key: cord-0988358-mzjrqf88
authors: Dong, Mengzhen; Zhang, Jie; Ma, Xuefeng; Tan, Jie; Chen, Lizhen; Liu, Shousheng; Xin, Yongning; Zhuang, Likun
title: ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19
date: 2020-08-24
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2020.110678
sha: d1c638e9662f782fff1e24236033d6fd243f041e
doc_id: 988358
cord_uid: mzjrqf88

At the end of 2019, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Currently, it is breaking out globally and posing a serious threat to public health. The typically clinical characteristics of COVID-19 patients were fever and respiratory symptoms, and a proportion of patients were accompanied by extrapulmonary symptoms including cardiac injury, kidney injury, liver injury, digestive tract injury, and neurological symptoms. Angiotensin converting enzyme 2 (ACE2) has been proven to be a major receptor for SARS-CoV-2 and could mediate virus entry into cells. And transmembrane protease serine 2 (TMPRSS2) could cleave the spike (S) protein of SARS-CoV-2, which facilitates the fusion of SARS-CoV-2 and cellular membranes. The mRNA expressions of both ACE2 and TMPRSS2 were observed in the heart, digestive tract, liver, kidney, brain and other organs. SARS-CoV-2 may have a capacity to infect extrapulmonary organs due to the expressions of ACE2 and TMPRSS2 in the cells and tissues of these organs. It seems that there is a potential involvement of ACE2 and TMPRSS2 expressions in the virus infection of extrapulmonary organs and the manifestation of symptoms related to these organs in patients with COVID-19. Here, we revealed the expressions of ACE2 and TMPRSS2 in extrapulmonary organs, and we also summarized the clinical manifestation and the management of extrapulmonary complications in patients with COVID-19.

Since the late 2019, a novel coronavirus, officially named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogen to cause pneumonia [1, 2] . As a member of the Betacoronavirus genus, SARS-CoV-2 has 82% genomic nucleotides identity with human severe acute respiratory syndrome coronavirus (SARS-CoV), and shares 76.47% amino acid sequence identity with SARS-CoV [3, 4] . The World Health Organization (WHO) named the disease caused by SARS-CoV-2 as coronavirus disease 2019 . Until April 20, 2020, the virus has swept through 213 countries, more than 2.2 million cases with have been confirmed and more than 150 000 cases died, which has been posing significant threats to public health. SARS-CoV-2 can cause respiratory diseases, and may lead to acute respiratory distress syndrome (ARDS), multiple organ failure, and J o u r n a l P r e -p r o o f even death in severe cases [1, 5] . In addition to typical symptoms such as cough and fever, some patients developed the symptoms in multiple systems such as cardiovascular system, digestive system and nervous system in the early stages of COVID-19, which brings more challenges to the timely diagnosis of patients [6, 7] .

Angiotensin converting enzyme 2 (ACE2) as a metalloproteinase is a carboxyterminal dipeptidyl peptidase [8] . The primary physiological role of ACE2 is involved in the regulation of vasoconstriction and blood pressure [9] [10] [11] . Transmembrane protease serine type2 (TMPRSS2), belonging to the type II transmembrane serine protease family, could cleave the coronavirus spike (S) protein [10, [12] [13] [14] [15] [16] . It was demonstrated that ACE2 and TMPRSS2 were crucial for the entry of SARS-CoV and SARS-CoV-2 into the host cells [11, 17, 18] . Cell entry of SARS-CoV-2 depends on binding of the S protein to the specific cellular receptor and S protein priming by host cell proteases.

As shown in Figure 1 , each S protein of SARS-CoV-2 consists of two subunits: a globular S1 domain at the N-terminal region, and the membrane-proximal S2 domain.

SARS-CoV-2 utilizes receptor-binding domain within the S1 domain to bind to the cellular receptor ACE2, which could trigger the effects of TMPRSS2 on the cleavage of protein S at the S1 and S2 sites, and priming cell membrane fusion for viral entry [17, 19, 20] . As receptors and mediators of virus entry are important for determining viral host and organ, the route of SARS-CoV-2 infection and the infected organ may depend on the expression and distribution of ACE2 and TMPRSS2 [21, 22] . Studies have shown that ACE2 and TMPRSS2 are expressed not only in lung tissues, but also in extrapulmonary organs including heart, kidney, liver, colon, esophagus, brain, gallbladder and testis, suggesting that SARS-CoV-2 may also affect extrapulmonary organs [23] [24] [25] [26] [27] .

In this review, the distributions of ACE2 and TMPRSS2 in extrapulmonary organs, and the characteristics and clinical managements of extrapulmonary organ injury caused by SARS-CoV-2 were summarized. We believe that this will be important in understanding on the infection of extrapulmonary organs in patients with COVID-19.

Studying the viral susceptibility of extrapulmonary organs is important for a deeper understanding for the pathogenesis of SARS-CoV-2 infection. Studies have shown that ACE2 and TMPRSS2 were expressed not only in the cells and tissues of lung, but also in extrapulmonary organs [25, [28] [29] [30] [31] [32] [33] (Figure 2 ). In this section, the expression levels of ACE2 and TMPRSS2 in extrapulmonary organs including heart, kidney, liver, digestive tract, brain and other organs were reviewed.

