells.227 During viral infection, IFN and TLR3 any respiratory symptoms, which may possibly cause a delay in
activation is sufficient to upregulate APOL1 gene expression.235 COVID-19 diagnosis.246,255
These findings suggest plausible mechanisms involving “two-hit”
of cytokine-mediated host response to SARS-CoV-2 infection and Pathogenesis of gastrointestinal complications of COVID-19. Gas-
genetic susceptibility.227,233 trointestinal injury associated with SARS-CoV-2 infection may be
Kidney injury may be related to blood coagulation disorder in attributed to several proposed mechanisms, including direct
COVID-19 patients. In a kidney autopsy report of a patient who cytotoxic damage, intestinal endothelial cell injury and throm-
died from COVID-19,236 the renal parenchyma showed diffuse boinflammation, dysregulated immune response.10 These
coagulative cortical necrosis, with widespread glomerular micro- mechanisms can interact with each other and in turn exacerbate
thrombi. Electron microscopy showed extensive cross-linked gastrointestinal injury.10
fibrin deposition and partially shed capillaries in the capillary The detection of SARS-CoV-2 RNA and viral protein in gastric,
lumen. It is suggested that thrombotic microangiopathy instead duodenal, and rectal glandular epithelial cells256 is indictive of
of DIC is manifestation of coagulopathy in COVID-19 patients the tropism of SARS-CoV-2 to the digestive system. Patients with
with kidney injury.237–239 Glomerular ischemia and endothelial diarrhea had higher positive rate for SARS-CoV-2 RNA in fecal
cell damage also appear in some cases.240 Glomerular ischemia samples than those without diarrhea.248 Current evidence shows
was observed in patients with fibrin thrombi in the glomerular that the gastrointestinal symptoms in COVID-19 may be caused
capillary loops, which may be related to coagulation activation in by the direct effects of SARS-CoV-2 on the gastrointestinal tract.
COVID-19 patients.6,241 In addition, an interaction between Ang II SARS-CoV-2 may invade the digestive system through ACE2, and
overactivity, and complement pathways could also influence AKI growing evidence supports the possible fecal-oral transmission
severity and outcomes. route of SARS-CoV-2. ACE2 is abundantly present in the
COVID-19 patients often present the respiratory and gastro- gastrointestinal epithelial cells, with the highest expression in
intestinal symptoms, which may cause fluid loss. Once the fluid is the small intestine, suggesting that the gastrointestinal tract
not refilled in time or insufficient, it may lead to insufficient renal may be susceptible to SARS-CoV-2 infection.256–258 TMPRSS2
perfusion. In a retrospective study of 5,449 COVID-19 patients,216 had relatively high expression levels in both the small intestine
AKI occurred in 36.6% of patients, and a majority of AKI patients and the colon.259 SARS-CoV-2 downregulates ACE2 expression
had urine sodium lower than 35 mmol/L, indicating a state of by binding its S protein, thereby contributing to inflammation
pre-renal azotemia. In addition, ARDS or respiratory failure can and injury of gastrointestinal epithelium.260–262 ACE2 deficiency
reduce cardiac output through hemodynamic changes and high in intestinal epithelial cells may be linked to malabsorption of
chest pressure, which may cause systemic inflammation and nutrients, altered gut microbiota composition, and intestinal
reduced renal perfusion induced by hypoxemia, leading to AKI.8 barrier dysfunction.263
Drug-induced nephrotoxicity may contributor to COVID-19- The activation of coagulation promotes thrombin generation,
related kidney injury.242 Some antivirals, antibiotics, and non- activates complement system and inhibits fibrinolysis, which
steroidal anti-inflammatory drugs (NSAIDs) given to patients with triggers thromboinflammation, leading to microthrombi deposi-
COVID-19 during hospitalization may have possible nephrotoxi- tion and microvascular dysfunction in the gastrointestinal
city and be involved in the development of AKI.243 A retro- system.94 COVID-19-related cytokine storm and hyperinflamma-
spective observational study showed that exposure to tory immune state might induce gut mucosal immune system
vancomycin and use of NSAIDs were risk factors associated with activation and enhance immune-mediated inflammatory
the development of AKI.244 response in the gastrointestinal system, which contribute to
gastrointestinal injury.94,260,264,265 The gut microbiota plays a
Gastrointestinal complications critical role in the maintenance of intestinal homeostasis, and
Adverse gastrointestinal events of COVID-19. Diarrhea and other altered microbiota composition is associated with intestinal
gastrointestinal symptoms are frequent in COVID-19 inflammation. Evidences suggest that SARS-CoV-2 infection is
patients.1,93,245 Severe COVID-19 patients are more likely to associated with alterations in the gut microbiota.266 Gut
develop gastrointestinal symptoms. The presence of digestive microbiota may be involved in the magnitude of COVID-19
symptoms is associated with the disease severity.246 Gastrointest- severity through modulation of host immune responses. More-
inal comorbidities of COVID-19 include hypomotility-related over, after resolution of COVID-19, the gut microbiota dysbiosis
complications, gastrointestinal bleeding, and bowel ischemia.247 may be associated with persisting symptoms.267 The pathogen-
Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and esis of the gut microbiota dysbiosis is multifactorial, possibly
abdominal pain may precede or accompany with pulmonary involving epithelial dysfunction, impaired production of anti-
symptoms in COVID-19 patients, and the incidence ranged from microbial peptide, as well as cytokine storm.266
~10 to 60%.247–250 The three most common symptoms were
anorexia, diarrhea, and nausea or vomiting from a meta-analysis Hepatobiliary complications
comprising 60 studies with 4243 patients.248 Anosmia and ageusia Adverse hepatobiliary events of COVID-19. Abnormal liver function
were commonly associated with nausea and anorexia after tests have been frequently observed in COVID-19 patients,
controlling for potential confounders.251 indicating that the liver is one of the most commonly affected
Gastrointestinal symptoms were more frequent in critically ill extrapulmonary organs by SARS-CoV-2. Clinical case studies show
patients with COVID-19 than critically ill patients without COVID- that liver dysfunction is associated with increased risk of mortality
19.252 Patients with COVID-19 who had diarrhea required more in COVID-19 patients. The prevalence of liver injury ranged from
ventilator support and intensive care than those without diar- 14.8 to 55% in COVID-19 patients.93,131,132,268–271 The pooled
rhea.250 The time from disease onset to admission in COVID-19 prevalence of liver function abnormalities was 19%.272 In a cohort

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including 2273 SARS-CoV-2-infected patients, acute liver injury is Drug-induced liver injury may also account for some
common but generally mild.273 Liver function abnormalities hepatobiliary complications in COVID-19.292 Antipyretic therapy
mainly manifest as slightly elevation in levels of alanine is frequently prescribed in COVID-19 patients. Acetaminophen
aminotransferase (ALT), total bilirubin (TBIL), and gamma- may induce significant liver damage or even cause liver failure
glutamyl transpeptidase (GGT).274 Aspartate aminotransferase in a dose-dependent mechanism.293 In clinical practice, multiple
(AST)-dominant elevation may be earlier, more frequent and drugs including antivirals,294 steroids and antibiotics were
significant in patients with severe COVID-19. AST levels showed commonly prescribed in COVID-19 patients, particularly those
the strongest correlation with mortality than other indicators of with severe and critically ill disease.295 Some of these drugs may
liver injury such as ALT, TBIL, and alkaline phosphatase (ALP) in have potential hepatotoxicity and result in liver dysfunction.
COVID-19 patients.275,276 However, COVID-19 associated severe
acute hepatitis has been rarely reported.277,278 Neurological and psychiatric complications
It is noteworthy that liver dysfunction is closely correlated Adverse neurological and psychiatric events of COVID-19. Neuro-
with disease severity of COVID-19. Patients with severe COVID- logical manifestations of COVID-19 including the central nervous
19 had higher prevalence of liver injury,1,131,185 and patients system (CNS)-associated and peripheral nervous system (PNS)-
with liver dysfunction were at higher risks of disease progres- associated ones were present in 18.1–82.0% of the patients. The
sion.269,271,279 The incidence rate of liver injury in deceased neurological symptoms were more common in those with
patients with COVID-19 was 78%.274 Liver failure is observed in severe COVID-19.12,296–298 COVID-19 has been reported to be
COVID-19 deaths and occurs more frequently among critically ill associated with increased risk of mental health disorders,299
patients.280 Of 141 critically ill COVID-19 patients during their such as depression, anxiety, schizophrenia, phobia,300
ICU stay, 4% developed acute acalculous cholecystitis and 1% obsessive–compulsive symptoms,301 post-traumatic stress dis-
developed acute pancreatitis.281 Patients with severe liver order (PTSD).302 A significant proportion of patients experienced
injury are more likely to have severe clinical course with high psychopathological complications, including 42% of anxiety,
risk of mortality. 31% of depression, 28% of PTSD, 20% of obsessive–compulsive
Patients with preexisting liver diseases such as non-alcoholic symptoms, and 40% of insomnia.303 The neurological and
fatty liver disease,282,283 cirrhosis284–286 are more susceptible to psychiatric complications of COVID-19 involve encephalitis,
SARS-CoV-2 infection and have worse clinical outcome. Chronic cerebral infarction, delirium, Guillain–Barré syndrome,304–307
hepatitis B and C were more common in patients with liver Miller Fisher syndrome,308 myopathy, neuromuscular disorders,
injury than those without.287 cephalgia, etc.309 Frontline health workers during the COVID-19
pandemic have displayed symptoms of anxiety, depression,
Pathogenesis of hepatobiliary complications of COVID-19. Under- insomnia.310,311 Long-term isolation triggers mental disorders
lying mechanisms may be systemic hyperinflammation induced such as depression and anxiety in some individuals.312
by cytokine storm, pneumonia-associated hypoxia, viral infection
in hepatocytes or cholangiocytes and drug-induced liver injury. Pathogenesis of neurological and psychiatric complications of
The cytokine storm may initiate a violent attack to the host and COVID-19. There are many potential gateways of SARS-CoV-2
result in liver injury. Dramatical increase in a wide range of neuroinvasion from the periphery to the brain. The expression of
proinflammatory cytokines and chemokines such as GM-CSF and ACE2 is relatively high in certain brain locations, such as the
IL-6 was observed in patients with liver dysfunction than those paraventricular nuclei of the thalamus and choroid plexus.313,314
with normal liver function.287 The liver biopsy showed that COVID- ACE2 is also expressed on the ventrolateral medulla and the
19-associated liver injury was likely immune-mediated.173 Taken nucleus of the tractus solitaries, areas involved in the regulation
together, the excessive inflammatory response triggered by SARS- of the respiratory cycle. This suggests that the virus may affect
CoV-2 infection may provoke liver injury. neurons regulating breathing.315 Coronavirus may directly infect
Hypoxemia due to ARDS, systemic inflammatory response sensory neurons in the olfactory epithelium and then spread to
syndrome, dysfunction of other organs can contribute to CNS from olfactory neurons.313,316 NRP1 is expressed of the
ischemia or reperfusion-induced liver dysfunction in patients olfactory epithelium, and can facilitate SARS-CoV-2 cell entry and
with COVID-19. Hypoxia-induced hepatocyte death and produc- infectivity.27 Moreover, the capillary blood vessels and lymphatics
tion of inflammatory cytokines can be found in hepatic are abundant in the nasal mucosa, which may favor virus
ischemia/reperfusion models.288 Moreover, histopathological invasion.317,318 SARS-CoV-2 may possibly invade the brain from
findings of the liver in COVID-19 patients showed the watery the bloodstream through the impaired blood–brain barrier319 and
degeneration of a few hepatocytes, which was probably due to leak into the interstitial fluid and the cerebral spinal fluid
ischemia and hypoxia.269 through the intracerebral lymphatic system. SARS-CoV-2 may
SARS-CoV-2 was detected in a proportion of liver biopsy also enter the fourth ventricle directly through a damaged
specimens in COVID-19 patients,289 but it remains unclear blood–cerebrospinal fluid barrier.320
whether SARS-CoV-2 directly infects hepatocytes or cholangio- The association between systemic inflammatory response and
cytes via ACE2. The upregulation of ACE2 expression in the liver neurological or psychiatric diseases reflects that both innate and
was caused by compensatory proliferation of hepatocytes adaptive arms of immune system may affect the brain.321,322
derived from the bile duct epithelial cells in a mouse model of Systemic inflammation leads to acute brain damage with
acute liver injury. Some neonatal hepatocytes expressed ACE2 cognitive impairments and psychiatric symptoms indicative of
and were susceptible to SARS-CoV-2 infection during this neurodegeneration.301,323 Nearly 80% of septic patients with
compensatory process.290 Pathological and electron micro- bacteremia develop sepsis-associated encephalopathy324 and
scopic findings revealed typical coronavirus particles in the delirium.323 CNS-resident cells such as astrocytes and microglia
cytoplasm of hepatocytes from two cases of COVID-19.291 represent the first line of defense of the CNS against systemic
Histologically, the predominant histological features of SARS- inflammation and infection. Systemic inflammation allows infil-
CoV-2-infected liver were massive apoptosis and binuclear tration of various DAMPs into the nervous system, triggering
hepatocytes. The GGT and ALP levels were elevated in deceased reactive astrogliosis325 and microgliosis.326 Dystrophic astrocytes
patients, which may indicate biliary tract injury. All the and microglia may be involved in the pathological development
aforementioned findings suggest that liver injury may not only of neurodegenerative disorders.
involve hepatocyte damage but also cholangiocyte dysfunction Hypoxia inevitably damages the brain. The greatest central
in patients with COVID-19. fatigue in acute hypoxia occurs when arterial oxygen saturation

