key: cord-0972881-3jpbizga
authors: Zhao, Wenbin; Li, Hanmeng; Li, Jianghua; Xu, Bin; Xu, Jian
title: The mechanism of multiple organ dysfunction syndrome in patients with COVID‐19
date: 2022-02-08
journal: J Med Virol
DOI: 10.1002/jmv.27627
sha: 34cb00f4caf2e48a967ccbbaf59e8c38e236b34e
doc_id: 972881
cord_uid: 3jpbizga

In late 2019, an outbreak of coronavirus disease 2019 (COVID‐19) arose, caused by severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2). This disease rapidly became a public health event of international concern. In addition to the most typical symptoms of dyspnea, numerous patients with COVID‐19 exhibited systemic symptoms, such as cardiovascular disease, liver and kidney failure, and disorders in coagulation. At present, clinical data indicates that numerous patients who are critically ill die from multiple organ dysfunction syndromes (MODS). Moreover, the entry of SARS‐CoV‐2 into cells causing severe pathology and progressive organ failure is precisely mediated by the human angiotensin‐converting enzyme 2 protein. This plays a role in maintaining both fluid and electrolyte homeostasis, ensuring the stability of the internal environment. Therefore, the present review aimed to investigate the pathogenesis of MODS caused by SARS‐CoV‐2 infection based on the current clinical data and previous studies.

The coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a public health emergency of international concern since its outbreak in late December 2019, causing mass transmission worldwide. As the mutation of the virus increases, more and more people are at risk of infection. By November 2021, there were over 2.5 billion cumulative confirmed cases of COVID-19 worldwide, including more than 5.16 million deaths.

All humans are susceptible to developing the disease associated with SARS-CoV-2, but the conditions following infection differed between patients. 1 Although there have been a considerable number of asymptomatic infections, numerous patients with COVID-19 exhibited symptoms of fever, dry cough, fatigue, and myalgia, and severely ill patients in particular certain specific populations presented with dyspnea and hypoxemia, which may result in acute respiratory distress syndrome (ARDS). 2 In addition to severe respiratory damage, cardiovascular digestive system, urinary system, and immune system are also greatly affected, affecting the prognosis. Researchers 3 analyzed the clinical characteristics of 41 COVID-19 patients and found that five patients had combined acute myocardial injury, three patients had combined acute kidney injury, and most of them were severe patients. In a statistical study by Chen 4 

An inflammatory cytokine storm occurs when an organism is infected by microorganisms that cause the release of a large number of inflammatory factors, which not only kills the virus, bacteria but also causes permanent damage to normal cells, resulting in damage to various organs. 5 The study 6 found that plasma cytokine levels were higher in COVID-19 patients compared to healthy subjects, while plasma IL-2, IL-7, IL-10, granulocyte colony-stimulating factor and recombinant human interferon-inducible protein-10, MCP-1, macrophage inflammatory protein-1A, and TNF-α levels were incrsased in critically ill patients, compared with non critically ill patients. Moreover, results of a further studiey demonstrated that IL-6 played a unique role in the development of a hyperinflammatory response following SARS-CoV-2 infection, and this could be used as a marker for understanding the severity of the disease and predicting patient prognosis. 7, 8 When SARS-CoV-2 directly infects endothelial cells that highly express angiotensinconverting enzyme 2 (ACE2), thus causing inflammation, IL-6 is released to increase vascular permeability and promote the release of pro-inflammatory factors in the endothelial cells themselves, thereby enhancing the release of cytokine. 9 The release of a large number of inflammatory factors eventually evolves into an uncontrolled systemic inflammatory cytokine storm that damages various organs leading to MODS.

Oxidative stress is a phenomenon caused by the loss of regulation of the production and accumulation of reactive oxygen species (ROS) in cells and tissues and the inhibition of the activity of endogenous antioxidant system. 10 15 The receptor-binding domain of the viral spike proteins and ACE2 has several cysteine residues.

Molecular dynamic simulations showed that the binding affinity was significantly impaired when all the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were reduced to thiol groups. 16 GSH-peroxidase is a key antioxidant enzyme that converts peroxides and hydroxyl radicals into nontoxic forms by the oxidation of reduced GSH into GSH disulfide, which is then reduced to GSH by GR. 17 Under oxidative stress, the lack of a reducing environment would significantly favor viral protein binding to cell surface ACE2.

