A number of pneumonia cases caused by the 2019 novel coronavirus (COVID-19) are reported globally. According to recent publications, the most common symptoms in patients infected with COVID-19 were fever and cough . However, the incidence of other clinical features differs in different reports.
To address this issue, the authors pooled data from three reports and found that the incidence of leukopenia, fever, and diarrhea in the three studies showed a statistically significant difference.
Among these symptoms, diarrhea showed the smallest p value (p = 0.016), suggesting that the criteria for diagnosing diarrhea may differ in different hospitals. Due to different criteria, clinicians may underestimate the value of this symptom in clinical practice, and it may affect preliminary diagnostic accuracy.
The ACE2 receptor is highly expressed in the human small intestine
Recent studies showed that the spike (S) protein of COVID-19 shared the same cellular entry receptor ACE2 as SARS-CoV. In terms of the importance of ACE2 in modulating intestinal inflammation and diarrhea, the expression profiles of ACE2 in various human tissues were examined and ACE2 was found to be highly expressed in the human small intestine. Interestingly, the ACE2 RNA level was quite low in the lung tissues of healthy donors.
Since the distribution of ACE2 may determine the route of COVID-19 infection, we next evaluated the expression of ACE2 in different cell populations of the small intestine by analyzing single-cell RNA sequencing (scRNA-Seq) data. Based on scRNA-Seq data, the authors analyzed 7,216 single cells derived from the small intestine of normal C57BL/6 mice.
They thus discovered that the small intestine tissues contained at least eight distinct cell groups according to their corresponding marker gene expression profiles. For example, the LGR5 gene was highly expressed in the small intestine stem cell group, and was significantly reduced in other cell groups.
ACE2 was then found to be highly expressed in proximal and distal enterocytes . Interestingly, when they examined the expression profiles of two other virus receptors (ANPEP receptor for the HCoV-229E virus and DPP4 receptor for the MERS-CoV virus), it was found that the RNA levels of these two virus entry receptors also were highly expressed in proximal and distal enterocytes, consistent with the expression profile of ACE2.
Currently, COVID-19 infection routes remain elusive. The distribution of the COVID-19 entry receptor could determine the route of infection, and the route of infection is essential for understanding pathogenesis, both vital for infection control.
Based on the current findings, the authors have proposed that:
- The incidence of diarrhea may have been underestimated in previous investigations.
- Small intestinal epithelial cells that express ACE2 could be more vulnerable to attack in COVID-19.
In this study, ACE2 was shown to be highly expressed in the small intestine, especially in proximal and distal enterocytes. Consistently, another group has recently reported a similar expression pattern in the human digestive system. Interestingly, other virus receptors such as DPP4 showed expression patterns similar to those of ACE2 in the small intestine. DPP4 is a known receptor for MERS-CoV through interaction with the MERS-CoV spike protein.
According to a recent publication, Zhou et al reported that human intestinal cells expressing DPP4 were highly susceptible to MERS-CoV and sustained robust viral replication, suggesting that the human intestinal tract may serve as an alternative infection route for MERS. -CoV.
In terms of the fact that the majority of patients in the outbreak reported a link to a wild animal market, this observation raises an important question about whether this virus is transmitted through contaminated food when the food reaches the small intestine.
ACE2 is known to control intestinal inflammation and diarrhea. Therefore, the interaction between COVID-19 and ACE2 could disrupt the function of ACE2 and cause diarrhea
Here, the authors found that the incidence of diarrhea differs significantly in different reports. As COVID-19 is highly homologous to SARS-CoV and about 20% to 25% of SARS patients have diarrhea, it is confusing to observe the relatively low incidence (2%–3%) of diarrhea in two hospital cohorts in Wuhan . The underestimation may result from the fact that we do not yet have precise criteria for diarrhea.
The WHO definition of diarrhea is having three or more liquid or loose stools per day or having more stools than a healthy person. To some extent, this criterion is subjective. Emerging evidence shows that COVID-19 RNA can be detected in stool samples like in SARS. According to the postulation of the epidemiological characteristics of SARS, which is transmitted by the fecal-oral route, COVID-19 could use the same route for transmission.
Taken together, the symptoms of diarrhea could be underestimated. Information on stool frequencies and the Bristol stool scale should be carefully collected. When infected patients with diarrhea visit the gastroenterology department, it may increase the risk of infection for healthcare workers.
To reduce healthcare-associated infection, physicians should be careful when their patients complain of diarrhea.
Letter from readers
SARS-CoV-2 induced diarrhea as an onset symptom in COVID-19 patients
by Y. Song, P. Liu, X. Shi et al http://dx.doi.org/10.1136/gutjnl-2020-320891
The authors read with great interest the recent publication by Kumar et al, on gastrointestinal tract (GIT) symptoms (vomiting, diarrhea and abdominal pain) among hospitalized children admitted with influenza A H1N1 virus infection. It was concluded there that patients with GIT symptoms should not be ignored due to the infectivity of the virus, especially during the outbreak period.
Now, coronavirus disease 2019 (COVID-19) starting in Wuhan has spread rapidly throughout China and other countries. According to the latest reports, the most common symptoms at the onset of the disease included fever, fatigue, dry cough, myalgia, and dyspnea, and the least common symptoms were headache, abdominal pain, diarrhea, nausea, and vomiting. Few patients initially presenting with only GIT symptoms were reported.
On January 29, 2020, a 22-year-old man presented to the local fever clinic with a 4-day history of diarrhea and low-grade fever. The highest temperature was 38.3°C and diarrhea was 3 to 4 times a day. No other abnormalities were observed. He took two types of Chinese patent medicines for gastrointestinal discomfort for 3 days, but the symptoms did not improve significantly.
- Regular stool examination and bacterial cultures showed negative results for common pathogens.
- Lung auscultation revealed rhonchi, and a chest x-ray was performed, showing pneumonia in the bilateral lungs.
He confessed that he had a history of a short stay in Wuhan on January 22. Considering her travel history, a clinical diagnosis of suspected COVID-19 was made and local health departments were immediately notified.
A nasopharyngeal swab sample was collected according to the guideline, and then the patient was admitted to the isolation room. On February 2, the detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) for the sample was confirmed positive by a real-time reverse transcriptase PCR assay .
Detection of viral pathogens including influenza A and B, parainfluenza, respiratory syncytial virus, rhinovirus, adenovirus, and four common coronavirus strains (HKU1, NL63, 229E, and OC43) was also performed, and all results were negative .
On admission, the patient reported persistent diarrhea , no fever, no cough, no dyspnea, and no chest pain. Vital signs were within normal ranges. The patient received supportive care and antiviral therapy, including oral lopinavir and ritonavir tablets , 6 U twice daily, and oral administration of acetylcysteine tablets for expectoration. During hospitalization, the patient’s body temperature was normal and he had less diarrhea.
Furthermore, there were no obvious alterations in liver function and coagulation function. After antiviral treatments, the patient’s diarrhea improved and then disappeared completely. On February 16, the SARS-CoV-2 nucleic acid detection became negative , and the CT result showed that the inflammation decreased significantly in both lungs. He made a full recovery and was discharged.
A relevant study has revealed that up to 30% of Middle East Respiratory Syndrome (MERS) patients and 10.6% of SARS patients have diarrhea.
The MERS coronavirus has also been shown to survive in simulated gastrointestinal juice and has the ability to infect intestinal organoid models. Hui and Zumla have suggested that SARS-CoV can transmit via the fecal-oral route.
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