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The mechanism underlying extrapulmonary complications of the coronavirus. . .
Ning et al.
12
(SaO2) is ≤75%, a level that coincides with increasing impair- related entry mediators including TMPRSS2, NRP1, and transfer-
ments in neuronal activity.327 Hypoxia increases ROS production rin receptor (TRFC), with selectively high expression of NRP1.354
leading to oxidative damage to neural cells.328 Excessive ROS Evidence demonstrates that SARS-CoV-2 can infect human
production can directly degenerate or modify cellular macro- pancreatic β cell, thereby attenuating the secretion of pancrea-
molecules, including membranes, proteins, lipids, and DNA, and tic insulin and inducing β cell apoptosis, which possibly
result in activation of inflammatory cascade and protease contribute to worsening hyperglycemia seen in COVID-19
secretion, finally contributing to brain injury.328 Brain hypoxia is patients.354 Elevated blood glucose levels in COVID-19 patients
also directly linked to activation of inflammatory pathways by are related to insulin resistance, which indicates pancreatic
stimulating hypoxia-inducible factors and the NF-κB signaling β-cell dysfunction or apoptosis, as well as insulin’s inability to
cascade, which promote the release of proinflammatory fac- dispose of glucose into cellular tissues.355 Whether ACE2 was
tors.329 Severe hypoxia may cause extensive damage to brain expressed in thyroid tissue or other endocrine organs remains
structure, leading to cognitive and neurodegeneration defects. controversial.356
Three main mechanisms appear to be responsible for the Cytokine disorders and T-cell depletion were observed in
occurrence of ischemic strokes in COVID-19,330,331 including a patients with diabetes, which may be associated with poor
hypercoagulable state, vasculitis, and cardiomyopathy. COVID-19 clinical outcomes.97,357–360 The function of NK cells that play
can induce an immune-thrombotic and DIC, which can explain for important role in controlling infection is impaired in patients
thrombosis on a consumptive basis.332 Other studies have with type 2 diabetes. Glycated hemoglobin was an independent
suggested that thrombosis occurs in 20–30% of critically ill predictor of NK cell activity in patients with type 2 dia-
COVID-19 patients, even with prophylaxis.333,334 betes.361,362 In the animal model, hyperglycemia was found to
Stressors exacerbate both systemic inflammation and infla be the main cause of systemic inflammation.363 Hyperglycemia
mmatory damage to the brain by activating the hypothal and insulin resistance promote synthesis of advanced glycation
amic–pituitary–adrenal axis.335 Levels of CRP demonstrate association end products and proinflammatory cytokines, oxidative stress,
with levels of depression.336 Neuroinflammation is largely associated and adhesion molecules that mediate tissue inflammation,364
with several neuropsychiatric and neurocognitive diseases,337 which may be underlying mechanisms responsible for adverse
including depression, psychosis and neurodegeneration. Depression outcome in patients with diabetes. Potential pathogenetic links
is a well-known risk factor of dementia, and psychological burden of between COVID-19 and diabetes include disrupted glucose
COVID-19 may increase the neurodegenerative disease rates in the homeostasis, inflammation, altered immune status and activa-
aftermath of the pandemic.338 tion of the RAS.11 Elevated glucose levels directly induce viral
replication and proinflammatory cytokine production, which
Endocrine and metabolic complications may favor SARS-CoV-2 infection and monocyte response
Adverse endocrine and metabolic events of COVID-19. Endocrine through hypoxia-inducible factor-1a (HIF-1α)/glycolysis-depen-
and metabolic systems can also be involved in COVID-19.339 dent axis.365 Elevated cytokines, imbalance of Th1/Th2 cytokine
Database from Chinese Centers for Disease Control and Preven- ratio, decreased peripheral CD8+ T cells and NK cell counts
tion (CDC) showed that of 20,982 patients with COVID-19, 5.3% contribute to the high mortality of COVID-19 patients with type
had diabetes.340 Among COVID-19 patients with chronic comor- 2 diabetes.366
bidities, type 2 diabetes was the second most common morbidity
(7.4%).341 Diabetes is one of the most relevant comorbidities Other extrapulmonary complications
associated with adverse prognosis of COVID-19.342–344 A study on Co-infection. The prevalence, incidence, and characteristics of
72,314 COVID-19 patients reported that the mortality rate of existing viral or bacterial co-infection in COVID-19 patients is not
patients with diabetes was 7.3%, which was higher than those well understood and has been raised as a major concern. It was
without diabetes (2.3%).345 A whole-population study showed reported in a meta-analysis of 28 studies including 3448 patients
that compared with patients without diabetes, the odds ratios for with COVID-19 showed that bacterial estimated co-infection was
in-hospital COVID-19-related death were 3.51 in those with type 1 identified in 3.5% of patients and secondary bacterial infection in
diabetes and 2.03 with type 2 diabetes.346 Pregnant women with 15.5% of patients.367 The overall proportion of COVID-19 patients
diabetes might be more vulnerable to the severe effects of with bacterial infection was 7.1% but varied in different patient
COVID-19.347 populations, ranging from 5.8% in hospitalized patients to 8.1% in
The resultant complications including hyperglycemia and critically ill cases and up to 11.6% in deceased cases.367 The most
diabetic ketoacidosis were associated with poor prognosis of common organisms reported were Mycoplasma species, Haemo-
COVID-19 patients. Acute hyperglycemic crisis, diabetic ketoaci- philus influenzae and Pseudomonas aeruginosa.367 Another meta-
dosis and hypertonic hyperglycemia are serious acute metabolic analysis of 30 studies including 3834 patients reported that 7% of
complications usually caused by infection.348 Of 2366 patients hospitalized COVID-19 patients had a bacterial co-infection.368 The
hospitalized with COVID-19, 157 (6.6%) patients developed pooled proportion of a viral co-infection was 3%, with respiratory
diabetic ketoacidosis, 94% of whom had preexisting type 2 syncytial virus and influenza A being the most common
diabetes, 0.6% had preexisting type 1 diabetes, and 5.7% patients pathogens.368 Another meta-analysis including 8 studies reported
had no previous diagnosis of diabetes.349 viral co-infections including rhinovirus/enterovirus and influenza A
Approximately 15% of mild to moderate COVID-19 patients had were the most frequent co-infected pathogen. Coronavirus,
thyroid dysfunction.350 Of 50 COVID-19 patients without previous respiratory syncytial virus, parainfluenza, metapneumovirus, and
history of thyroid disease, 56% (28/50) had low thyroid-stimulating influenza B virus were also reported as co-pathogens.369 To date,
hormone (TSH) levels.351 The levels of serum TSH and total the reports on fungal co-infections are scarce or lack of detailed
triiodothyronine (T3) in patients with COVID-19 were significantly information. A study from China performing fungal culture in all 99
lower than in those without COVID-19.352 The degree of decrease in COVID-19 patients at admission confirmed five (5%) cases with
TSH and total T3 levels was positively correlated with the disease fungal infection, including Aspergillus flavus, Candida glabrata, and
severity of COVID-19.351 Low free T3 due to nonthyroidal illness C. albicans.370 Another study reported that 5.8% of the patients had
syndrome is associated with in-hospital mortality in patients in the fungal co-infection in 52 critically ill patients, including A. flavus, A.
ICU requiring mechanical ventilation.353 fumigatus, and C. albicans.371 A German study showed that COVID-
19-associated invasive pulmonary aspergillosis (IPA) was found in
Pathogenesis of endocrine and metabolic complications of COVID- five (26.3%) of 19 consecutive critically ill patients with ARDS.372 It
19. Insulin-producing pancreatic β cells express ACE2 and should be critically paid attention to the probability of COVID-19