Therefore, it is speculated that SARS-CoV-2 may cause ACE2expressing cells with GSH depletion, thus leading to oxidative stress.

This may mean that the histocyte is more susceptible to SARS-CoV-2 infection and ultimately causing systemic multiple organ damage. . 22 In addition, ACE2 can also directly degrades AngII to Ang

(1−7). 23 

Results of previous studies have suggested that high activity of the RAAS system in the heart and the production of cardiomyocyte AngII accelerate the progression of heart failure. Yamamoto 33 7) can counteract the effects of AngII to some extent. These findings may imply that when SARS-CoV-2 is infected with ACE2, levels in the cardiac system may consequently decrease, and symptoms such as heart failure may occur in critically ill patients as well.

Previous research indicated that patients with COVID-19 exhibit a 14.8%−53% probability of developing concurrent liver injury, with abnormal serum ALT/AST levels and mildly elevated bilirubin levels. 4, 40 In severe cases, the albumin level decreased to 26.3−30.9 g/L, and the proportion of liver injury was significantly higher in patients with severe disease than in those with mild disease. 40 Liver injury caused by SARS-CoV-2 through multiple pathways mainly includes moderate steatosis, lobular and portal inflammation, apoptosis, and bile duct proliferation. 41 The expression of ACE2 in hepatic duct cells is much higher than that in hepatocytes, so the liver damage caused by 

Previous studies have demobnstrated that the prevalance of COVID-19 is increased in patients with underlying diseases such as chronic obstructive pulmonary disease, coronary heart disease, liver and kidney failure, hypertension, diabetes, and cerebrovascular disease, and so forth. 49 downregulation during viral infections. 48 As numerous underlying diseases afflicting the elderly may be more complex and severe, this age group may be affected the most. Studies reported "inflameaging," a chronic mild inflammation in aging that is associated with elevated systemic levels of pro-inflammatory cytokines which may promote underlying diseases. 51 It is speculated that "inflame-aging" caused a cytokine storm in elderly patients with COVID-19, by altering the expression of ACE2 receptor, producing excessive ROS, aging adipocyte activity, altering the levels of autophagy and mitochondrial autophagy, immune aging, and reducing vitamin D (VD). 52 This is precisely verified by the age-related ACE2 dysregulation. 53 This may also explain why elderly people with these underlying diseases exhibited a high rate of COVID-19 infection (31.2%). 54 Most of the critically ill patients in the ICU are also elderly, 55 and acutely ill patients progress to ARDS, sepsis, shock, and multi-organ dysfunction, and even failure within a week. Moreover, previous that described the pathology and the molecular changes in patients with COVID-19 suggested that immunosenescence is also a major driver of high mortality in elderly patients, which hampers pathogen recognition, alert signaling, and clearance. 56 The main manifestations of immune aging are thymus atrophy resulting in reduced T cell output, decreased natural killer cell activity, ineffective pathogen recognition, and macrophage activation. 57 These age-related changes are thought to be due to pathogenic, genetic, and lifestyle factors that affect the cells' epigenetic status and the diversity of immune cells. 58 These factors indicated that both aging and numerous diseases may exacerbate the impact of SARS-COV-2 in the elderly and may eventually lead to MODS.

Results of previous studies have demonstrated that COVID-19 and its severity is associated with overweight and obesity. Notably, obese patients frequently suffer from cardiovascular dysfunction, hypertension, type 2 diabetes, and other fundamental diseases. 59 Therefore, obesity may be an important risk factor for the development of severe COVID-19. In patients who are overweight or obese, macronutrient excess in the adipose tissues stimulates adipocytes to release TNF-α, IL-6, and other pro-inflammatory mediators and to reduce the production of the anti-inflammatory adiponectin, thus predisposing to a proinflammatory state and oxidative stress. 60 The lack of cardiovascular and anti-inflammatory protective factors of the ACE2/ang(1−7)/Masr axis triggered a cytokine storm due to the physiological conditions of the adipose tissue and viral induction. Results of aprevious study demonstrated that both SARS-CoV-2 infection and obesity appear to share some common metabolic and inflammatory response pathways. 61 In Germany, patients with ARDS were more commonly overweight or obese (83%) versus those with normal body mass index (BMI) (42%). 62 In China, patients with overweight/obesity were more likely to be hospitalized longer than those with normal BMI. 63 

In conclusion, the severity of COVID-19 may be impacted by multisystem failure, which includes underlying disease and ACE2 expression in humans ( Figure 2 ). We also need to consider that the current rate of SARS-CoV-2 variation is rapid, with implications for both infection and 

The author declares that there are no conflict of interests.