The mRNA expressions of ACE2 in different human organs were analyzed and the results showed that ACE2 was expressed in the heart [27, 34] . Furthermore, Chen et al analyzed the feature of ACE2 expressions among cardiac cell types and found that ACE2 was specifically expressed in pericyte [35] . Moreover, RNA sequencing from 40 patients with failing hearts and 15 normal donors revealed that myocardial ACE2 expressions were significantly increased in patients with heart failure, which was further validated at the protein level by proteomics profiling from 8 heart failure and 8 normal donors [35] . Another study also showed that the expression of ACE2 in heart tissues of patients with underlying heart disease was higher than that in normal heart tissues [36] . These two studies suggested that the expression of ACE2 in heart tissue of patients with underlying heart disease was higher than that in normal heart tissue. Guo et al analyzed the mRNA expression of TMPRSS2 from the Genotype-Tissue Expression (GTEx) database, and the results showed that TMPRSS2 is also expressed in the heart [29] . By single-cell RNA sequencing (scRNA-Seq) to profile the gene expression landscapes of 4,000 cardiac cells from human embryos, Qi et al revealed that the cardiomyocytes from the heart contain 6% ACE2-expressed cells and 0.8% TMPRSS2-expressed cells, and the cardiovascular progenitor cells contain 12.5% ACE2-expressed cells and 0.4% TMPRSS2-expressed cells, respectively [27] . These data showed that both ACE2 and TMPRSS2 were expressed in the heart.

Expression analysis from the GTEx database showed that kidney displayed the fifth high expression of ACE2 [35] . To investigate the expression of ACE2 in kidney, Lin et al analyzed the public single-cell transcriptome dataset of normal kidneys from J o u r n a l P r e -p r o o f healthy donors, the results showed that the ACE2 was distributed across multiple cell types and was mostly enriched in proximal tubule cells [32] . Fan et al confirmed the specific ACE2 expression in tubular cells from the Gene Expression Omnibus (GEO) dataset, while it was not observed in immune cells and glomerular parietal epithelial cells. RNA and protein expression data of ACE2 in different human tissues and cancer cell lines were obtained from three online datasets including the Cancer Cell Line Encyclopedia (CCLE), GTEx database, and the Human Protein Atlas dataset, and the results indicated that both mRNA and protein expression levels of ACE2 were relatively high in kidney cells especially in renal tubular cells [37] . Meanwhile, Suryawanshi et al analyzed the data of kidney tissues in scRNA-Seq datasets, and found that either proximal tubular cells or tubular progenitor cells in the kidney co-expressed ACE2 and TMPRSS2 [38] . The data of the scRNA-seq from GEO dataset (GSE134355) showed that ACE2 and TMPRSS2 expression levels were high in nephron epithelial cells, epithelial cells, endothelial cells, and mesangial cells of the kidney [27] . Recently, Pan et al also found that the TMPRSS2 gene was co-expressed with ACE2 in kidney podocytes [31] . These data showed that both ACE2 and TMPRSS2 were highly expressed in tissues and cells of kidney.

Chai et al analyzed the scRNA-seq data from GEO database (GSE124395) to evaluate ACE2 gene expression in liver, the results showed that ACE2 was highly expressed in cholangiocytes, which level was about 20 times higher than that in hepatocytes [39] .

The GTEx database also showed that both ACE2 and TMPRSS2 were expressed in the liver [29] . Zhou et al identified that TMPRSS2 is highly expressed in hepatocytes from Human Cell Atlas database [26] . Recently, Wen et al indicated that ACE2 and TMPRSS2 are specifically co-expression in TROP2 + liver progenitors of human liver tissue using scRNA sequencing [40] . These data indicate that ACE2 expression is expressed at a relative low level in hepatocytes and mainly located in cholangiocytes, while TMPRSS2 is expressed in hepatocytes.

A previous study showed that ACE2 could be found in the upper esophagus, and it J o u r n a l P r e -p r o o f could be detected in stratified epithelial cells and absorptive enterocytes of the ileum and colon [41] . Quantitative mRNA expression profiling of ACE2 across 72 human tissues by Harmer et al showed that ACE2 was expressed at a high level in gastrointestinal tissues [42] . Zhang et al analyzed 4 datasets with single-cell transcriptomes of esophagus, gastric, ileum, colon and lung, and the data showed that ACE2 was not only highly expressed in the type II alveolar cells (AT2) of lung but also in the stratified epithelial cells, ileum absorptive enterocytes cells and colon enterocytes [33] . Similarly, the immunofluorescent staining of esophagus, stomach, duodenum and rectum showed that ACE2 was stained mainly in the cytoplasm of gastrointestinal epithelial cells [43] . Besides, the scRNA-seq data showed that ACE2 was significantly elevated in the proximal and distal enterocytes [44] . Guo et al suggested that TMPRSS2 was highly expressed in almost all organs of the digestive tract including colon, stomach, small intestine and esophagus [29] . Using published scRNA-seq data and seven in-house normal colon samples, Lee et al reported that the co-expressions of ACE2 and TMPRSS2 transcripts were mainly observed in the small intestine and colon [45] . The highest expressions of TMPRSS2 and ACE2 were found in enterocytes among the intestinal cell types [26] .These data showed that TMPRSS2 and AEC2 are highly expressed in the digestive tract.

Analysis using the GTEx database showed that both TMPRSS2 and ACE2 are expressed at relatively low levels in the brain cortex [29] . Chen et al found that ACE2 was relatively highly expressed in some important brain areas such as the substantia nigra and brain ventricles using seven brain transcriptome databases [24] . ACE2 was expressed at high level in the piriform cortex of human brain, and its expression could also be detected in many neurons including both excitatory and inhibitory neurons, and some non-neuron cells including astrocytes and oligodendrocytes in human middle temporal gyrus and posterior cingulate cortex [24] . Qi et al analyzed the scRNA-seq data of substantia nigra and cortex of brain from GEO database, the results showed that both ACE2 and TMPRSS2 were expressed in the oligodendrocyte precursor cells and the astrocytes of the substantia nigra and cortex [27] . There are J o u r n a l P r e -p r o o f limited reports on the expressions of ACE2 and TMPRSS2 in peripheral nervous system. Brann et al analyzed the ACE2 and TMPRSS2 expression in different cell type from human scRNA-seq dataset (GSE139522), and found that neither olfactory sensory neurons nor olfactory bulb neurons expressed these two genes, while ACE2 and TMPRSS2 were expressed in the non-neuronal cells including the sustentacular cells and olfactory bulb pericytes [46] . These data showed that ACE2 and TMPRSS2 could also be co-expressed in the nervous system.