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13
accompanied by fungal infections.373 The tuberculosis and SARS- of skin varies, including maculopapular rashes, urticaria, petechiae/
CoV-2 co-infection has been rarely reported.374,375 purpura, vesicles, chilblains, livedo racemosa, and distal ischemia or
A number of immunocompromised individuals were hospita- necrosis.390 The trunk is a prone area of skin lesions, but the
lized with COVID-19 and some were diagnosed with secondary involvement of extremities may also occur. Most of the skin lesions
infections.376 The specific source and pathogens of these are self-resolving, and do not appear to be related to the disease
infections have not yet been fully identified. SARS-CoV-2 severity. Cutaneous involvement may be primarily attributed to an
infection-induced diffuse alveolar injury combined with intra- immune response to viral protein or nucleotides, or vasculitis and
alveolar neutrophilic infiltration and vascular congestion.377 These thrombotic vasculopathy secondary to systemic consequences
histologic damages could pave the way for secondary infections caused by COVID-19.391 Pathological examination revealed the
including bacterial or fungal infection such as COVID-19- existence of pauci-inflammatory thrombogenic vasculopathy in the
associated invasive pulmonary aspergillosis (CAPA).373 Besides, purpuric skin lesions, and the colocalization of SARS-CoV-2 S
COVID-19 patients are usually characterized by lymphopenia and protein with C4d and C5b-9 in both normally-appearing and
immune dysfunction, which also help facilitate pathogen inva- grossly involved skin.392
sion.94 A case control study reported that steroids use was also a
significant risk factor for bacterial infection in patients with severe Reproductive complication. A concern has been raised that SARS-
to critically ill COVID-19.378 Critically ill patients were more likely to CoV-2 may cause damage to testis, and even result in the
develop fungal co-infections.371 infertility. In patients with COVID-19, luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) levels were elevated, w
Ocular complication. According to a systematic review including hile testosterone and dihydrotestosterone levels markedly
4432 patients from 35 studies, the prevalence rate of ocular decreased.393 In recovered male patients, the count, concentration
manifestations was 11.3% in adult patients with COVID‐19.379 and motility of sperm were still declined slightly, although sexual
Ocular manifestations are non-specific, and conjunctivitis hormones have returned to normal levels.394 Patients with a
manifested as redness, watering, discharge, and foreign body longer recovery time showed poorer sperm quality. Pathological
sensations, is the most commonly reported.380 Other ocular studies conducted on deceased COVID-19 patients found
complications include dry eye, blurred vision, ocular pain, vacuolation and detachment from the tubular basement mem-
photophobia and itchiness, etc. Notably, ocular signs and brane of Sertoli cells, the destruction of seminiferous tubules, the
symptoms were the initial presentation in 3.3% COVID-19 reduction of Leydig cells, and the inflammatory infiltrate of T
patients.379 Patients with severe pneumonia have a significantly lymphocytes in the interstitium.395 ACE2 and TMPRSS2 expression
higher likelihood of ocular manifestations than mild-to- is abundant in spermatogonial cells, interstitial cells, and support-
moderate pneumonia. ing cells of testis, suggesting the testis as a potential target of
The conjunctiva is directly exposed to the environment, and SARS-CoV-2 infection.396 The immune responses triggered by
easily contaminated with respiratory droplets or hands carrying SARS-CoV-2 produce lots of inflammatory mediators and induce
the virus. A pooled data showed that the positive rate of SARS- oxidative stress in testicular cells, potentially damaging the DNA of
CoV-2 RNA was 7.4% in the ocular surface of COVID-19 patients.379 spermatozoa. In addition, SARS-CoV-2 causes damage to Leydig
Several studies have already demonstrated the expressions of cells, and subsequently lowers testosterone secretion, which may
ACE2 and TMPRSS2 in the cornea and conjunctiva, although their ultimately disrupt the process of spermatogenesis.397
expressions were obviously lower in comparison to other tissues, There is no evidence that pregnancy and childbirth alter
such as lung and digestive tract.381 In vitro study demonstrated susceptibility to SARS-CoV-2 infection. These studies did not report
that SARS-CoV-2 can directly infect the corneal cells from human severe maternal complications in pregnant women with COVID-
eyes and hESC-derived eye organoids.382 Although conjunctiva is 19. A few studies have revealed an increased risk of preterm birth
unlikely to be a preferred entry gateway for SARS-CoV-2, the and cesarean delivery, but it is unclear whether these results are
expressions of SARS-CoV-2 in tears and conjunctival secretions directly related to SARS-CoV-2.398 There is no direct data
partially explain ocular complications. supporting mother-to-child transmission of SARS-CoV-2, but
newborns of COVID-19 infected mothers have tested positive for
Ear-nose-throat (ENT) complication. Mounting evidence indicates SARS-CoV-2-specific antibodies and were also presenting with
that olfactory and gustatory dysfunction is closely correlated increased IL-6 levels.399
with COVID-19.383 A systematic review summarized that olfactory
and gustatory loss was observed in 41.0% and 38.2% of COVID- Hematopoietic system complication. The hematopoietic system
19 patients, respectively.384 In particular, some patients may only produces immune cells that can defeat viral infections and is a
have olfactory or gustatory loss in the absence of other clinical source of hematopoietic stem cells (HSC) and progenitor cells
symptoms. A multicenter study from Europe reported that 11.8% (HPC). Human HSC and HPC express ACE2 on the cell surface,
of patients presented with olfactory loss as their first symp- making them susceptible to SARS-CoV-2 infection. SARS-CoV-2 S
toms.385 Most patients get recovery from the symptoms within protein binds to ACE2, induces defects in human HPC colony-
4–6 weeks of follow-up, and only 3.59% and 3.27% of patients forming ability and inhibits the expansion of HSC and HPC
with olfactory and gustatory loss, respectively, showed partial subpopulations in vitro.400 In addition, in human very small
recovery beyond 8 weeks.386 embryonic stem cells (VSELs) and HSCs, the interaction of ACE2
The viruses may induce an inflammatory response of nasal with S protein activates the NLRP3 inflammasome, which may
mucosa or directly damage the olfactory neuroepithelium. SARS- cause cell pyrolysis.401 The plasma of severe COVID-19 patients
CoV-2 may not directly enter olfactory sensory neurons due to induces HPC to produce suppressive bone marrow cells in vitro, in
lacking of ACE2 receptor expression, but rather attack the relation to the high levels of IL-6 and IL-10 in plasma.402
supporting and stem cells of olfactory epithelium expressing The hemoglobin level of patients with severe COVID-19
ACE2 receptor.387 COVID-19 patients with influenza-like illness significantly decreased, but the circulating nucleated red blood
displayed the increased frequency of olfactory loss.386 However, cells increased. SARS-CoV-2 may directly infect human erythroid
olfactory loss was also reported in COVID-19 patients without progenitor cells, resulting in the formation and expansion of
nasal symptoms or significant inflammation.388 erythroid progenitor cell colonies, thereby increasing stress
erythropoiesis.403
Dermatologic complication. Cutaneous manifestations have been Multiomics analysis revealed increased proliferation and meta-
reported in 1.8% to 20.4% of COVID-19 patients.389 The appearance bolic hyperactivity of plasmablasts in peripheral blood of patients

Signal Transduction and Targeted Therapy (2022)7:57

The mechanism underlying extrapulmonary complications of the coronavirus. . .
Ning et al.
14

Fig. 4 Potential therapeutic targets against COVID-19 which may be involved in virus replication, immune response, vascular endothelial
coagulation system and important organs related complications. a SARS-CoV-2 virus invades host cells. Viral replication involves multiple
steps: attachment, penetration, uncoating, replication, assembly, and release. b Viral infection induces an antiviral response, recruiting innate
and adaptive immune cells such as macrophages, neutrophil, dendritic cells, T cells, B cells, and NK cells, and leads to cytokine storm. c SARS-
CoV-2 invades endothelial cells and affects the coagulation system, increasing the risk of embolism and bleeding. d These host–virus
interaction may affect multiple important organs and cause severe complications. The therapeutic targets of these steps are shown in
this figure

