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      Upper Gastrointestinal Bleeding Caused by SARS-CoV-2 Infection

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      , MD, PhD 1 , , BMed 1 , , MMed 1 , , MD, PhD 1 , , BMed 1 , , BMed 1 , , MD, PhD 2 , , MD, PhD 3 , 4 , 5 ,
      The American Journal of Gastroenterology
      Wolters Kluwer

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          Abstract

          INTRODUCTION Since the novel coronavirus (SARS-CoV-2) (1) spread across the world, evidence has emerged that the gastrointestinal tract may be a potential transmission route and target organ (2). Of 98 patients with SARS-CoV-2 infection at our institution, 1 patient developed upper gastrointestinal bleeding during hospitalization, the diagnosis and management of which are described below. CASE REPORT A 77-year-old man from Wuhan, China, with no previous gastrointestinal illness was admitted to our hospital with a 6-day history of fever, cough, and fatigue. He was diagnosed with SARS-CoV-2 infection after evaluation and testing (3). His infection progressed rapidly, and tracheal intubation and mechanical ventilation were required on hospital day 4. On hospital day 10, he acutely developed coffee-ground emesis with a decrease in the hemoglobin level indicative of upper gastrointestinal bleeding. With continued bleeding despite intravenous octreotide (25 μg/h) and esomeprazole (8 mg/h) infusions and nasogastric administration of a traditional Chinese hemostatic agent (Yunnan white drugs 0.5, 4/d), urgent gastroscopy was deemed necessary and was performed 12 hours later. On inspection of the esophagus, multiple round herpetic erosions and superficial ulcers (4–6 mm in size) were visualized in the proximal esophagus (Figure 1). The surface of erosions and ulcers of these lesions had white exudate and blood clots. The lesions themselves were friable and bled easily on contact. Specimens were collected from esophageal lesions and peripheral blood for SARS-CoV-2 RNA detection. The tissue specimens tested positive for SARS-CoV-2 RNA, with lymphocytic infiltration typical of viral esophagitis. The remainder of the examination was normal. This confirmed that the esophageal lesions and upper gastrointestinal bleeding were caused by SARS-CoV-2 infection of the esophagus. After gastroscopy, a nasogastric tube was positioned with the tip at the level of the esophageal lesions. A topical mucosal protective agent (aluminum phosphate gel, 20 g three times a day) and hemostatic therapy (thrombin, formulated as 16 U/mL in ice-cooled water, 50 mL every 2 hours) were administered through the nasogastric tube for 72 hours, although the head of bed was raised 30° to prevent reflux, and some of the infused medications could have flowed into the stomach. Bleeding stopped within 48 hours, but despite escalation of respiratory support, the patient died of respiratory failure on hospital day 33. DISCUSSION We describe for the first time, an unusual case of esophageal mucosal lesions caused by SARS-CoV-2 resulting in upper gastrointestinal bleeding. The diagnosis was confirmed by virus RNA detection in the esophageal lesions. Although endoscopic hemostasis was not possible because of diffuse friability, bleeding stopped with topical mucosal protective and hemostatic agents administered via a nasogastric tube, along with systemic octreotide and esomeprazole infusions. We can draw several conclusions from this case. First, we conclusively demonstrate that SARS-CoV-2 can infect the esophagus and can cause mucosal lesions, potentially from the virus binding to ACE2 protein expressed by gastrointestinal cells (4). We found multiple round herpetic erosions and superficial ulcers in the esophagus, with lymphocytic infiltration, which is consistent with the endoscopic and histopathologic characteristics of viral esophagitis (5). Our findings indicate that when patients with SARS-CoV-2 infection develop upper gastrointestinal bleeding, infectious esophagitis from SARS-CoV-2 needs to be considered in addition to other potential etiologies of bleeding (5). It is unknown whether other parts of the gastrointestinal tract can be similarly involved with SARS-CoV-2 infection. Second, endoscopic hemostasis could not be achieved because of diffuse erosions, friability, and bleeding in the esophageal lesions. Instead, we continued intravenous octreotide and proton pump inhibitor therapy, and we infused a topical mucosal protective agent (aluminum phosphate gel) and iced thrombin solution through a nasogastric tube positioned at the level of the esophageal lesions. Thrombin can promote platelet aggregation and can generate stable fibrin through the coagulation cascade to promote coagulation, which we have found useful when endoscopic hemostasis is not possible. Therefore, although supportive management can be of value, endoscopic therapy may not be possible. Finally, because we isolated SARS-CoV-2 viral RNA from the esophageal lesions, it will be of utmost importance for endoscopy personnel to pay close attention to adequate personal protective equipment and measures to mitigate exposure when performing endoscopic procedures in patients infected with SARS-CoV-2. In addition, endoscopes and operating instruments should be thoroughly cleaned and disinfected to avoid cross infection. In summary, upper gastrointestinal bleeding caused by SARS-CoV-2 is a new and important challenge for gastroenterologists with implications on potential for spread of infection through endoscopy. CONFLICTS OF INTEREST Guarantor of the article: Hong Shan, MD, PhD, supervised the study and accept full responsibility for the conduct of the study, and he has had access to the data and have control of the decision to publish. Specific author contributions: X.L. designed the study and revised the draft. S.H., R.L., Z.Z., and X.L. planned and conducted the study. X.Z. collected and interpreted data. J.L. drafted the manuscript. Financial support: This work was supported by the Task-Force Project on the Prevention and Control of Novel Coronavirus of Guangdong Province (20201113), the 3 Major Constructions of Sun Yat-sen University (the Task-Force Project on the Prevention and Control of Novel Coronavirus of Sun Yat-sen University), the Emergency Task-Force Project on the Prevention and Control of Novel Coronavirus of Zhuhai 2020. Potential competing interests: None to report. Informed patient consent: All patient-specific examinations and treatments have obtained the patient's confirmation.

