Severe Acute Respiratory Syndrome-Associated Coronavirus 2 Infection and Organ Dysfunction in the ICU: Opportunities for Translational Research

Abstract

Objectives: Since the beginning of the coronavirus disease 2019 pandemic, hundreds of thousands of patients have been treated in ICUs across the globe. The severe acute respiratory syndrome-associated coronavirus 2 virus enters cells via the angiotensin-converting enzyme 2 receptor and activates several distinct inflammatory pathways, resulting in hematologic abnormalities and dysfunction in respiratory, cardiac, gastrointestinal renal, endocrine, dermatologic, and neurologic systems. This review summarizes the current state of research in coronavirus disease 2019 pathophysiology within the context of potential organ-based disease mechanisms and opportunities for translational research.

Data sources: Investigators from the Research Section of the Society of Critical Care Medicine were selected based on expertise in specific organ systems and research focus. Data were obtained from searches conducted in Medline via the PubMed portal, Directory of Open Access Journals, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, and Web of Science from an initial search from December 2019 to October 15, 2020, with a revised search to February 3, 2021. The medRxiv, Research Square, and clinical trial registries preprint servers also were searched to limit publication bias.

Study selection: Content experts selected studies that included mechanism-based relevance to the severe acute respiratory syndrome-associated coronavirus 2 virus or coronavirus disease 2019 disease.

Data extraction: Not applicable.

Data synthesis: Not applicable.

Conclusions: Efforts to improve the care of critically ill coronavirus disease 2019 patients should be centered on understanding how severe acute respiratory syndrome-associated coronavirus 2 infection affects organ function. This review articulates specific targets for further research.

Keywords: angiotensin-converting enzyme 2 receptor; coronavirus disease 2019; critical illness; pandemic; severe acute respiratory syndrome–associated coronavirus 2.

Figure 1.

Tissues expressing angiotensin-2 receptor (angiotensin-converting enzyme [ACE] 2) and related COVID-19 symptoms. ARDS = acute respiratory distress syndrome, GI = gastrointestinal.

Figure 2.

Proposed host immune responses secondary to severe acute respiratory syndrome–associated coronavirus 2 (SARS-CoV-2) infection. Although several host immune responses are activated by SARS-CoV-2 infection, all mechanisms appear to activate janus kinase/signal transducer and activator of transcription (JAK/STAT), p38 mitogen-activated protein kinase (MAPK), and/or nuclear factor–κB (NF-κB) pathways. This leads to release of proinflammatory cytokines (tumor necrosis factor [TNF] α, interleukin [IL]–6, IL-1β) and chemokines (C-X-C motif ligand [CXCL] 1, CXCL10), and immune cell recruitment. Current evidence implicates three potential mechanisms. 1) Direct viral infection induces host cell death and the release of multiple damage/danger-associated molecular patterns (DAMPs), which increase proinflammatory cytokine and chemokine secretion. 2) Activation of NLRP3 inflammasome and pyroptosis triggers a cascade of proinflammatory cytokines such as IL-1β. 3) Viral infection dysregulates the renin-angiotensin system (RAS) by down-regulating the ACE2 receptor, which leads to decreased angiotensin (Ang) 1–7, increased AngII, and subsequent AngII-receptor type 1 (AT1R) activation. This ultimately activates JAK/STAT, p38 mitogen-activated protein kinase (MAPK), and NF-κB pathways and induces a proinflammatory state. CRP = C-reactive protein, NK = natural killer, NLRP3 = nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing-3.

Figure 3.

Proposed mechanism for severe acute respiratory syndrome–associated coronavirus 2 (SARS-CoV-2)–induced coagulopathy and thrombotic microangiopathy. The SARS-CoV-2 virus directly injures cells/tissues and induces local and systemic inflammatory cascades, which induce the release of cytokines and damage/danger-associated molecular patterns (DAMPs) and activate three interconnected procoagulation pathways. Coagulation factor XII is activated during the contact phase of coagulation, thereby activating complement, thrombin, and a positive feedback loop for inflammation. Inflammation damages endothelial cells, further activating thrombin and polymorphonucleated cells (PMNs) via tumor necrosis factors (TNFs) and tissue factor (TF). Cytokines and DAMPs also directly activate PMNs, which initiates the development of NETosis and activates platelets. Activated platelets, neutrophil extracellular traps (NETs), and fibrin combine to form clinically significant clots in patients with coronavirus disease 2019 infections. CLOT = clot formation, EC = endothelial cell, FXII = factor XII, FXIIa = activated factor XII, HMWK = high molecular weight kininogen, NETosis = neutrophil extracellular traps, PK = prekallikrein, Plt = platelet.