with severe COVID-19, as well as IFN-activated circulating treatments can be divided into two categories depending on the
megakaryocyte expansion and increased erythrocyte production target, one is acting on the host cells or immune system, and the
characterized by hypoxic signaling.404 Another study has shown other is on SARS-CoV-2 itself.
that there is a tendency for myeloid skewing in circulating HSCs ACE2 and TMPRSS2 have been characterized as possible host
and HPCs in patients with COVID-19, and the frequency of targets to block SARS-CoV-2 from entering host cells. It is reported
common lymphoid progenitor cells is lower in severe patients, that a designed peptide inhibiting SARS-CoV-2 binding to ACE2
while granulocyte/macrophage progenitor cells/neutrophil-like and may theoretically block SARS-CoV-2 infection.410 Recombinant
cells appear in severe and fatal cases.405 human ACE2 protein and anti-spike monoclonal antibody could
inhibit SARS-CoV-2 S protein-induced platelet activation. Micro-
RNA molecules targeting ACE2 may be exploited to regulate the
THE IMPLICATION FOR THERAPEUTICS SARS-CoV-2 receptor. Administration of microRNA 200c inhibits
Currently, antivirals, glucocorticoids, and immunoglobulin treat- both ACE2 mRNA and ACE2 protein levels in human iPSC-derived
ments are still debating for their effectiveness of significant cardiomyocytes and primary cardiomyocytes of COVID-19 rat
improvement in the survival of patients with severe COVID-19. The model, which is a potential regimen for cardiovascular complica-
unconstrained host inflammatory response is the main driver of tions of COVID-19.411 Besides, excessive ACE2 may competitively
the pathology of severe COVID-19. For COVID-19 in the acute bind with SARS-CoV-2, thereby neutralizing the virus and rescuing
setting, 6 mg daily of dexamethasone (equivalent to 40 mg of cellular ACE2 activity which negatively regulates the RAS to
prednisone) for 10 days reduced mortality from 25·7% to 22·9%, protect the lung.410,412,413 Therefore, treatment with a soluble
The results were more striking in patients requiring oxygen or form of ACE2 may be effective against SARS-CoV-2 infection.
invasive ventilation.406 However, chronic glucocorticoids increased Treatment with anti-androgenic drugs reduced ACE2 expression
the odds of hospitalization for COVID-19 in patients with and protected hESC-derived lung organoids against SARS-CoV-2
rheumatic disease.407 Systemic glucocorticoids increased the odds infection. Umifenovir, trade name Arbidol has been used to treat
of COVID-19 related death in patients with inflammatory bowel COVID-19 in China. The primary mode of action of umifenovir is to
disease.408 It is proposed that dexmedetomidine should be inhibit viral attachment by binding to envelope protein.414
considered in COVID-19 patients admitted to ICU when sedation Camostat mesylate, an orally available serine protease inhibitor,
is required, during the early disease course to help prevent the is a potent inhibitor of TMPRSS2 and has been hypothesized as a
onset or progression of multiorgan dysfunction.409 Further clinical potential antiviral drug against COVID-19, by inhibiting virus-cell
studies are warranted to optimize the individual strategies with membrane fusion and hence SARS-CoV-2 replication.259,415,416
these medications. Nafamostat mesylate, which is FDA-approved for indications
Alternatively, targeting the key mechanisms responsible for the unrelated to coronavirus infection, inhibits viral entry with roughly
pathogenesis of COVID-19, including viral entry and replication, 15-fold higher efficiency than camostat mesylate, but requires
cytokine storm, lymphopenia and endothelial damage and intravenous dosing.417
thromboinflammation, may be promising treatment strategies for Chloroquine and hydroxychloroquine may elevate endosomal pH
severe COVID-19 (Fig. 4 and Table 1). Potential anti- SARS-CoV-2 and hinder viral entry and RNA release process.418 However, two

Signal Transduction and Targeted Therapy (2022)7:57

 Table 1. Clinical studies of potential therapeutic options for COVID-19

Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Virus Virus entry into the host and Blocking receptor-binding domain Ensovibep NCT04870164 United Kingdom 24 Phase 1
binding with the host cell
receptor
Virus Virus entry into the host and TMPRSS2 inhibitor Camostat Mesilate NCT04470544 United States 264 Phase 2
binding with the host cell
receptor
Virus Virus entry into the host and TMPRSS2 inhibitor Camostat Mesilate NCT04583592 United States 295 Phase 2
binding with the host cell
receptor
Virus Virus entry into the host and Block viral entry RhACE2 APN01 NCT04335136 Turkey 185 Phase 2
binding with the host cell
receptor
Virus Viral replication and Antiviral activity Niclosamide NCT04558021 Turkey 200 Phase 3
clearance

Signal Transduction and Targeted Therapy (2022)7:57

Virus Viral replication and Broad antiviral activity Peg-IFN Lambda NCT04534673 United States 40 Phase 2
clearance
Virus Viral replication and Broad antiviral activity Remdesivir NCT04560231 Pakistan 30 Phase 1
clearance
Virus Viral replication and Broad antiviral activity Remdesivir NCT04738045 Egypt 90 Phase 4
clearance
Virus Viral replication and Broad antiviral activity Favipiravir NCT04499677 United Kingdom 240 Phase 2
clearance
Virus Viral replication and Broad antiviral activity Lopinavir/Ritonavir NCT04466241 Côte D’Ivoire 294 Phase 3
clearance
Virus Viral replication and Inhibit viral replication Amantadine NCT04952519 Poland 500 Phase 3
clearance
Virus Viral replication and Inhibit viral replication Amantadine hydrochloride NCT04854759 Poland 200 Phase 3
Ning et al.

clearance
Virus Viral replication and Interference with viral leflunomide NCT04361214 United States 20 Phase 1
clearance proliferation
Virus Viral replication and Antiviral activity Nafamostat Mesilate NCT04390594 Senegal 186 Phase 3
clearance
Virus Viral replication and Antiviral activity Niclosamide NCT04753619 Iraq 150 Phase 2
clearance
Virus Viral replication and Broad antiviral activity Favipiravir NCT04425460 China 256 Phase 3
clearance
Virus Viral replication and Broad antiviral activity Sofosbuvir NCT04535869 Egypt 50 Phase 3
clearance
Virus Viral replication and Broad antiviral activity Ribavirin NCT04828564 Turkey 100 Phase 2
clearance
Virus Viral replication and Inhibit viral replication Chlorpromazine (CPZ) NCT04366739 France 40 Phase 3
clearance
Virus Viral replication and Inhibit viral replication Chlorpromazine NCT04354805 Egypt 100 Phase 3
clearance
Virus Viral replication and Antiviral activity Nafamostat Mesylate NCT04418128 South Korea 84 Phase 3
clearance
Virus Viral replication and Broad antiviral activity Favipiravir NCT04400682 Turkey 30 Phase 1
clearance
Virus Viral replication and Broad antiviral activity Remdesivir NCT04280705 United States 1062 Phase 3
clearance
The mechanism underlying extrapulmonary complications of the coronavirus. . .

15
 16
Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Virus Viral replication and Broad antiviral activity Remdesivir NCT04401579 United States 1033 Phase 3
clearance
Virus Viral replication and Broad antiviral activity Remdesivir NCT04345419 Egypt 200 Phase 2
clearance
Virus Viral replication and Broad antiviral activity Favipiravir NCT04407000 Turkey 30 Phase 1
clearance
Virus Viral replication and Broad antiviral activity Lopinavir and ritonavir NCT04252885 China 86 Phase 4
clearance
Virus Viral replication and Broad antiviral activity Lopinavir/ritonavir NCT04276688 Hong Kong 127 Phase 2
clearance
Virus Viral replication and Interference with viral LAU-7b: fenretinide NCT04417257 United States 240 Phase 2
clearance proliferation
Virus Viral replication and Broad antiviral activity Favipiravir NCT04501783 Russian Federation 168 Phase 3
clearance
Virus Viral replication and Interference with viral Leflunomide NCT05007678 United Kingdom 178 Phase 3
clearance proliferation
Virus Viral replication and Antiviral activity Niclosamide NCT04399356 United States 73 Phase 2
clearance
Virus Viral replication and Broad antiviral activity Favipiravir NCT04359615 Iran 40 Phase 4
clearance
Virus Viral replication and Broad antiviral activity Sofosbuvir NCT04530422 Egypt 250 Phase 3
Ning et al.
The mechanism underlying extrapulmonary complications of the coronavirus. . .

clearance
Immune system Cytokine storm IL-6 Antagonist Siltuximab, tocilizumab NCT04486521 Saudi Arabia 860 −
Immune system Cytokine storm IL-6 inhibitor Clazakizumab NCT04659772 USA 1 Phase 2
Immune system Cytokine storm IL-6 inhibitor Clazakizumab NCT04343989 USA 180 Phase 2
Immune system Cytokine storm Anti-IL-6 immunoglobulin G1 Sirukumab NCT04380961 USA 212 Phase 2
kappa (IgG1k) monoclonal
antibody (mAb)
Immune system Cytokine storm Anti-IL-6 receptor antibody Tocilizumab NCT04730323 Pakistan 93 Phase 4
Immune system Cytokine storm Anti-IL-6 receptor antibody Sarilumab NCT04661527 Spain 60 Phase 2
Immune system Cytokine storm Interferon gamma blocking Emapalumab NCT04324021 USA 16 Phase 2
antibody Phase 3
Immune system Cytokine storm Interleukin-IL-17A Antagonist Secukinumab NCT04403243 Russia 70 Phase 2
Immune system Cytokine storm IL-17 inhibitor ixekizumab NCT04724629 Brazil 60 Phase 3
Immune system Cytokine storm Tumor necrosis factor inhibitors Infliximab NCT04734678 Egypt 84 −
Immune system Cytokine storm IL-1β inhibitor Canakinumab NCT04362813 USA 454 Phase 3
Immune system Cytokine storm GM-CSF inhibitor Lenzilumab NCT04351152 USA 520 Phase 3
Immune system Cytokine storm Monoclonal antibody against GM- Gimsilumab NCT04351243 USA 227 Phase 2
CSF
Immune system Cytokine storm IL-23 inhibitor Risankizumab NCT04583956 USA 1 Phase 2
Immune system Immunomodulatory Immune support Biological: HB-adMSCs NCT04348435 USA 55 Phase 2

Signal Transduction and Targeted Therapy (2022)7:57

Immune system Immunomodulatory Specific cytotoxic T lymphocytes SARS-CoV-2 antigen-specific NCT04742595 USA 16 Phase 1
cytotoxic T lymphocyte
Immune system Immunomodulatory Immunomodulatory RAPA-501-Allo off-the-shelf therapy NCT04482699 USA 88 Phase 1
of COVID-19 Phase 2
Immune system Immunomodulatory Immunomodulatory NKG2D-ACE2 CAR-NK cells NCT04324996 China 90 Phase 1
Phase 2
 Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Immune system Immunomodulatory Reduce the proinflammatory state MSC NCT04611256 Mexico 20 Phase 1
and promoting the regeneration
of damaged tissues
Immune system Immunomodulatory Immunomodulatory T memory cells and NK cells NCT04578210 Spain 58 Phase 1
Phase 2
Immune system Immunomodulatory Regulates inflammation and Infusion IV of Mesenchymal NCT04416139 Mexico 10 Phase 2
immunity Stem cells
Immune system Anti-inflammatory effects Anti-inflammatory effects Autologous activated platelet- NCT04715360 Indonesia 30 Phase 1
rich plasma Phase 2
Immune system Anti-inflammatory effects Inhibit the inflammatory response UC-MSCs NCT04339660 China 30 Phase 1
Phase 2
Immune system Anti-inflammatory effects Reduce lung inflammation and MSC exosome inhalation NCT04491240 Russia 30 Phase 1
pathological impairment Phase 2
Immune system Immunomodulatory Immune-mediated inflammatory Mesenchymal stromal cells NCT04361942 Spain 24 Phase 2

