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      SARS-CoV-2-Induced Vomiting as Onset Symptom in a Patient with COVID-19

      case-report
      1 , , 2 , 1
      Digestive Diseases and Sciences
      Springer US
      SARS-CoV-2, COVID-19, Gastrointestinal symptoms, Vomiting

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          Abstract

          Introduction The two recent reports by Xiao et al. [1] and Song et al. [2] concerned SARS-CoV-2-induced diarrhea in patient with COVID-19. The typical symptoms at onset of illness included fever, dry cough, fatigue, myalgia, and dyspnea [3]. Patients with gastrointestinal tract symptoms alone as onset symptom are very rare. Here, we reported SARS-CoV-2-induced vomiting as onset symptom in a patient with COVID-19. Case Report On February 7, 2020, a 68-year-old male was admitted to hospital for “paroxysmal vomiting for 7 days, fever for 1 day”. The patient developed paroxysmal vomiting 7 days ago. He bought antiemetic at the pharmacy, and his vomiting symptoms eased slightly after taking the antiemetic. One day before admission, he had a fever with a temperature of 38.0 °C. He has no history of exposure to Wuhan, but his nephew had a history of exposure to Wuhan. On admission, his chest CT showed pneumonia in the bilateral lungs and ground-glass opacities in the right lung. We suspected that he was infected with SARS-CoV-2. A pharyngeal swab sample and stool sample were collected. On admission, the count of total T lymphocyte decreased and IL-6 slightly increased. There were no obvious abnormal in hepatic function and renal function (Fig. 1 and Table 1). Fig. 1 Chest CT images. The images showed the ground-glass opacities in right lung Table 1 Clinical laboratory results of the patient Measure Patient results (hospital day 2) Normal range White blood cell count (109/L) 6.45 3.5–9.5 Neutrophil count (109/L) 4.64 1.8–6.3 Lymphocyte count (109/L) 0.88 1.1–3.2 Total T lymphocyte (%) 48 50.0–84.0 Absolute value of total T lymphocyte (μL) 475 955–2860 T helper cell (%) 37 27.0–51.0 T helper cell absolute value (μL) 366 550–1440 T suppressor cell (%) 12 15.0–44.0 T suppressor cell absolute value (μL) 114 320–1250 T helper cell/T suppressor cell 3.08 0.71–2.78 Aspartate transaminase (U/L) 31 13–35 Alanine transaminase (U/L) 19 7–40 Total bilirubin (µmol/L) 10.5 5–21 Creatinine (µmol/L) 56 30–90 Urea nitrogen (mmol/L) 6.15 2.8–7.2 Uric acid (µmol/L) 114 155–357 Creatine kinase (U/L) 203 26–140 CK-MB (U/L) 15 0–24 Hypersensitive C-reactive protein (mg/L) 83.5 0.068–8.2 IL-2 (pg/mL) 1.17 0.08–5.71 IL-4 (pg/mL) 2.76 0.10–2.80 IL-6 (pg/mL) 18.20 1.18–5.30 TNF-α (pg/mL) 2.68 0.10–2.31 IFN-γ (pg/mL) 1.60 0.16–7.42 On February 8, 2020, real-time reverse transcriptase polymerase chain reaction (rRT-PCR) of the pharyngeal swab and stool sample were both positive for SARS-CoV-2. He still had vomiting symptom after admission, without diarrhea, cough, dyspnea or chest pain. He was given antiviral therapy, including α-interferon atomization inhalation (5 million U per time, Bid), oral lopinavir/ritonavir (2 capsules each time, Bid) and ribavirin 500 mg (intravenous infusion, Bid). Xuebijing (100 ml, Bid) and Chinese herb were also used. After treatments, his body temperature of patient was normal, and his vomiting gradually disappeared. On 26 February and 29 February, rRT-PCR of the pharyngeal swab and stool sample were both negative. The result of CT scan on 26 February showed that the inflammation was significantly decreased in the bilateral lungs and the ground-glass opacities in the right lung had resolved. Now, he was discharged and returned home. Discussion A kind of novel coronavirus (2019-nCoV) pneumonia broke out in Wuhan, Hubei province of China, in early December 2019 and has been declared the sixth public health emergency of international concern by the World Health Organization. Subsequently, this pneumonia was named coronavirus disease 2019 (COVID-19). The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%), while diarrhea was uncommon (3.8%) [4]. Some studies have reported SARS-CoV-2-induced diarrhea, but there have been fewer reports of vomiting. It has been proven that SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as a viral receptor to enter the target cell [5]. Except for the respiratory system, ACE2 receptors are highly abundantly expressed in the glandular cells of gastric, duodenal, and rectal epithelia [6]. Therefore, SARS-CoV-2 binds to the ACE2 receptor that is abundantly expressed in gastrointestinal system as a possible reason for gastrointestinal infection [7]. ACE2 is considered as an important regulator of intestinal inflammation, which may be the potential mechanism by which diarrhea in COVID-19 is caused. After viral entry, virus-specific RNA and proteins are synthesized in the cytoplasm to assemble new virions, which can be released to the gastrointestinal tract [1]. Isolated infectious SARS-CoV-2 from stool indicates the possible fecal–oral transmission route of SARS-CoV-2 [1]. SARS-CoV RNA was found in the sewage water of two hospitals in Beijing treating patients with SARS [8]. Therefore, fecal–oral transmission may be another route for SARS-CoV-2 spread. Prevention of fecal–oral transmission should be taken into consideration to control the spread of SARS-CoV-2. Although SARS-CoV2 RNA is detectable in stool samples, confirmation of viability from viral culture is lacking. Currently, SARS-CoV-2 is breaking out in the worldwide. Patients initially presented with only vomiting are easily misdiagnosed or missed. Therefore, the gastrointestinal symptoms caused by SARS-CoV-2 should be paid attention to. In China, rRT-PCR testing for SARS-CoV-2 from stool is performed routinely in patients and is used as guidance for the disposition of patients with COVID-19.

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          Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

          In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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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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                Author and article information

                Contributors
                fubao0607@126.com , zyyxyfxy@163.com
                kun@vip.163.com
                Journal
                Dig Dis Sci
                Dig. Dis. Sci
                Digestive Diseases and Sciences
                Springer US (New York )
                0163-2116
                1573-2568
                28 April 2020
                : 1-3
                Affiliations
                [1 ]GRID grid.413390.c, Department of Critical Medicine, , Affiliated Hospital of Zunyi Medical University, ; Zunyi, 563000 China
                [2 ]GRID grid.413390.c, Radiology Department, , Affiliated Hospital of Zunyi Medical University, ; Zunyi, 563000 China
                Article
                6285
                10.1007/s10620-020-06285-4
                7186322
                b5c96ab2-48bc-4d8c-a743-1cbd125fb1c0
                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 9 April 2020
                : 17 April 2020
                Categories
                Case Report

                Gastroenterology & Hepatology
                sars-cov-2,covid-19,gastrointestinal symptoms,vomiting
                Gastroenterology & Hepatology
                sars-cov-2, covid-19, gastrointestinal symptoms, vomiting

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