Moreover, ACE2 and TMPRSS2 were also reported to be co-expressed in some other organs [27, 29, 37, 47] . It has been revealed that both ACE2 and TMPRSS2 are expressed in testis by scRNA sequencing and expression profile analysis, indicating that testicular cells might be the potential targets of SARS-CoV-2. Another report revealed that multiple kinds of cells in the nose, including nasal brushing epithelial cells, nasal turbinate epithelial cells, and nasal airway epithelial cells, contained ACE2-expressed and TMPRSS2-expressed cell clusters [27] . Moreover, ACE2 and TMPRSS2 were also expressed in pancreas, breast, prostate and thyroid [29, 37, 47] , and these organs might also be the targets of SARS-Cov-2.

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Recently, autopsy analysis by Fox et al revealed that the histopathology of the heart was consistent with the typical pattern of viral myocarditis [48] . SARS-CoV-2 RNA was detected in the cardiac tissues of the patients with COVID-19 [49] . These data suggested that SARS-CoV-2 may directly infect heart.

The epidemiology of COVID-19 reported that cardiac injury was one of the most severe organ damages [5, 50, 51] . The clinical manifestations of cardiac injury in COVID-19 patients are complex and could present with heart failure, arrhythmias or acute myocardial infarction (AMI) [5, 52, 53] . Inciardi et al reported the first case who had the symptom of heart failure at first and later the patient was positive for SARS-CoV-2 using nucleic acid test [52] . Cardiac injury is a common symptom in patients with COVID-19. Shi et al reported that 19 .7% (82/416) patients with COVID-19 had cardiac injury [54] . Moreover, there were 5 (12%) patients with acute cardiac injury in a cohort including 41 COVID-19 patients, and 4 (31%) of 13 patients with acute cardiac injury in the intensive care unit (ICU) [50] . Furthermore, a study by Wang et al showed that there were 10 (7.2%) patients with acute cardiac injury and 23 (16.7%) patients presented with arrhythmia of 138 COVID-19 patients, while acute cardiac injury was observed in 8 (22.2%) of 36 patients with CIVID-19 in the ICU [5] .

These cases suggested that SARS-CoV-2 may cause serious heart damage, which should be widespreadly concerned. Furthermore, acute cardiac injury is more prevalent in severe cases with COVID-19 [5, 50, [55] [56] [57] [58] (Table 1) . And it has been reported that COVID-19 patients with cardiac injury had higher mortality than those without cardiac injury [54] .

In this review, we also summarized the possible relationship between basic heart disease and further cardiac injury [54, [59] [60] [61] [62] (Table 2 had basic heart disease including coronary heart disease and chronic heart failure. And J o u r n a l P r e -p r o o f only 25 (7.5%) patients with basic heart disease of 334 COVID-19 patients without cardiac injury [54] . Similarly, Liu et al suggested that 5 (33.3%) patients with basic heart disease in 15 COVID-19 patients had cardiac injury compared with 10 (3.7%) patients with basic cardiovascular diseases of 276 COVID-19 patients without cardiac injury [59] . Other studies also indicated that the patients with basic cardiovascular disease are more likely to present heat injury in COVID-19 patients [60, 61] . In view of the points above, COVID-19 patients with underlying cardiac conditions seem to have higher rates of cardiac injury.

Recently, autopsy analysis on six COVID-19 patients showed that varying degrees of acute tubular necrosis were observed in all the renal specimens. Nucleoprotein (NP) antigens and NP positive inclusion body of SARS-CoV-2 could be seen in kidney tissues from all the samples. Moreover, virus-like particles were seen in kidney tissues by transmission electronic microscope (TEM) [63] . Su et al analyzed kidney abnormalities in 26 autopsies of patients with COVID-19 and found that diffuse proximal tubular damage with the loss of brush border were observed. Further investigation showed that diffuse necrosis can be seen under the light microscope and electron microscopic examination also showed the clusters of coronavirus particles with distinctive spikes in the tubular epithelium and podocytes [64] . It was reported that both NP antigens and RNA of SARS-CoV-2 were detected in urine of COVID-19 patients [65, 66] . These data coincide with the finding of the SARS-CoV-2 invasion in kidney. Collectively, SARS-CoV-2 could directly infect human renal tubules and lead to kidney damage.

Recent studies have shown that the incidence of acute kidney injury(AKI) in COVID-19 patients ranged from 0.5%-28.5%, and higher frequency of renal function damage with elevated blood urea nitrogen (BUN) or serum creatinine (Scr) was observed in COVID-19 patients [1, 5, 50, 51, 53, [55] [56] [57] [67] [68] [69] [70] [71] [72] [73] (Table 3) for urinary protein and 57 (44.2%) patients were positive for hematuria [55] . Another study also showed that about 14% patients with COVID-19 had abnormal renal function [67] . Moreover, COVID-19 patients with more severe disease progression have higher rates of AKI. Huang and colleagues reported that 3 (23.1%) of 13 patients with AKI in the ICU were observed, and none of the 28 patients who did not require care in the ICU suffered AKI [50] . Xu et al found that the fatality rate was obviously higher in COVID-19 patients with AKI than those without renal injury [53] .