Signal Transduction and Targeted Therapy (2022)7:57

Immune system Immunomodulatory Virus neutralization. Other Convalescent plasma NCT04476888 Pakistan 110 −
possible mechanisms include
antibody-dependent cytotoxicity
and phagocytosis
Immune system Immunomodulatory Prevent or shut down the COVID-19 convalescent plasma NCT04374526 Italy 29 Phase 2
continuous inflammatory Phase 3
response caused by the virus
Immune system Immunomodulatory Improve high inflammation state Therapeutic plasma exchange NCT04751643 France 132 −
and respiratory function
Immune system Immunomodulatory Immunomodulatory Intravenous immunoglobulin (IVIG) NCT04500067 Ukraine 76 Phase 3
Immune system Immune reconstitution Immune reconstitution Recombinant interleukin-7 (CYT107) NCT04442178 USA 48 Phase 2
Immune system Immunomodulatory Prevent or shut down the COVID-19 convalescent plasma (CCP) NCT04421404 USA 42 Phase 2
continuous inflammatory
Ning et al.

response caused by the virus

Immune system Immunomodulatory Immunomodulatory Monoclonal antibody to S protein of NCT04840459 USA 1000 Phase 2
SARS-CoV-2
Immune system Immunomodulatory Immunomodulatory SARS-CoV-2 antibody-based IVIG NCT04521309 Pakistan 50 Phase 1
therapy Phase 2
Immune system Immunomodulatory Immunomodulatory JS016 (anti-SARS-CoV-2 monoclonal NCT04931238 China 200 Phase 1
antibody)
Immune system Immunomodulatory Immunomodulatory plasma therapy using convalescent NCT04356534 Ireland 40 −
plasma with antibody against SARS-
CoV-2
immune system Cytokine storm Regulation of the inflammatory Vitamin D, Omega DHA/EPA, vitamin NCT04828538 Mexico 3600 −
cytokine response C, vitamin B complex, and zinc
acetate
Immune system Immune activation Suppressor of cytokine activation Zofin: derived from human NCT04384445 USA 20 Phase 1、
amniotic fluid Phase 2
Immune system Intense inflammatory Adjunct immune modulation Vitamin C NCT04401150 Canada 800 Phase 3
cascade therapies
Immune system Cytokine storm Human normal immunoglobulin IVIG NCT04500067 Ukraine 76 Phase 3
Immune system Cytokine storm Human normal immunoglobulin Human immunoglobulin NCT04350580 France 146 Phase 3
Immune system Cytokine storm Immunosuppressant Ciclesonide NCT04377711 USA 400 Phase 3
Immune system Cytokine storm Vitamin Cholecalciferol NCT04552951 Spain 80 Phase 4
The mechanism underlying extrapulmonary complications of the coronavirus. . .

17
 18
Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Immune system Cytokine storm Vitamin Vitamin D3, vitamin C/Zinc, NCT04780061 Canada 200 Phase 3
vitamin K2/D
Immune system Cytokine storm Vitamin Oral 25-hydroxyvitamin D3 NCT04386850 Islamic Republic 1500 Phase 2,3
Immune system Cytokine storm Mesenchymal stem cells HB-adMSCs NCT04348435 USA 55 Phase 2
Immune system Cytokine storm Bone marrow-derived extracellular DB-001 NCT04493242 USA 120 Phase 2
vesicles
immune system Elevated numbers of NETs degradation rhDNase I NCT04409925 Canada 25 Phase 1
neutrophils
Endothelial Pulmonary edema Abl2/Arg inhibitors Imatinib NCT04794088 Netherlands 90 Phase 2
Endothelial Acute respiratory distress DNase inhibitors Dornase alfa NCT04355364 France 100 Phase 3
syndrome
Endothelial Excessive blood clotting Vasodilator and inhibitor of Dipyridamole NCT04391179 United States 100 Phase 2
platelet aggregation
Endothelial Endothelial dysfunction Endothelial cell modifying Defibrotide NCT04652115 United States 42 Phase 2
Endothelial Endothelial dysfunction Endothelial cell modifying Defibrotide NCT04348383 Spain 150 Phase 2
Endothelial Complement-mediated Terminal complement inhibitor Eculizumab NCT04346797 France 120 Phase 2
diseases
Endothelial Endothelial dysfunction Increase NO production and Atorvastatin + L-arginine + folic acid NCT04631536 Lebanon 80 Phase 3
release + nicorandil + nebivolol
Endothelial Endothelial injury PAI-1 inhibitor TM5614 NCT04634799 United States 80 Phase 2
Ning et al.
The mechanism underlying extrapulmonary complications of the coronavirus. . .

Endothelial Microvascular endothelial Platelet aggregation inhibitors Iloprost NCT04420741 Denmark 80 Phase 2
dysfunction
Endothelial Vascular endothelial Restore endothelial glycocalyx Suloexide NCT04483830 Mexico 243 Phase 2
dysfunction and Inhibit thrombosis Phase 3
Endothelial Endothelial injury C5a inhibitor Ravulizumab NCT04570397 United States 32 Phase 3
Endothelial Vascular dilation Angiogenesis inhibitors BEVACIZUMAB NCT04822818 France 174 Phase 3
Endothelial Vascular leakage decrease vascular FX06 NCT04618042 France 50 Phase 2
hyperpermeability
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04360824 USA 170 Phase 4
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin, unfractionated heparin, NCT04486508 Iran 600 Phase 3
atorvastatin, matched placebo
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04354155 USA 40 Phase 2
Coagulation system Higher hypercoagulability Anticoagulation Low-molecular-weight heparin, NCT04359212 Italy 90 –
fondaparinux
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04408235 Italy 300 Phase 3
Coagulation system Higher hypercoagulability Anticoagulation Tinzaparin, unfractionated heparin NCT04344756 France 808 Phase 2
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04345848 Switzerland 200 Phase 3
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin, heparin NCT04359277 USA 77 Phase 3
Coagulation system Higher hypercoagulability Anticoagulation Low-molecular-weight heparin NCT04362085 Canada 465 Phase 3
(LMWH), unfractionated
heparin (UFH)

Signal Transduction and Targeted Therapy (2022)7:57

Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04366960 Italy 189 Phase 3
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin, heparin, lovenox NCT04367831 USA 100 Phase 4
Coagulation system Higher hypercoagulability Anticoagulation Heparin NCT04372589 USA 1200 Phase 3
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04373707 France 602 Phase 4
Coagulation system Higher hypercoagulability Anticoagulation Low-molecular-weight heparin NCT04393805 Italy 744 –
 Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Coagulation system Higher hypercoagulability Anticoagulation Rivaroxaban, enoxaparin NCT04394377 Brazil 615 Phase 4
Coagulation system Higher hypercoagulability Anticoagulation Enoxaparin NCT04401293 USA 257 Phase 3
Coagulation system Higher hypercoagulability Anticoagulation Rivaroxaban NCT04416048 Germany 400 Phase 2
Coagulation system Higher hypercoagulability Platelet inhibition Tirofiban, clopidogrel, acetylsalicylic NCT04368377 Italy 5 Phase 2
acid, fondaparinux
Coagulation system Reduced vitamin K status Vitamin K supplementation Vitamin K2 in the form of NCT04770740 Netherlands 40 Phase 2
menaquinone-7 (MK-7), placebo
Cardiovascular Dysfunction of RAAS Recover the function of ACE2- Recombinant bacterial ACE2 NCT04375046 China 24 Phase 1
RAAS receptors-like enzyme of B38-CAP
(rbACE2)
Cardiovascular Dysfunction of RAAS RAAS inhibition RAAS inhibitor NCT04508985 Canada 40 /
Cardiovascular Cardiovascular disease or Anti-inflammatory Cannabidiol NCT04615949 Arizona, USA 422 Phase 2、
risk factors Phase 3

Signal Transduction and Targeted Therapy (2022)7:57

Vascular endothelial system Coagulation disorders Anticoagulant Enoxaparin Atorvastatin NCT04486508 Islamic Republic 600 Phase 3
Circulatory system Vascular endothelial injury, FXa inhibitor, HMG-CoA inhibitor Apixaban, Atorvastatin NCT04801940 UK 2631 Phase 3
cytokine storm
Vascular endothelial system Cytokine storm, vascular Vitamin C Vitamin C NCT04401150 Canada 800 Phase 3
endothelial injury
Vascular endothelial system Vascular endothelial injury Phyto preparation Hesperidin NCT04715932 Canada 216 Phase 2
Cardiac, kidney multiorgan failure Sodium–glucose cotransporter-2 Dapagliflozin NCT04350593 USA、Argentina、 1250 Phase 3
(SGLT-2) inhibitor Brazil、Canada、
India、Mexico、
UK
Cardiovascular Acute cardiac injury Cardioprotective medicines Aspirin, clopidogrel, rivaroxaban, NCT04333407 UK 3170 −
atorvastatin, omeprazole
Cardiovascular Thrombotic events Anticoagulation or anti- Apixaban, aspirin NCT04498273 USA 7000 Phase 3
Ning et al.

platelet agents
Cardiovascular Thrombotic events Anti-inflammatory and Enoxaparin, unfractionated heparin, NCT04486508 Iran 600 Phase 3
antithrombotic function atorvastatin
Cardiovascular Dysregulated immune Immunomodulatory and EDP1815, dapagliflozin and NCT04393246 UK 1407 Phase 2、
response cardiovascular drugs Ambrisentan Phase 3
Cardiovascular Cardiac injury Reduce cardiac injury Colchicine tablets NCT04355143 USA 150 Phase 2
Cardiovascular Thrombotic events Anticoagulation agent Rivaroxaban NCT04757857 Brazil 1000 Phase 4
Cardiovascular Thrombotic events Antagonize plasminogen activator TM5614 NCT04634799 USA 80 Phase 1、
inhibitor Phase 2
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin NCT04492254 Australia 1370 Phase 3
Cardiovascular Thrombotic events Anticoagulation agent Apixaban NCT04746339 Brazil 1000 Phase 4
Cardiovascular Longer-term complications Improve the quality of life Apixaban, atorvastatin NCT04801940 UK 2631 Phase 3
occurring in the
convalescent phase
Cardiovascular Thrombotic events Anticoagulation agent Rivaroxaban NCT04416048 Germany 400 Phase 2
Cardiovascular Endothelial dysfunction Improve endothelial function Atorvastatin + L-arginine + folic acid NCT04631536 Lebanon 80 Phase 3
+ nicorandil + nebivolol
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin, apixaban NCT04512079 USA、Brazil、 3600 Phase 4
Colombia、India、
Mexico
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin NCT04400799 Germany、 1000 Phase 3
Switzerland
The mechanism underlying extrapulmonary complications of the coronavirus. . .

