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Review
. 2022 Feb 23;7(1):57.
doi: 10.1038/s41392-022-00907-1.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

Qin Ning #  1 , Di Wu #  2 , Xiaojing Wang  2 , Dong Xi  2 , Tao Chen  2 , Guang Chen  2 , Hongwu Wang  2 , Huiling Lu  3 , Ming Wang  2 , Lin Zhu  2 , Junjian Hu  2 , Tingting Liu  2 , Ke Ma  2 , Meifang Han  4 , Xiaoping Luo  5
Affiliations
Review

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

Qin Ning et al. Signal Transduct Target Ther. .

Abstract

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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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
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
Fig. 2
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
Fig. 3
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
Fig. 4
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
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