Furthermore, in another study investigating 193 patients with COVID-19 at hospital admission, more severe patients had higher rates of AKI, and the Cox regression analysis also suggested that COVID-19 patients who developed AKI had a significantly higher mortality risk [55] . Therefore, AKI is more prevalent in severe cases with COVID-19.

An autopsy report of a 50-year-old patient with COVID-19 showed moderate microvesicular steatosis and mild lobular activity in liver tissues [74] . Moreover, Zhao et al used human liver ductal organoids as a tool to investigate the SARS-CoV-2 infection and the tissue damage induced by SARS-CoV-2 ex vivo, and the results showed that the expression of SARS-CoV-2 NP was easily detected in the patchy areas of the hepatic duct, indicating that liver ductal organoids were susceptible to SARS-CoV-2 infection [75] . In addition, SARS-CoV-2 infection could disrupt the barrier and bile acid transporting functions of cholangiocytes, which indicated that SARS-CoV-2 might directly induce cholangiocyte injury and consequently bile acid accumulation [75] . In view of the points above, liver damage in the COVID-19 patients might be directly caused by the viral infection.

Abnormal liver functions were frequently reported in COVID-19 patients [50, 76, 77] .

Epidemiologic studies showed that almost half of the patients had differing degrees of liver damage [1, 5, 50, 51, 53, [55] [56] [57] [69] [70] [71] [72] (Table 4) [1] .Similarly, a nationwide study involving 1099 patients with COVID-19 in China showed that more than 20% of patients had elevated ALT and AST, and 10.5% of patients had elevated TBIL [51] . It was revealed that the levels of direct bilirubin, indirect bilirubin, ALT, alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) were significantly higher in males than that in females with COVID-19, and multivariate logistic regression analysis showed that male was an important independent risk factor for predicting acute liver injury (ALI) in COVID-19 patients [76, 78] . These data indicated that male patients with COVID-19 may be more susceptible to liver injury. Furthermore, multiple studies found that AST, ALT, and TBIL were significantly higher in patients treated in the ICU than that in non-ICU patients [5, 50] . Li et al suggested that among the patients with abnormal liver function, moderate and severe types of patients were more likely to have liver injury (58.8% and 66.7%, respectively) [79] . Fu et al analyzed the relationship between ALI and mortality risk in 355 COVID-19 patients, and the results showed that ALI is more common in the critically ill patients and ALI at the early stage increased death risk of COVID-19 patients [78, 80] . Together, abnormal liver functions might be associated with the severity of patients with COVID-19.

Epithelial cells of the esophagus, stomach, duodenum and rectum in one COVID-19 patient tested positive for SARS-CoV-2 RNA, and the staining of viral NP was also visualized in the cytoplasm of epithelial cells in stomach, duodenum and rectum [43] .

Moreover, minimally invasive autopsies were performed on three patients died of COVID-19, and the results showed that some epithelial cells of the gastrointestinal mucosa were degenerated, necrotic and detached [81] . These studies strongly supported that SARS-CoV-2 may directly infect the epithelial cells of digestive tract.

Multiple studies have identified that the SARS-CoV-2 RNA was detected in anal swabs [82] , rectal swabs [83] , and stool specimens [43, 84] of COVID-19 patients. It has been demonstrated that SARS-CoV-2 RNA could be detected in feces from more than half of COVID-19 patients [43, 85] . In another study, Xing et al reported that SARS-CoV-2 RNA was detected in the feces of three pediatric cases with COVID-19 J o u r n a l P r e -p r o o f in Qingdao, China, and the persistence of SARS-CoV-2 in the digestive tract lasted for 6-30 days [84] . The possibility of fecal-oral transmission of SARS-CoV-2 infection needs to be taken into account. Furthermore, as shown in Table 5 , long duration of SARS-CoV-2 detection in digestive tract by RT-PCR has been reported, and viral RNA remained detectable in the digestive tract for 2-20 days after nucleic acid turned negative in respiratory samples [43, [82] [83] [84] [85] [86] [87] [88] [89] [90] . The studies suggested that SARS-CoV-2 could be detected from respiratory tract specimens during the early period to digestive tract specimens during the late period, and viral nucleic acid tests in both the respiratory and digestive tract are necessary to confirm the complete clearance of virus.

Some COVID-19 patients presented gastrointestinal symptoms such as diarrhea, nausea, vomiting and abdominal pain [91] . Holshue et al reported the first case of COVID-19 patient in the USA, which had nausea and vomiting before admission [86] .

Multiple studies found that gastrointestinal symptoms, including diarrhea (2.0%-43.8%), nausea and vomiting (1.0%-20.7%), and abdominal pain (2.2%-19.1%), were common at presentation in COVID-19 patients [1, 5, 6, 43, 50, 51, 55, 56, 58, 70-72, 77, 85, 92-100] (Table 6 ). In a cohort of 212 patients with COVID-19 in Wuhan, China, gastrointestinal symptoms were described in up to 64.5% [93] . Moreover, Sun et al showed that 72 (86.7%) critically ill patients with COVID-19 had gastrointestinal injury (GI) during hospital stay, and the survival curves showed that the mortalities of patients with GI was greater than that of patients without GI [101] . Jin et al also found that the rate of the severe type was markedly higher in COVID-19 patients with GI symptoms than that in those without GI symptoms [94] . These data suggested that GI is one of the common extrapulmonary organ injuries in COVID-19 patients and may be related to the severity of the disease. On the other hand, many studies showed that patients with COVID-19 could present initially with the typical gastrointestinal symptoms, and diarrhoea may even occur earlier than pyrexia or respiratory symptom in some cases with COVID-19 [5] [6] [7] . Luo et al reported that 183 of 1141 COVID-19 cases presented initially only with gastrointestinal symptoms [7] . The COVID-19 patients initially only with gastrointestinal symptoms are more difficult to diagnose J o u r n a l P r e -p r o o f and might be overlooked, which could lead to potentially serious consequences.