19
 20
Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin NCT04646655 Italy 300 Phase 3
Cardiovascular Viral injury of the vascular Monoclonal antibody that targets Crizanlizumab NCT04435184 USA 50 Phase 2
endothelium P-selectin
Cardiovascular Myocardial infarction in Antiarrhythmic effect Atorvastatin, atorvastatin-ezetimibe NCT04900155 Russian Federation 200 −
combination with COVID-19
Cardiovascular Thrombotic events Antithrombotic therapy Apixaban NCT04650087 USA 5320 Phase 3
Cardiovascular Thrombotic events Thromboprophylaxis Rivaroxaban NCT04662684 Brazil 320 Phase 3
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin NCT04345848 Switzerland 200 Phase 3
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin, heparin NCT04367831 USA 100 Phase 4
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin NCT04354155 USA 40 Phase 2
Cardiovascular Thrombotic events Anticoagulation therapy Therapeutic anticoagulation NCT04362085 Canada 465 Phase 3
Cardiovascular Thrombotic events Anticoagulation agent Thromboprophylaxis NCT04360824 USA 170 Phase 4
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin NCT04373707 France 602 Phase 4
Cardiovascular Acute pulmonary Decrease pulmonary arterial PDNO NCT04885491/ Sweden 16 Phase 1、
hypertension (aPH) and/or pressure 2020-002982-33 Phase 2
acute Cor pulmonale (ACP)
Cardiovascular Hyperviscosity Plasma exchange Therapeutic plasma exchange NCT04441996 USA 20 Phase 4
Cardiovascular Thrombotic events Anticoagulation therapy Edoxaban, colchicine NCT04516941 Belgium、Italy、 420 Phase 3
Spain、
Switzerland
Ning et al.
The mechanism underlying extrapulmonary complications of the coronavirus. . .

Cardiovascular Thrombotic events Anticoagulation therapy Tinzaparin NCT04730856 Spain 600 Phase 3
Cardiovascular Thrombotic events Anticoagulation therapy Enoxaparin NCT04508439 Mexico 130 −
Cardiovascular Coagulopathy Anticoagulation therapy Therapeutic anticoagulation NCT04444700 Brazil 465 Phase 3
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin 2020-003125-39 Germany 1370 −
Cardiovascular Thrombotic events Anticoagulation agent Low-molecular-weight heparin 2020-001709-21 France 550 −
Cardiovascular Thrombotic events Anticoagulation agent Enoxaparin 2020-005624-10 Germany 1000 −
Cardiovascular Downregulation of ACE2 Anti-inflammatory and Omega3-FA NCT04658433 Jordan 100 −
antithrombotic function-RAAS
Cardiovascular Cardiovascular disease or Renin–angiotensin system ACEi、ARB NCT04591210 Canada, 1155 Phase 3
risk factors inhibitors-RAAS Brazil, Mexico
Cardiovascular Viral cell invasion Increase ACE2 expression and Discontinuation/continuation of NCT04338009 USA 152 −
improve mechanisms of host ACEi、ARB
defense or hyperinflammation-
RAAS
Cardiovascular ARDS RAAS regulator Telmisartan NCT04355936 Argentina 400 Phase 4
Cardiovascular Overaction of RAS Similar peptide to Ang(1–7)-RAAS TRV027 NCT04419610 UK 30 Phase 1
Cardiovascular Viral entry and viral Recombinant human angiotensin- RhACE2 APN01 NCT04335136 Austria、 185 Phase 2
replication converting enzyme 2 -RAAS Denmark、
Germany、Russian
Federation、UK
Respiratory system Host viral entry TMPRSS2 inhibitors Nafamostat Mesilate NCT04352400 Italy 256 Phase 2、

Signal Transduction and Targeted Therapy (2022)7:57

Phase 3
Immune and respiratory system Cytokine storm Prophylactic corticosteroid Methylprednisolone NCT04355247 Puerto Rico 20 Phase 2
Respiratory system Cytokine storm Mesenchymal stem cells Umbilical cord-derived mesenchymal NCT04333368 France 40 Phase 1
stromal cells
Respiratory system Cytokine storm Biomarker-tailored steroid Methylprednisolone NCT03852537 USA 44 Phase 2
Respiratory system Viral growth Broad-spectrum antiparasitic Ivermectin NCT04739410 Pakistan 50 Phase 4
 Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Respiratory system Cytokine storm Antioxidant Sodium pyruvate NCT04871815 USA 50 Phase 2,3
Respiratory system Cytokine storm Antihistamines Cetirizine and famotidine NCT04836806 USA 160 Phase 4
Respiratory system Viral growth Broad-spectrum antiviral Remdesivir NCT04978259 Finland 202 Phase 4
Respiratory system Viral growth Broad-spectrum antiviral Favipiravir NCT04694612 Nepal 676 Phase 3
Respiratory system Viral growth Broad-spectrum antiviral Triazavirin NCT04973462 Egypt 80 Phase 4
Respiratory system Viral growth Broad-spectrum antiviral Ivermectin NCT04673214 Mexico 114 Phase 3
Respiratory system Viral growth Broad-spectrum antiviral Lopinavir/ritonavir NCT04466241 Cote d’Ivoire 294 Phase 2,3
Respiratory system Host viral entry Vaccine based on peptide EpiVacCorona NCT04780035 Russian Federation 3000 Phase 3
antigens
Respiratory system Viral growth Broad-spectrum antiparasitic Nitazoxanide 500 mg oral tablet NCT04406246 Mexico 150 Phase 4
Respiratory system Viral growth, cytokine storm Broad-spectrum antiviral Ivermectin and doxycycline NCT04523831 Bangladesh 400 Phase 3
Respiratory system Viral growth Broad-spectrum antiviral Ivermectin tablets, doxycycline NCT04729140 USA 150 Phase 4

Signal Transduction and Targeted Therapy (2022)7:57

tablets
Respiratory system Cytokine storm Antioxidant Sodium pyruvate NCT04824365 USA 60 Phase 2,3
Respiratory system Viral growth RNA polymerase inhibitor Favipiravir NCT04600999 Hungary 150 Phase 3
Respiratory system Viral growth, Cytokine storm ACE2 inhibitor Hydroxychloroquine NCT04354428 USA 300 Phase 2,3
Respiratory system Host viral entry Acetylcholine agonists Nicotine patch NCT04583410 France 1633 Phase 3
Respiratory system Viral growth Broad-spectrum antiparasitic AVIGAN NCT04529499 Kuwait 780 Phase 3
Respiratory system Viral growth Broad-spectrum antiparasitic Ivermectin NCT04646109 Turkey 66 Phase 3
Respiratory system Viral growth Broad-spectrum antiparasitic Favipiravir NCT04600895 USA 1150 Phase 3
Respiratory system Cytokine storm Cytokine inhibitor Pirfenidone NCT04856111 India 48 Phase 4
Respiratory system Cytokine storm M2 protein inhibitor Amantadine hydrochloride NCT04854759 Poland 200 Phase 3
Respiratory system Cytokine storm Convalescent plasma Convalescent plasma NCT04558476 Belgium 500 Phase 2
Ning et al.

Respiratory system Cytokine storm, vascular VEGF inhibitor Nintedanib 150 MG [Ofev] NCT04541680 France 250 Phase 3
endothelial injury
Respiratory system Host viral entry Acetylcholine agonists Nicotine NCT04608201 France 220 Phase 3
Respiratory system Cytokine storm Interferon beta-1a SNG001 NCT04732949 USA 610 Phase 3
Respiratory system Cytokine storm SSRI Fluvoxamine NCT04668950 USA 1100 Phase 3
Lung and coagulation system Host viral entry and higher Protease TMPRSS2 inhibition Nafamostat mesilate, placebo NCT04352400 Italy 256 Phase 3
hypercoagulability
Respiratory system Cytokine storm IL-6-blocking antibodies Clazakizumab, placebo NCT04343989 USA 180 Phase 2
Nervous system Cytokine storm, Endogenous molecule mPEA and umPEA NCT04568876 Italy 40 Phase 4
neuroinflammation
Central nervous system Cytokine storm, Sedation drugs Isoflurane inhalant product, NCT04415060 Canada 752 Phase 3
sedatives needed sevoflurane inhalant product
Central Nervous System Cytokine storm, Anti-adrenergic medications Propranolol hydrochloride NCT04467086 Canada 108 Phase 3
sedatives needed
Neuropsychological system Cytokine storm, post-viral C1 inhibitor Ruconest NCT04705831 USA 40 Phase 4
fatigue syndrome
Peripheral nervous system Cytokine storm, Phyto preparation BNO 1030 NCT04797936 Ukraine 133 Phase 4
Nasopharyngitis
Central nervous system Cytokine storm Analgesics Cannabis, medical NCT03944447 USA 200000 Phase 2
Central nervous system Cytokine storm, acute Surgery Sphenopalatine ganglion block with NCT04636034 Denmark 60 Phase 3
brain damage local anesthetic
Neuropsychiatric system Viral growth, Cytokine storm ACE2 inhibitor Hydroxychloroquine, apixaban NCT04788355 Brazil 176 Phase 3
The mechanism underlying extrapulmonary complications of the coronavirus. . .