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          Most cited references5

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            Evidence for Gastrointestinal Infection of SARS-CoV-2

            Since the novel coronavirus (SARS-CoV-2) was identified in Wuhan, China, at the end of 2019, the virus has spread to 32 countries, infecting more than 80,000 people and causing more than 2600 deaths globally. The viral infection causes a series of respiratory illnesses, including severe respiratory syndrome, indicating that the virus most likely infects respiratory epithelial cells and spreads mainly via respiratory tract from human to human. However, viral target cells and organs have not been fully determined, impeding our understanding of the pathogenesis of the viral infection and viral transmission routes. According to a recent case report, SARS-CoV-2 RNA was detected in a stool specimen, 1 raising the question of viral gastrointestinal infection and a fecal-oral transmission route. It has been proven that SARS-CoV-2 uses angiotensin-converting enzyme (ACE) 2 as a viral receptor for entry process. 2 ACE2 messenger RNA is highly expressed and stabilized by B0AT1 in gastrointestinal system, 3 , 4 providing a prerequisite for SARS-CoV-2 infection. To further investigate the clinical significance of SARS-CoV-2 RNA in feces, we examined the viral RNA in feces from 71 patients with SARS-CoV-2 infection during their hospitalizations. The viral RNA and viral nucleocapsid protein were examined in gastrointestinal tissues from 1 of the patients. Methods From February 1 to 14, 2020, clinical specimens, including serum, nasopharyngeal, and oropharyngeal swabs; urine; stool; and tissues from 73 hospitalized patients infected with SARS-CoV-2 were obtained in accordance with China Disease Control and Prevention guidelines and tested for SARS-CoV-2 RNA by using the China Disease Control and Prevention–standardized quantitative polymerase chain reaction assay. 5 Clinical characteristics of the 73 patients are shown in Supplementary Table 1. The esophageal, gastric, duodenal, and rectal tissues were obtained from 1 of the patients by using endoscopy. The patient’s clinical information is described in the Supplementary Case Clinical Information and Supplementary Table 2. Histologic staining (H&E) as well as viral receptor ACE2 and viral nucleocapsid staining were performed as described in the Supplementary Methods. The images of fluorescent staining were obtained by using laser scanning confocal microscopy (LSM880, Carl Zeiss MicroImaging, Oberkochen, Germany) and are shown in Figure 1 . This study was approved by the Ethics Committee of The Fifth Affiliated Hospital, Sun Yat-sen University, and all patients signed informed consent forms. Figure 1 Images of histologic and immunofluorescent staining of gastrointestinal tissues. Shown are images of histologic and immunofluorescent staining of esophagus, stomach, duodenum, and rectum. The scale bar in the histologic image represents 100 μm. The scale bar in the immunofluorescent image represents 20 μm. Results From February 1 to 14, 2020, among all of the 73 hospitalized patients infected with SARS-CoV-2, 39 (53.42%), including 25 male and 14 female patients, tested positive for SARS-CoV-2 RNA in stool, as shown in Supplementary Table 1. The age of patients with positive results for SARS-CoV-2 RNA in stool ranged from 10 months to 78 years old. The duration time of positive stool results ranged from 1 to 12 days. Furthermore, 17 (23.29%) patients continued to have positive results in stool after showing negative results in respiratory samples. Gastrointestinal endoscopy was performed on a patient as described in the Supplementary Case Clinical Information. As shown in Figure 1, the mucous epithelium of esophagus, stomach, duodenum, and rectum showed no significant damage with H&E staining. Infiltrate of occasional lymphocytes was observed in esophageal squamous epithelium. In lamina propria of the stomach, duodenum, and rectum, numerous infiltrating plasma cells and lymphocytes with interstitial edema were seen. Importantly, viral host receptor ACE2 stained positive mainly in the cytoplasm of gastrointestinal epithelial cells (Figure 1). We observed that ACE2 is rarely expressed in esophageal epithelium but is abundantly distributed in the cilia of the glandular epithelia. Staining of viral nucleocapsid protein was visualized in the cytoplasm of gastric, duodenal, and rectum glandular epithelial cell, but not in esophageal epithelium. The positive staining of ACE2 and SARS-CoV-2 was also observed in gastrointestinal epithelium from other patients who tested positive for SARS-CoV-2 RNA in feces (data not shown). Discussion In this article, we provide evidence for gastrointestinal infection of SARS-CoV-2 and its possible fecal-oral transmission route. Because viruses spread from infected to uninfected cells, 6 viral-specific target cells or organs are determinants of viral transmission routes. Receptor-mediated viral entry into a host cell is the first step of viral infection. Our immunofluorescent data showed that ACE2 protein, which has been proven to be a cell receptor for SARS-CoV-2, is abundantly expressed in the glandular cells of gastric, duodenal, and rectal epithelia, supporting the entry of SARS-CoV-2 into the host cells. ACE2 staining is rarely seen in esophageal mucosa, probably because the esophageal epithelium is mainly composed of squamous epithelial cells, which express less ACE2 than glandular epithelial cells. Our results of SARS-CoV-2 RNA detection and intracellular staining of viral nucleocapsid protein in gastric, duodenal, and rectal epithelia demonstrate that SARS-CoV-2 infects these gastrointestinal glandular epithelial cells. Although viral RNA was also detected in esophageal mucous tissue, absence of viral nucleocapsid protein staining in esophageal mucosa indicates low viral infection in esophageal mucosa. After viral entry, virus-specific RNA and proteins are synthesized in the cytoplasm to assemble new virions, 7 which can be released to the gastrointestinal tract. The continuous positive detection of viral RNA from feces suggests that the infectious virions are secreted from the virus-infected gastrointestinal cells. Recently, we and others have isolated infectious SARS-CoV-2 from stool (unpublished data), confirming the release of the infectious virions to the gastrointestinal tract. Therefore, fecal-oral transmission could be an additional route for viral spread. Prevention of fecal-oral transmission should be taken into consideration to control the spread of the virus. Our results highlight the clinical significance of testing viral RNA in feces by real-time reverse transcriptase polymerase chain reaction (rRT-PCR) because infectious virions released from the gastrointestinal tract can be monitored by the test. According to the current Centers for Disease Control and Prevention guidance for the disposition of patients with SARS-CoV-2, the decision to discontinue transmission-based precautions for hospitalized patients with SARS-CoV-2 is based on negative results rRT-PCR testing for SARS-CoV-2 from at least 2 sequential respiratory tract specimens collected ≥24 hours apart. 8 However, in more than 20% of patients with SARS-CoV-2, we observed that the test result for viral RNA remained positive in feces, even after test results for viral RNA in the respiratory tract converted to negative, indicating that the viral gastrointestinal infection and potential fecal-oral transmission can last even after viral clearance in the respiratory tract. Therefore, we strongly recommend that rRT-PCR testing for SARS-CoV-2 from feces should be performed routinely in patients with SARS-CoV-2 and that transmission-based precautions for hospitalized patients with SARS-CoV-2 should continue if feces test results are positive by rRT-PCR testing.
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              Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection

              Objective To study the GI symptoms in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. Design We analysed epidemiological, demographic, clinical and laboratory data of 95 cases with SARS-CoV-2 caused coronavirus disease 2019. Real-time reverse transcriptase PCR was used to detect the presence of SARS-CoV-2 in faeces and GI tissues. Results Among the 95 patients, 58 cases exhibited GI symptoms of which 11 (11.6%) occurred on admission and 47 (49.5%) developed during hospitalisation. Diarrhoea (24.2%), anorexia (17.9%) and nausea (17.9%) were the main symptoms with five (5.3%), five (5.3%) and three (3.2%) cases occurred on the illness onset, respectively. A substantial proportion of patients developed diarrhoea during hospitalisation, potentially aggravated by various drugs including antibiotics. Faecal samples of 65 hospitalised patients were tested for the presence of SARS-CoV-2, including 42 with and 23 without GI symptoms, of which 22 (52.4%) and 9 (39.1%) were positive, respectively. Six patients with GI symptoms were subjected to endoscopy, revealing oesophageal bleeding with erosions and ulcers in one severe patient. SARS-CoV-2 RNA was detected in oesophagus, stomach, duodenum and rectum specimens for both two severe patients. In contrast, only duodenum was positive in one of the four non-severe patients. Conclusions GI tract may be a potential transmission route and target organ of SARS-CoV-2.
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                Author and article information

                Journal
                Am J Gastroenterol
                Am. J. Gastroenterol
                AJGAST
                ACG
                ACG
                The American Journal of Gastroenterology
                Wolters Kluwer (Philadelphia, PA )
                0002-9270
                1572-0241
                20 July 2020
                : 10.14309/ajg.0000000000000757
                Affiliations
                [1 ]Department of Gastroenterology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China;
                [2 ]Department of Respiratory, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China;
                [3 ]Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China;
                [4 ]Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China;
                [5 ]Department of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
                Author notes
                Correspondence: Hong Shan, MD, PhD. E-mail: shanhong@ 123456mail.sysu.edu.cn .
                Article
                AJG-20-0581
                10.14309/ajg.0000000000000757
                7396212
                32694288
                9843f655-b60a-435d-8e26-96160cd64c79
                © 2020 by The American College of Gastroenterology

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

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                Gastroenterology & Hepatology

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