Together, digestive tract symptoms (especially diarrhea) are the main complications of COVD-19 patients, which should be noticed during the outbreak of COVID-19.

Transmission electron microscopy of autopsy sections showed the presence of SARS-CoV-2 viral-like particles in frontal lobe brain and neural cell bodies [102] .

Moreover, researchers confirmed the presence of SARS-CoV-2 in cerebrospinal fluid by genome sequencing [103, 104] . The pathological mechanism may be the invasion of SARS-CoV-2 into the nervons system. The viral-like particles in brain capillary endothelium was also observed [102] , which suggested that hematogenous route might act as the pathway for SARS-CoV-2 to the brain. In addition, study using the mouse model have shown that SARS-CoV can lead to neuroinvasion via disruption of the nasal epithelium and subsequent neuronal dissemination [105] , which suggested that coronavirus may use the olfactory nerve to enter the brain.

The symptoms from nervous system of COVID-19 patients, including headache, dizziness, anosmia, and dysgeusia, have been observed in the clinic [1, 5, 50, 51, 55, 70-72, 100, 106-108] (Table 7) . Disturbance of consciousness and seizures can occur as complications in the cases with severe COVID-19 [103] . It was convincing enough that the neurological deficits of patients with COVID-19 could be ongoing if it did not get noticed [106] . It was indicated that SARS-CoV-2 can cause nervous system damage [104] .

The neurological deficits, meningo-encephalitis and acute myelitis in COVID-19 patients have been reported in the USA, Switzerland and China [104, [109] [110] [111] . According to a recent study, 53 out of 214 (24.8%) COVID-19 patients had central nervous system (CNS) symptoms including dizziness, headache, impaired consciousness, ataxia, and epilepsy [106] . Up to 70.3% of patients with COVID-19 have headache, and clinical manifestations of dizziness were found from 6.7% to 16.8% of the patients with COVID-19 [5, 55, 71, 100, 106] . Olfactory and gustatory disorders are prevalent peripheral nervous system (PNS) symptoms in COVID-19 patients. In patients with mild and moderate COVID-19, a high proportion of patients presented olfactory and gustatory dysfunctions, and olfactory dysfunction appeared prior to the other J o u r n a l P r e -p r o o f symptoms in some cases [106-108, 112, 113] . These studies showed that the damage of neurological system may also act as a significant feature of COVID-19.3.6 Indirect

In addition to direct damage caused by the virus, other mechanisms have been hypothesized to be involved in the injury of the extrapulmonary organs in patients with COVID-19. Recent studies demonstrated that a rapid reduction of T lymphocytes was observed in the peripheral blood of COVID-19 patients [74, 114] . Qin et al also found that both helper T cells and suppressor T cells in COVID-19 patients were decreased [115] . The abnormal innate immune responses could promote virus infection and exacerbate extrapulmonary organ injury [116] . Moreover, drugs used in the treatment of COVID-19 may cause the damages of extrapulmonary organs. For example, most patients with COVID-19 showed signs of gastrointestinal and liver damages after being treated with lopinavir-ritonavir [85] . Chloroquine significantly prolonged the QTc interval in patients with COVID-19 [117] . Furthermore, hypoxia or microthromboses might also be the possible causes for extrapulmonary organ injuries in patients with COVID-19 [118] .

Until now, there have not been specific treatments for COVID-19 and its management is mainly based on patient isolation and supportive medical care when it is necessary.

In this review, we also focus on the clinical therapies and management for extrapulmonary organ injury of COVID-19 patients. Venous-venous (V-V) extracorporeal membrane oxygenation should be considered for the COVID-19 patients with the severe pulmonary decompensation and the failure to oxygenate [119] . Kanrenone, furosemide, and bisoprolol may be effective for heart failure in COVID-19 patients [52] . In addition, Wang et al proposed that a potential anti-oxidative therapy could alleviate cardiogenic casualties caused by COVID-19 [120] . A proper dose of Vitamin C, Vitamin E, curcumin and baicalin may ameliorate cardiac injuries of critically ill patients with COVID-19 [120] . However, some drugs used to treat COVID-19, including chloroquine, hydroxychloroquine, azithromycin and lopinavirritonavir, may increase the risk of QT prolongation and ventricular arrhythmias [117, 121] . Guzik and colleagues advocate follow-up for regular assessment of cardiovascular risk in all COVID-19 patients who have survived [122] .

The indicators of kidney damage were associated with high risk of in-hospital death of patients with COVID-19 [67] . For the treatment of patients with COVID-19, there should be prompt screening for risk factors of AKI and the indicators of kidney damage. The use of nephrotoxic drugs should be avoided unless it is absolutely J o u r n a l P r e -p r o o f necessary in the treatment of patients with COVID-19 [123] . Cao et al found that lopinavir
itonavir might reduce AKI in the treatment of COVID-19 patients [124] . Therefore, clinicians should pay attention to kidney damage and the related treatment for patients with COVID-19.