21
 22
Table 1. continued
Target: organs or systems Pathological phenomenon Mechanism of action Treatment Clinical trial Country Number of Trial phase
patients

Neuropsychiatric system Cytokine storm, Nicotinamide riboside Niagen NCT04809974 USA 100 Phase 4
brain damage
Respiratory system, Cytokine storm IL-6 blocker Fluoxetine NCT04377308 USA 2000 Phase 4
Neuropsychiatric system
Central Nervous System Cytokine storm CB1 and CB2 agonists Cannabidiol NCT04467918 Brazil 100 Phase 2,3
Neuropsychiatric system Cytokine storm, NMDA inhibitor Ketamine NCT04769297 USA 30 Phase 4
brain damage
Kidney Cytokine storm Hormone replacement therapy Extracorporeal mesenchymal stromal NCT04445220 United States 22 Phase 1,
cell therapy (SBI-101 Therapy) Phase 2
Kidney Cytokine storm Hormone replacement therapy AN-69 Oxiris membrane or the NCT04597034 Mexico 35 −
standard AN-69 membrane
Kidney AKI,ARDS and COVID-19 Cytopheretic device Device: SCD NCT04395911 United States 22 −
Kidney Thrombotic C5a inhibitor Ravulizumab NCT04570397 United States 32 Phase 3
microangiopathy
Kidney Host viral entry Urine alkalinisation to prevent Sodium Bicarbonate 150Meq/L/ NCT04655716 United Kingdom 80 Phase 3
binding of SARS-COV-2 to renal D5W Inj
tubular epithelial cells
Kidney Acute kidney injury Renal protection Nicotinamide riboside NCT04818216 United States 100 Phase 2
Kidney Acute kidney injury extracorporeal CO2 removal Device: extracorporeal CO2 removal NCT04351906 Germany 20 −
(ECCO2R) therapy
Ning et al.
The mechanism underlying extrapulmonary complications of the coronavirus. . .

Kidney Sepsis, severe acute kidney Plasma expansion with Ringer’s 7,5 ml/kg mL Ringer’s acetate NCT02765191 Sweden 20 −
injury, COVID-19 Acetate
Gastrointestinal Minimize/avoid any immune Immune response inhalable hydroxychloroquine (HCQ) NCT04477083 Egypt 40 −
response supportive and symptomatic
treatment
Gastrointestinal / / Hydroxychloroquine NCT04351620 United States 20 Phase 1
Gastrointestinal / / No intervention NCT04401124 China 500 −
Gastrointestinal Gut microbes Gut microbes Omni-Biotic Pro Vi 5 NCT04813718 Austria 20 −
Gastrointestinal / / Swallowing evaluation with the EAT- NCT04346212 Spain 300 −
10 and the volume-viscosity
swallowing test (V-VST)
Gastrointestinal / / / NCT04838834 United States 472 −
Gastrointestinal / / Laparoscopic appendectomy NCT04786041 Israel 200 −
Endocrine system Uncontrolled blood glucose Antiviral drug combined with an Drug: Baricitinib NCT04970719 Bengal 382 Phase 3
anti-inflammatory Drug: Dexamethasone
Drug: Remdesivir
Endocrine system β-cell function Insulinotropic amino acids Stimulation test with arginine NCT04463849 Italy 90 −
infusion in order to verify the
possible existence of damage to the
beta cell function induced by COVID-
19 infection
Endocrine system Cytokine storm Decrease blood sugar; increase Drug: Pioglitazone 30 mg NCT04535700 Spain 76 Phase 4
ACE2 expression

Signal Transduction and Targeted Therapy (2022)7:57

Endocrine system Interleukin-1 (IL-1) blocking IL-1beta activity Drug: Canakinumab NCT04510493 Switzerland 116 Phase 3
beta system
Endocrine system Decrease in TNF-alpha, Anti-inflammatory and Drug: Pioglitazone 45 mg NCT04604223 Kuwait 1506 Phase 4
interleukin, hs CRP, leptin inflammation-resolving
and other inflammatory
markers
 The mechanism underlying extrapulmonary complications of the coronavirus. . .
Ning et al.
23
Number of Trial phase randomized controlled trials, RECOVERY419 and WHO SOLIDARITY
trials,420 confirmed that these regimens failed to provide any clinical
Phase 2

Phase 3

Phase 1
Phase 3
benefit for COVID-19 patients.
Nsps participate in various steps of virus life cycle, including

−
RNA transcription and translation, protein synthesis, processing
and modification, virus replication and infection. Among these,
patients

nsp5 3CLpro, nsp3 PLpro, nsp12 RdRp and helicase are the most

1002
important targets for the development of small-molecule
156

250
70

56

inhibitors because of their biological functions and vital enzyme

active site.421 The protein sequence similarity between SARS-CoV-
2 and SARS-CoV RdRp is up to 96%.422 Thus, broad-spectrum
Czech Republic

antiviral drugs acting on RdRp including nucleoside analogs, e.g.,

remdesivir, favipiravir, and molnupiravir, may potentially block
Country

SARS-CoV-2 replication.423,424 ACTT-1 study of intravenous

Mexico

Egypt

Spain

remdesivir in adults who were hospitalized with COVID-19

Iraq

showed that remdesivir was superior to placebo in shortening

recovery time.425 However, DisCoVeRy study demonstrated no
clinical benefit of remdesivir use in patients hospitalized for
NCT04516759

NCT04542213

NCT04733625
NCT04569825
NCT04334928
Clinical trial

COVID-19 who were symptomatic for more than 7 days, and

required oxygen support.426 Remdesivir undergoes intracellular
activation to form an analog of adenosine triphosphate GS-
443902 that selectively inhibits viral RNA polymerases and has
broad-spectrum activity against coronavirus.427 In an animal
model molnupiravir is orally active against SARS-CoV-2, and
preliminary data of phase 2a trial showed that molnupiravir is
highly effective at reducing SARS-CoV-2 RNA and has a favorable
safety and tolerability profile.428 Protease inhibitors targeting viral
3CLpro are attractive therapeutic options for COVID-19.429
Drug: Linagliptin tablet

Drug: cholecalciferol

Protease inhibitor lopinavir–ritonavir showed significant inhibitory

effects on SARS-CoV-2 in vitro.430 However, the LOTUS294 and
Drug: AZD1656

RECOVERY431 clinical trials independently showed no benefit of

Ophtamesone

using lopinavir–ritonavir in reducing mortality rate, hospital time

Treatment

Truvada

nor progression to mechanical ventilator intervention. There are

three SARS-CoV-2 virulence factors nsp1, nsp3c, and ORF7a
related to interfering host’s innate immunity and assisting
immune escape, suggesting that nsp1, nsp3c, and ORF7a may
be potential targets for antiviral drug development.421,432 The
Dipeptidyl Peptidase-4 Inhibitor
Glucokinase (GK; hexokinase 4)

efficacy of existing antiviral ribonucleoside and ribonucleotide

Regulate immune function

Pre-exposure phrophylaxis

analogs, such as remdesivir, can be decreased by the viral

proofreading exonuclease nsp14-nsp10 complex. Nsp14-nsp10
Mechanism of action

inhibitors were identified that increase antiviral potency of

remdesivir. A model compound, sofalcone, inhibits the exonu-
Nasal steroid

clease activity of SARS-CoV-2 in vitro, and synergistically enhances

the antiviral effect of remdesivir.433 Nsp3 in SARS-CoV-2 serves to
activator

(DPP4i)

counteract the antiviral function of host Poly ADP-ribose

polymerase (PARP) which is NAD+-consuming enzymes. There-
fore, NAD+ and NAD+-consuming enzymes play crucial roles in
immune responses against viral infection. Thorough mechanistic
Pathological phenomenon

understandings of SARS-CoV-2 replication will likely facilitate the

development of general antiviral strategies.434
Decrease blood sugar

Decrease blood sugar

A minimally pathogenic human betacoronavirus (OC43) was

used to infect physiologically-relevant human pulmonary fibro-
Host viral entry
Cytokine storm
Cytokine storm

blasts MRC5 to facilitate rapid antiviral discovery in a preclinical

model. Several FDA-approved agents that can attenuate both
OC43 and SARS-CoV-2 viral replication, including lapatinib,
doramapimod, and tanespimycin. Importantly, lapatinib inhibited
SARS-CoV-2 RNA replication by over 50,000-fold. Further, both
lapatinib and doramapimod could be combined with remdesivir
to improve antiviral activity in cells. These findings reveal novel
Pre-exposure phrophylaxis

therapeutic avenues that could limit SARS-CoV-2 infection.435

Target: organs or systems

The knowledge accumulated to date indicates that COVID-19

Table 1. continued

severity and the associated mortality rate derive either from a

Endocrine system

Endocrine system

Endocrine system

dysregulated immunopathology induced directly by SARS-CoV-2

infection or by the tissue damage caused by the immune response
against SARS-CoV-2.15 Therefore, the altered immune response
represents the important target for therapeutic interventions
aimed at modifying the immunopathogenesis of COVID-19.
ENT

