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. 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