The evaluation of liver function is usually mild during disease progression of COVID-19 and could be recovered without treatment [1] . However, severe liver injury had also been reported in patients with COVID-19 [1, 78] . When severe liver damage occurs, liver protective drugs were usually used for the treatment of patients with COVID-19 [125] . It was reported that glycyrrhizic acid and its derivatives might play important roles in the treatment of liver disease and also have an antiviral activity against SARS-CoV-2 [126, 127] . The artificial liver system (ALS) is one of the effective methods for treating liver failure, and its treatment mechanism is based on the ability of liver cell regeneration [128] . And ALS is vital to reduce the mortality for critical patients with COVID-19 and offers treatment options for COVID-19 patients with severe liver injury [129] .

Clinicians should be alert for gastrointestinal symptoms of COVID-19 patients, especially as they may occur before the onset of pyrexia and respiratory symptoms.

Moreover, there might be fecal-oral transmission for SARS-COV-2 [43, 86] . Therefore, COVID-19 patients need to pay attention to hand hygiene and contact precautions, which could help minimize the risk of exposure and transmission. Diarrhea is the most common symptom of the digestive tract injury of COVID-19 patients [93, 94] .

Adequate fluid rehydration and potassium monitoring should be performed in the treatment of COVID-19 patients with diarrhea [130] . Hashimoto et al suggested that ACE2 expression in the epithelial cells was required for maintaining amino acid homeostasis and the ecology of gut microbiome in intestine [131] . In addition, in a pilot study of 15 patients with COVID-19, Zuo et al found that the fecal microbiome continued to change during hospitalization, and the change in fecal microbiome was associated with the severity of COVID-19 [132] . Therefore, we speculate that J o u r n a l P r e -p r o o f gastrointestinal tract symptoms in COVID-19 patients may have some relationship with the gut microbiota, and the gut microbiota might be a new therapeutic target.

Actually the National Health Commission of China recommended that probiotics can be used to maintain the balance of intestinal microecology and prevent secondary bacterial infection in the treatment of severe patients with COVID-19 [133] . The gastrointestinal symptoms of the patients might be relieved and even completely disappeared after starting antiviral therapy [134] . Camostat is an effective inhibitor of TMPRSS2 and can be used to treat the reflux esophagitis and chronic pancreatitis [135] , and it may be effective in COVID-19 patients with digestive symptoms.

Sudden anosmia needed to be recognized as one of the important symptoms of SARS-COV-2 infection. The median onset of acute anosmia and dysgeusia features was 3.3 days after onset of COVID-19, and most patients had a rapid recovery, which indicated that olfactory dysfunction and dysgeusia may be self-limiting [108] .

Antiepileptic therapy with lacosamide, levetiracetam and phenytoin was used for seizures control in the treatment of COVID-19 patients [136] . SARS-CoV-2 could act as an infective trigger and may lead to a systemic inflammatory response syndrome, and prompt invasive treatment should be adopted to avoid hypoxic neurotoxicity and prevent CNS injuries [136] . In conclusion, clinical physical examination of the nervous system, prompt endotracheal intubation and rapid mechanical respiratory support should be proposed for the COVID-19 patients with neurological symptoms.

There is a potential pathogenicity of SARS-COV-2 to testis, pancreas, breast, prostate and thyroid, and functional changes in these organs should also be monitored in the management of COVID-19 patients [26, 27, 38] . For example, due to the potential pathogenicity of SARS-COV-2 to testicular tissues, the possible testicular damage caused by the virus may exist as a late complication [27, 137] . Therefore, clinicians should take care of the possible occurrence of orchitis. Following-up and evaluation of the reproductive functions should also be done in recovered male patients with COVID-19.

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So far, more than 1 million patients with COVID-19 have been clinically cured and discharged. However, multiple discharged COVID-19 patients were positive for SARS-CoV-2 again [138] . In a cohort form Guangdong, China, 14.5% (38/262) of convalescent patients from COVID-19 were re-detected to be positive for SARS-CoV-2 during their followed-up period [139] . Similarly, the data from Brunei Darussalam showed that 19.8% (21/106) recovered patients were found to be re-positive for SARS-CoV-2 detection [140] . The re-detectable positive patients were confirmed by RT-PCR tests on anal or nasopharyngeal swabs. These studies suggest that a proportion of recovered patients still may be virus carriers.

The SARS-CoV-2 virus could be detected in respiratory specimens, stool, urine, serum, kidney tubules and gastrointestinal epithelium from COVID-19 patients [43, 86, 141, 142] . Moreover, the viral RNA in urine and stool specimens remained positive after throat swabs turned negative, and the viral RNA can persist in feces for up to 30 days [84, 143] . Yao et al detected SARS-CoV-2 virus by digital PCR on tissue sections from the lung, liver, heart, intestine and skin of a COVID-19 patient who was ready-for-discharge but died of cardiac arrest. The patient was positive for SARS-CoV-2 in the cells and tissues of lung, and the results highlight the remaining of SARS-CoV-2 in the lung of discharged COVID-19 patient [144] . In addition, Shastri et al demonstrated for the first time that male subjects have delayed viral clearance of SARS-CoV-2, and suggested that testicular viral reservoirs may play an important role in viral persistence in males [145] . It seemed that SARS-CoV-2 may be stored in the lung or extrapulmonary organs, which may be the reason for the virus positive again in discharged patients.