Targeting the specific COVID-19 immune profiles, such as by

Signal Transduction and Targeted Therapy (2022)7:57

The mechanism underlying extrapulmonary complications of the coronavirus. . .
Ning et al.
24
inhibiting inflammation or enhancing lymphocytes are promising support routine empirical use of prophylactic anticoagulation in
treatment strategies for severe cases. Targeting cytokine storm patients with COVID-19.454–456 A retrospective analysis indicated
and the signaling pathways have been considered as potentially that therapeutic anticoagulation was associated with lower
effective strategies to modulate the hyperinflammatory response mortality among hospitalized COVID-19 patients compared with
against SARS-CoV-2 infection.436 Anti-cytokine therapy such as IL- prophylactic anticoagulation, although not statistically signifi-
6, TNF-α and IL-1 antagonists have been suggested for the cant.457 While two other studies showed that therapeutic antic-
alleviation of hyperinflammation.357 In hospitalized COVID-19 oagulation did not significantly improve the prognosis nor
patients with hypoxia and systemic inflammation, IL-6R antagonist increase the risk of bleeding compared with prophylactic antic-
tocilizumab improved survival and other clinical outcomes.437,438 oagulation in patients hospitalized with COVID-19 and elevated
However, a randomized trial in patients with severe or critical D-dimer concentration.458,459 A study in France involving 10
COVID-19, tocilizumab failed to improve clinical outcomes, and it patients with ischemic stroke caused by macrovascular embolism
might increase mortality.439 A randomized, double-blind trial did showed that early intravenous thrombolysis and mechanical
not show efficacy of another IL-6R antagonist sarilumab in thrombectomy recanalization did not reverse the adverse out-
patients admitted to hospital with COVID-19 and receiving comes of patients.460 These controversial results demonstrate the
supplemental oxygen.440 Anti-IL-6 monoclonal antibodies such complexity of coagulation in COVID-19 patients.
as siltuximab and sirukumab are under investigation for COVID-19 To date, the research on the mechanism of COVID-19 related
patients. Aberrant high GM-CSF levels have been detected in coagulation disorders has proposed a series of molecules and
circulating lymphocyte populations, excluding NKs and B cells, pathways that may be used as clinical intervention targets. First,
from patients with COVID-19 admitted to ICU.78 Therefore, the disorders in the coagulation system include colocalization of
potential of GM-CSF-blocking antibodies such as lenzilumab (LIVE- coagulation factor XII and NETs,153 increased biological function of
AIR study) and gimsilumab to treat COVID-19 is being evaluated CD142 which exposed onto surface of cell-released extracellular
by researchers and pharmaceutical companies.441 vesicles,461,462 overactivation of the complement component
Other possible strategies under clinical and preclinical investi- anaphylatoxin-NET axis,462 overactivation of platelet via binding
gation for inhibiting macrophage activation include the blockade to S protein by ACE2.145 Studies shows that by targeting these
of certain cytokines, inhibition of C-C chemokine receptor type 5 molecules will improve the coagulation state in vitro. Second, a
(CCR5)-mediated migration and CD14 blockade by monoclonal reduction in fibrinolysis also plays an important role in COVID-19-
antibodies.441 Strategies such as MSC-based therapy, Treg-based associated coagulopathy, and promoting fibrinolytic activity is a
therapy and blood purification may also represent alternative possible way to change the coagulation disorder in patients.463–465
effective approach to alleviating SARS-CoV-2-related immuno- Third, studies have found that vascular endothelial cells activation
pathology.15 SARS-CoV-2 has demonstrated to induce apoptosis of and dysfunction mediate inflammation and abnormal coagulation
circulating lymphocytes by P53 activation.442 T cells from COVID- in COVID-19 patients.106,107 In addition, some other factors can
19 patients expressed higher levels of the exhausted marker PD-1. also play a role by influencing the above three systems, such as
Increasing PD-1 expression on T cells was observed as disease RAS,466 complement and coagulation cascade signaling,125,467,468
progressed.97 The efficacy of PD-1 monoclonal antibody, camre- mineralocorticoid receptor (MR) and its downstream target
lizumab plus thymosin have been evaluated in a clinical trial for galectin-3 (Gal-3),469 IL-6,124 extrahepatic vitamin K insuffi-
COVID-19 treatment.443 Circulating NK cell numbers were found ciency,470 etc. These molecules and pathways form a complex
significantly reduced in COVID-19 patients with severe disease,444 network leading to the complexity of the disease and the difficulty
and showed increased expression of inhibitory receptor TIM-3.445 of the treatment. Some drugs targeting the above molecules and
Chimeric antigen receptor (CAR) -engineered NK cells are also pathways have entered clinical trials, such as inhaled rhDNase1
being tested for treating COVID-19.446 (targeting the NETs), recombinant bacterial ACE2 receptors-like
PAI-1 inhibitors significantly enhance the bronchoalveolar enzyme of B38-CAP, RAS inhibitor, mineralocorticoid receptor
fibrinolytic system and relieve symptoms of COVID-19 by antagonist (MRA) canrenoate potassium, the IL-6 inhibitor
increasing fibrinolytic protein levels that effectively remove clazakizumab, vitamin K2, etc.
fibrin.447 There is increasing evidence that complement is involved Accumulating literature has demonstrated the beneficial
in SARS-CoV-2 pathology, and that complement inhibitors may effects of n-3 polyunsaturated fatty acids (n-3 PUFA) toward
reduce the severity of COVID-19 complications and the number of the cardiovascular system, which include ameliorating uncon-
intensive care or deaths, especially with ekuzumab showing trolled inflammatory reactions, reduced oxidative stress and
preliminary efficacy.448 Defibrotide can counteract endothelial mitigating coagulopathy.471 Due to the favorable safety profile of
activation and hypercoagulability induced by NETs and histone n-3 PUFAs and their metabolites, it is reasonable to consider n-3
H4, promote endothelial remodeling and prevent endothelial PUFAs as potential adjuvant therapies for the clinical manage-
dysfunction.449 Blocking vascular endothelial growth factor (VEGF) ment of COVID-19 patients. Targeting RAGE to prevent SARS-
and VEGF receptor -mediated signaling improves oxygen perfu- CoV-2-mediated multiple organ failure is also a promising
sion and anti-inflammatory responses, and reduces clinical therapy.472 Pharmacological agents frequently used in athero-
symptoms in patients with severe COVID-19. A humanized sclerotic conditions, such as statins and aspirin, appear to lower
monoclonal antibody against VEGF, Bevacizumab plus standard the incidence of serious COVID-19 complications and mortality
care can be very beneficial for patients with severe COVID-19.450 rates.473 Oxytocin (OXT) can protect the heart and vasculature
The lung function of COVID-19 patients improved significantly through suppressing hypertension and brain-heart syndrome,
after FX06 administration, which may be attributed to its and promoting regeneration of injured cardiomyocytes.474
immunomodulatory properties and its ability to protect the Exogenous OXT can be used safely without the side-effects seen
endothelial barrier and reduce vascular hypertonicity.451 in remdesivir and corticosteroid.474
Given hypercoagulability was commonly seen in patients with A retrospective observational study of COVID-19 patients with
COVID-19, studies suggest that low-molecular weight heparin type 2 diabetes found that sitagliptin treatment during hospita-
(LMWH) should be used for early and long-term drug-induced lization was associated with reduced mortality and improved
thrombosis prevention.452 Consistently, in a cohort of critically ill clinical outcomes.475 Evidence suggests that insulin and dipeptidyl
COVID-19 patients with a high prevalence of thromboembolic peptidase-4 (DDP4) inhibitors can be used safely in COVID-19
events, enhanced thromboprophylaxis was associated with patients with diabetes. Metformin and sodium-glucose cotran-
reduced ICU mortality without an increased hemorrhagic risk.453 sporter-2 (SGLT-2) inhibitors might need to be withdrawn in
However, results from some other multicenter studies did not patients at high risk of severe disease.476

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Ning et al.
25
SARS-COV-2 VACCINATION potential mechanisms underlying of SARS-CoV-2-induced pul-
The vaccination of SARS-CoV-2 vaccine may become one of the monary and extrapulmonary complications may ultimately lead to
most effective means to terminate COVID-19 epidemic. The the development of potential therapeutic approaches for COVID-
current vaccine development mainly uses viral S protein, S protein 19, which will eventually eradicate COVID-19 across the globe.
receptor-binding domain, or S protein subunits as antigens. The Nevertheless, given the rapidly evolving scenario due to the
technical strategies477 include: viral vaccines (live attenuated emergence of SARS-CoV-2 variants and ongoing vaccination
vaccines and inactivated vaccines), viral-vectored vaccines (repli- campaigns, more studies are warranted to achieve comprehensive
cating and non-replicating), nucleic acid vaccines (DNA vaccines knowledge of the multifaceted interaction between the host and
and mRNA vaccines), protein subunit vaccines (recombinant SARS-CoV-2.
protein vaccines, protein subunit vaccines and virus-like particle
vaccines). As of January 7, 2022, 137 of the 331 vaccine projects
announced by the WHO478 have entered the clinical trial stage. At ACKNOWLEDGEMENTS
present, several vaccines produced in China, the United States and We thank Mengxin Lu, Yuting Diao, Xue Hu, Meiwen Han, Xitang Li, Suping Hai,
Europe have been the first to vaccinate people on a large scale. Qiang Gao, and Wenhui Wu for their assistance with literature searching. Received
However, the main challenge is the reduction of the protective funding from: The National Key Research and Development Program of China
(2021YFC2600200); Chinese National Thirteenth-Five Years Project in Science and
power of the vaccine due to the mutation of the SARS-CoV-2.
Technology (2017ZX10202201); Science and Technology Department of Hubei
Efforts to develop polyvalent vaccines479 against different strains (2020FCA044); Wuhan Science and Technology Bureau (2020020601012228,
may be a solution, but the mutation of SARS-CoV-2 is rapid which 2020020601012236); Huazhong University of Science and Technology
makes the development of vaccine extremely difficult. Another (2020kfyXGYJ065).
option is to develop oral and spray vaccines.480 The advantage lies
in that it can increase the mucosal immune response and improve
the effectiveness of neutralizing antibodies; low-temperature AUTHOR CONTRIBUTIONS
storage is no longer required, and the transportation problem is Q.N. and D.W. contributed equally to this paper as co-first authors. Q.N., X.L. and M.H.
solved, thereby facilitating use and promotion. A phase I clinical contributed equally to this paper as co-corresponding authors. D.W., X.W., D.X., T.C.,
study481 showed that nebulization of one dose of the spray type G.C., H.W., M.W., L.Z., J.H., T.L., K.M. and M.H. contributed to literature search, and
vaccine Ad5-nCoV required only 1/5 of the dose for intramuscular writing of the manuscript. All authors have read and approved the article.
injection, and nebulization of two doses of Ad5-nCoV produced
antibody and cellular immune responses comparable to that of a
single dose of intramuscular injection of this vaccine. Moreover, ADDITIONAL INFORMATION
high levels of neutralizing antibodies can be produced by booster Competing interests: The authors declare no competing interests.
immunization using nebulization after intramuscular injection.
With the emergence of the delta variant, the third dose of
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