Jian Xu and Hanmeng Li designed the study and prepared the outline.

Hanmeng Li performed literature review research and prepared the first draft. Wenbin Zhao and Hanmeng Li cooperated in drafting and revising the sentences. All authors contributed to revising the manuscript. All authors read and signed the paper manuscript.

This is a review article; data openly available in a public repository that issues datasets with DOIs. The data that support the findings of this study are openly available in PubMed at doi:10.1152/physiolgenomics.

F I G U R E 2 Angiotensin converting enzyme 2 (ACE2)-mediated injury of different organs. The spike protein of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) can bind to the ACE2 receptor, mediating virus entry into host cells. The balance of angiotensin-converting enzyme (ACE)/ACE2 is disrupted by the action of the virus, promoting the development of inflammation and fibrosis. These intensify the attack of the virus, leading to organ damage including the lungs, heart, liver, and kidneys. AngI, angiotensinI; AngII, angiotensinII; Ang (1−7), angiotensin (1−7); Ang (1−9), angiotensin (1−9); RAAS, renin−angiotensin−aldosterone system

The COVID-19 pandemic: a global health crisis

Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19)

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Cytokine storm and sepsis disease pathogenesis

Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients

An inflammatory cytokine signature predicts COVID-19 severity and survival

Interleukin-6 is a biomarker for the development of fatal severe acute respiratory syndrome coronavirus 2 pneumonia

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

Oxidative stress: harms and benefits for human health

Mitochondrial dysfunction and oxidative stress in aging and cancer

Pathomechanismen des Organversagens. Zelluläre Sauerstoffverwertungsstörung im Rahmen der Sepsis

Contribution of oxidative stress in the mechanisms of postoperative complications and multiple organ dysfunction syndrome

Clinical features of patients infected with the 2019 novel coronavirus (COVID-19

Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in COVID-19 patients

Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19

Oxidative stress, aging, and diseases

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Angiotensinconverting enzyme 2 (ACE2) in disease pathogenesis

The renin-angiotensin-aldosterone system and its suppression

COVID-19' Working Group of the French Society of Pharmacology, Therapeutics. Renin-angiotensin-aldosterone system and COVID-19 infection

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

Comprehensive structural and molecular comparison of spike proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and their interactions with ACE2

Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: revised Ms SBMB 2020_166

Pathogenesis of acute respiratory distress syndrome

Imbalance between pulmonary angiotensin-converting enzyme and angiotensinconverting enzyme 2 activity in acute respiratory distress syndrome

Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19)

Manipulation of ACE2 expression in COVID-19

Deletion of angiotensinconverting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II

Myocardial infarction increases ACE2 expression in rat and humans

Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases

Angiotensin-converting enzyme 2 is an essential regulator of heart function

Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia

Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia

Angiotensinconverting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Pathophysiological mechanisms of liver injury in COVID-19

A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

COVID-19 and the liver

ACE2 alterations in kidney disease

ACE2 Deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes

Loss of angiotensinconverting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis

Covid-19 and kidney injury: pathophysiology and molecular mechanisms

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study

An update on Inflamm-aging: mechanisms, prevention, and treatment

The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging

The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) -China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

COVID-19 and the elderly: insights into pathogenesis and clinical decision-making

Immunosenescence: a key player in cancer development

Why does COVID-19 disproportionately affect older people? Aging

Insulin resistance in obesity: an overview of fundamental alterations

Obesity and inflammation: the linking mechanism and the complications

SARS-CoV-2 infection and obesity: common inflammatory and metabolic aspects

The characteristics of 50 hospitalized COVID-19 patients with and without ARDS

Clinical epidemiological analyses of overweight/obesity and abnormal liver function contributing to prolonged hospitalization in patients infected with COVID-19

Obesity and the risk of heart failure

Obesity and kidney disease

The mechanism of multiple organ dysfunction syndrome in patients with COVID-19