J o u r n a l P r e -p r o o f

The emergence of the novel coronavirus (SARS-CoV-2) from the late 2019 has become one of the most significant public health threats worldwide [1, 50, 146] . In addition to respiratory symptoms, SARS-CoV-2 was also shown to cause cardiac injury, kidney injury, liver injury, digestive tract injury and other symptoms, which indicated the effects of SARS-CoV-2 on extrapulmonary organs. The patients with severe COVID-19 were more likely to have acute cardiac injury, acute kidney injury, liver injury, gastrointestinal injury or nervous system injury [5, 50, 79, 94, 103] . ACE2 and TMPRSS2 could help SARS-CoV-2 entry into the human cells, and it has been showed that ACE2 and TMPRSS2 expressions are widely distributed across human tissues including lung, liver, kidney, heart, brain and multiple digestive tract organs [28, 33, 147, 148] . The co-expression of ACE2 and TMPRSS2 in the intestinal enterocytes may explain the disruption of intestinal absorption that leads to diarrhea [38, 149] .

Moreover, ACE2 and TMPRSS2 are highly expressed in renal tubular cells, implying that SARS-CoV-2 may directly bind to ACE2-positive cells in the kidney and destroy the function of renal tubules [32, 38] . Furthermore, ACE2 and TMPRSS2 were co-expressed in heart, which may be related with the attack of SARS-CoV-2 in heart and lead to cardiac injury in patients with COVID-19 [29, 35, 38] . Besides, the expression of ACE2 in the heart tissue of patients with underlying heart disease was higher than that of normal people, which may explain that COVID-19 patients with basic cardiovascular disease are more likely to progress to heat injury [35, 36] . It is noteworthy that all datasets confirm a consistently high expression of ACE2 in the testis, some datasets found that ACE2 and TMPRSS2 were also co-expressed in the testis, which indicated that testis are the potential targets of SARS-CoV-2 [26, 27, 148] .

Pan et al reported that 19% (6/34) of mild to moderate COVID-19 patients had scrotal discomfort as one of the symptoms, while SARS-COV-2 was not detected in semen of these patients with COVID-19 [150] . In another study, Li et al indicated the presence of SARS-CoV-2 in semen samples of six COVID-19 patients [151] . The direct influence of this virus on the male urogenital organs is still to be evaluated [152] . However, clinicians still should assess the reproductive function of male COVID-19 patients for J o u r n a l P r e -p r o o f prognosis. It was also found that the expression of ACE2 in adipose tissue was relatively high, which indicated that infection of SARS-CoV-2 may be related with obesity [34, 35] .

Recent studies of the epidemiological characteristics of COVID-19 have revealed that severe infection is more likely to occur in people with an existing chronic medical condition [1, 58] . Pinto et al analyzed over 700 lung transcriptome samples of severe COVID-19 patients with comorbidities and found that ACE2 was expressed at higher level in these patients compared to other groups, indicating that patients with comorbidities may have higher chances of developing severe COVID-19 [153] . Furthermore, the significantly higher expressions of ACE2 were detected in cardiac tissues of patients with heart failure and tumor tissues of patients with colorectal cancer, cervical squamous cell carcinoma, endocervical adenocarcinoma, pancreatic adenocarcinoma, rectum adenocarcinoma or kidney renal papillary cell carcinoma [35, [154] [155] [156] . Patients with cancer had a higher risk of COVID-19 than those without cancer [157] . Moreover, cancer history is one of the independent risk factors for mortality in hospitalized COVID-19 patients [158] . These studies may indicate that patients with existing chronic medical conditions are susceptible to the SARS-CoV-2 infection.

The understanding of the transmission routes for SARS-CoV-2 infection is crucial in controlling the outbreak. Respiratory droplets and close contact have been confirmed as the main transmission routes of SARS-CoV-2 [1, 50, 159] . The high expressions of ACE2 and TMPRSS2 in the digestive tract [26, 149] and the detection of SARS-CoV-2 in gastrointestinal tissue samples and feces [43, 89] , imply a fecal-oral transmission route for SARS-CoV-2 infection. Although it has been reported that ACE2 is expressed in human placenta, which provides a theoretical basis for the risk of vertical transmission of SARS-CoV-2, the existence of mother-to-child transmission of SARS-CoV-2 remains controversial [160] . 

All authors declare no conflicts of interest level. ACE2 and TMPRSS2 were expressed in the brain and heart; ACE2 expression is expressed at a relative low level in hepatocytes and mainly located in cholangiocytes, while TMPRSS2 is expressed in the hepatocytes and cholangiocytes; ACE2 and TMPRSS2 were highly expressed in kidney and intestinal epithelial cells. 

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

Severe acute respiratory syndrome-related coronavirus: The species and its viruses -a statement of the Coronavirus Study Group

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province

Don't Overlook Digestive Symptoms in Patients With 2019 Novel Coronavirus Disease (COVID-19)

A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase

The emerging role of ACE2 in physiology and disease

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

Structure of SARS coronavirus spike receptor-binding domain complexed with receptor

Coronaviruses -drug discovery and therapeutic options

TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Human neutralizing antibodies elicited by SARS-CoV-2 infection

Virus receptors: binding, adhesion strengthening, and changes in viral structure

Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain

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

Systemic analysis of tissue cells potentially vulnerable to SARS-CoV-2 infection by the protein-proofed single-cell RNA profiling of ACE2, TMPRSS2 and Furin proteases

The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to COVID-19 infection

Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2

The clinical characteristics and mortal causes analysis of COVID-19 death patients

Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCoV, in the nasal tissue

Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis

Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection

The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell

Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2

Myocardial infarction increases ACE2 expression in rat and humans

ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection

Cell-Type-Specific Expression of Renin-Angiotensin-System Components in the Human Body and Its Relevance to SARS-CoV-2 Infection

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

scRNA-seq reveals ACE2 and TMPRSS2 expression in TROP2<sup>+</sup> Liver Progenitor Cells: Implications in COVID-19 associated Liver Dysfunction

Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding

Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme

Evidence for Gastrointestinal Infection of SARS-CoV-2

Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus

Relative Abundance of SARS-CoV-2 Entry Genes in the Enterocytes of the Lower Gastrointestinal Tract

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Expression of ACE2, the SARS-CoV-2 Receptor, and TMPRSS2 in Prostate Epithelial Cells

Vander Heide RS. Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans

Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical Characteristics of Coronavirus Disease 2019 in China

Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19)

Acute kidney injury at early stage as a negative prognostic indicator of patients with COVID-19: a hospital-based retrospective analysis

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China

Caution on Kidney Dysfunctions of COVID-19 Patients

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Clinical Features and Outcomes of 98 Patients Hospitalized with SARS-CoV-2 Infection in Daegu, South Korea: A Brief Descriptive Study

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical features and outcomes of 2019 novel coronavirus-infected patients with cardiac injury

Acute Myocardial Injury of Patients with Coronavirus Disease

Myocarditis and Severity Factors ： An Adult Cohort Study

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. medRxiv 2020:2020

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China

Diagnosis of Acute Respiratory Syndrome Coronavirus 2 Infection by Detection of Nucleocapsid Protein

Kidney disease is in-hospital death of patients with COVID-19

Acute kidney injury in patients hospitalized with COVID-19 in Wuhan, China: A single-center retrospective observational study

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the

Clinical features and treatment of COVID-19 patients in northeast Chongqing

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang, China: A retrospective, multi-centre case series

Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia

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

Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids

Clinical Features of COVID-19-Related Liver Functional Abnormality

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Acute liver injury and its association with death risk of patients with COVID-19: a hospital-based prospective case-cohort study

Risk factors related to hepatic injury in patients with corona virus disease

Clinical characteristics and influencing factors of patients with novel coronavirus pneumonia combined with liver injury in Shaanxi region

A pathological report of three COVID-19 cases by minimally invasive autopsies

Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes

Duration of viral detection in throat and rectum of a patient with COVID-19

Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore

First Case of 2019 Novel Coronavirus in the United States

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Detection of Novel Coronavirus by RT-PCR in Stool Specimen from Asymptomatic Child

Detection of SARS-CoV-2 in Different Types of Clinical Specimens

Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding

COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Gastrointestinal tract symptoms in coronavirus disease 2019: Analysis of clinical symptoms in adult patients

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms

Novel Coronavirus (2019-nCoV) Pneumonia

SARS-CoV-2 Infection in Children

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Epidemiological, clinical, and virological characteristics of 465 hospitalized cases of coronavirus disease 2019 (COVID-19) from Zhejiang province in China

Clinical and Epidemiological Characteristics of 1,420 European Patients with mild-to-moderate Coronavirus Disease

Acute gastrointestinal injury in critically ill patients with coronavirus disease 2019 in Wuhan, China

Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2)

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

Sars-Cov-2: Underestimated damage to nervous system

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection

COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report

Two patients with acute meningo-encephalitis concomitant to SARS-CoV-2 infection

Acute myelitis after SARS-CoV-2 infection: a case report

Isolated sudden onset anosmia in COVID-19 infection. A novel syndrome

Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak

Clinical and immunologic features in severe and moderate forms of Coronavirus Disease

Dysregulation of immune response in patients with COVID-19 in

Liver injury in COVID-19: The current evidence

Chloroquine-induced QTc prolongation in COVID-19 patients

SARS-CoV-2 Infection and the J o u r n a l P r e -p r o o f Liver

Management of Acute Myocardial Infarction During the COVID-19 Pandemic

An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Expert recommendations on blood purification treatment protocol for patients with severe COVID-19: Recommendation and consensus

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Liver injury in COVID-19: management and challenges

Glycyrrhizic acid in the treatment of liver diseases: literature review

COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies

Artificial extracorporeal liver support therapy in patients with severe liver failure

Controversial treatments: An updated understanding of the coronavirus disease 2019

Oral therapy for acute diarrhea. The underused simple solution

ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization

Novel coronavirus infection and gastrointestinal tract

SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19

Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

SARS-CoV-2 can induce brain and spine demyelinating lesions

Hundreds of severe pediatric COVID-19 infections in Wuhan prior to the lockdown

Positive RT-PCR Test Results in Patients Recovered From COVID-19

Clinical characteristics of the recovered COVID-19 patients with re-detectable positive RNA test

Probable causes and risk factors for positive SARS-CoV-2 test in recovered patients: Evidence from Brunei Darussalam

Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study

Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China

Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients

Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient

Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs

A Novel Coronavirus from Patients with Pneumonia in China

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

The protein expression profile of ACE2 in human tissues

Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2)

No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019

Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease

Could COVID-19 have an impact on male fertility?

ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe

Profiling ACE2 expression in colon tissue of healthy adults and colorectal cancer patients by single-cell transcriptome analysis

Single-cell RNA Analysis on ACE2 Expression Provides Insight into SARS-CoV-2 Blood Entry and Heart Injury

Genetic alteration, RNA expression, and DNA methylation profiling of coronavirus disease 2019 (COVID-19) receptor ACE2 in malignancies: a pan-cancer analysis

Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

Cancer history is an independent risk factor for mortality in hospitalized COVID-19 patients: a propensity score-matched analysis

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Regulation of the human placental (pro)renin receptor-prorenin-angiotensin system by microRNAs

Headache 62 (11.3%), dizziness 56 (10.2%) and confusion 17 (3.1%)

Anosmia 15 (35.7%), dysgeusia14 (33.3%) and both anosmia and dysgeusia 14 (33.3%)

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f