- Incidence of gastrointestinal symptoms
In the early stages of the pandemic, there was a shared misconception that children were not easily infected.33 With the spread of the pandemic, the number of infected children is increasing and there are many severe pediatric cases.34 It is sometimes difficult to distinguish the gastrointestinal symptoms of pediatric COVID-19 from those caused by another viral illness, side effects caused by drug use, and digestive tract symptoms such as nausea and diarrhea caused by gastrointestinal flora disturbance caused by the fever itself. Some studies have found that35 20.4% of children use antibiotics, which cause associated diarrhea, and the younger the patients with lower respiratory tract infection treated with intravenous antibiotics, the more severe their diarrhea is. However, this study found that the total incidence of gastrointestinal symptoms in children with COVID-19 was 21.5%; unfortunately, however, all studies did not describe a control group regarding the incidence of gastrointestinal symptoms between an antibiotic treatment group and non-antibiotic treatment group. In a meta-analysis40 (mainly adult studies), 60 studies (including 4,243 patients with COVID-19) were analyzed and the incidence of gastrointestinal symptoms was found to be 17.6%. Compared with the incidence rate of clinical manifestations of the gastrointestinal tract symptoms in adults, the incidence rate in children is relatively higher, which may be because the intestinal flora of children is infected and can easily cause flora disorder41.This study found that the incidence of gastrointestinal symptoms in children in China was higher than that in countries outside China (23.0% and 18.2%), while the incidence of gastrointestinal symptoms in Wuhan was higher than that outside Wuhan，China (41.2% and 15.1%).In a systematic review52，43 studies including 10,676 COVID-19 patients (confirmed by laboratory RTPCR testing),the overall analysisThe pooled prevalence of diarrhea symptoms across these studies was 7.7% (95% CI7.2 to 8.2). When analyzing by country (studies from China versus studies from other countries), the pooled prevalence of diarrhea in studies from countries other than China was much higher at 18.3% (95% CI 16.6 to 20.1). This is in comparison to studies from China where the prevalence was much lower: 5.8% (95% CI 5.3 to 6.4)
- Pathogenesis of COVID-19
Regarding the mechanism of infection of the severe acute respiratory syndrome severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is currently believed that the major determinant of SARS-CoV-2 infection is S protein, which binds to membrane receptors on host cells and mediates the fusion of viruses and cell membranes. Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE and one of the important receptors on the cell membrane of host cells. The interaction between the S protein and ACE2 promotes the invasion of host cells by SARS-CoV-2. The structure of the SARS-CoV-2 S protein is highly similar to that of the SARS coronavirus (SARS-CoV) S protein; SARS-CoV-2 S protein binds to ACE2 with higher affinity than the SARS-CoV S protein, indicating that SARS-CoV-2 has stronger invasion ability.36 ACE2 can control intestinal inflammation and diarrhea, and the interaction between SARS-CoV-2 and ACE2 may lead to diarrhea.37-38 ACE2 is highly expressed in the small intestine, especially in the proximal and distal intestinal epithelial cells, so the small intestine is more vulnerable to SARS-CoV-2 infection. Previous investigations may have underestimated the incidence of diarrhea among those infected with SARS-CoV-2. Further research is needed to determine whether diarrhea can provide value for the diagnosis of SARS-CoV-2. Regarding the Middle East Respiratory Syndrome coronavirus (MERS-CoV), which is highly homologous to SARS-CoV-2, it is believed that the intestinal tract is another route of infection and the incidence rate of diarrhea is 20–25%.39
- Pathological examination
At present, there has been no endoscopic and pathologic study of the digestive tract in pediatric COVID-19. However, a study in adults found that42 there is no obvious damage to the mucosal epithelium of the esophagus, stomach, duodenum, and rectum. In the inherent layers of the stomach, duodenum, and rectum, a large number of infiltrating plasma cells and lymphocytes were seen, accompanied by interstitial edema. ACE2, the virus host receptor, is mainly found in the cytoplasm of gastrointestinal epithelial cells and virus nucleocapsid proteins were found in the cytoplasm of duodenal and rectal glandular epithelial cells.
- Positive rate and significance of fecal nucleic acids
In a recent study42 of 73 hospitalized adult patients in China, the feces of 53.42% of the patients were positive for viral RNA, the duration of fecal positive results ranged from 1 to 12 days, and 23.29% of the patients were still fecal nucleic acid-positive after being confirmed respiratory nucleic acid-negative. Of the 59 patients with COVID-19 in Hong Kong,40 15 (25.4%) had gastrointestinal symptoms and nine (15.3%) had positive stool viral RNA test results. The detection rates of fecal viral RNA were 38.5% and 8.7% in people with and without diarrhea, respectively. The analysis of data collected in this study found that the positive rate of fecal nucleic acid in children with COVID-19 was 92.3% and the rate of fecal nucleic acid-positive children was much higher than that of adults. We do not attach importance to the detection of nucleic acid in children's feces, which is mainly based on the detection of respiratory tract nucleic acid samples. In the early stage of China's epidemic, the discharge standard was reached with two negative respiratory samples (at least 24 h apart) and there are many cases of re-positivity after discharge;43 however, it is not known whether it is related to the absence of a stool nucleic acid test at the time of discharge. The positive rate of fecal nucleic acid in COVID-19 patients was 92.3% (24/26). After the test for nucleic acids in the respiratory tract specimen produced a negative result, 83.3% (20/24) were fecal nucleic acid-positive; one week after the respiratory tract nucleic acid negative, the fecal nucleic acid positive accounted for 54.4% (13/24). The longest time between a negative respiratory tract nucleic acid test and positive respiratory tract nucleic acid test exceeded 19 days. Therefore, fecal nucleic acid detection should be used as an indicator of discharge from the hospital.
In a recent report detailing from January 16, 2020 to February 8, 2020, China CDC reported 2,135 pediatric COVID-19 patients (including confirmed and suspected cases), 94 of whom were asymptomatic (4.4%).44 However, a recent study in New York45 reported that 29 (87.9%) of 33 pregnant women who tested positive for SARS-CoV-2 on admission did not have symptoms of COVID-19 at the time of treatment. A Boston research team46 found that 1/6 of the 147 homeless people with COVID-19 had symptoms (fever, cough, shortness of breath, etc.), but 5/6 of the patients did not have any symptoms. The results of the two studies are similar. This is very worrying data, because it shows that there are more asymptomatic patients than symptomatic ones, so controlling asymptomatic patients is the key to controlling the pandemic. However, it remains unknown whether children in whom the symptoms have resolved, with respiratory tract specimens negative and stool samples positive for viral nucleic acids, are asymptomatic infectious sources. Therefore, it is necessary to recommend that after recovery and discharge, pediatric patients be isolated at home for more than 2 weeks.
In terms of prognosis, in the United States,47 a retrospective comparative study was carried out in patients over 18 years old. The experimental group included 278 patients with fever and cough with COVID-19, and the control group included 238 patients with fever and cough due to a common respiratory tract infection. The incidence of gastrointestinal symptoms in the two groups was 34.8% and 26.4%, respectively (P = 0.04).47 In the 278 patients with COVID-19, the course of gastrointestinal symptoms was longer, but the mortality rate and rate of severe disease were lower than in those without gastrointestinal symptoms. At present, there is no prognostic study of children with COVID-19.
- Prevention and treatment
At present, there is no specific drug for COVID-19. Plasma therapy for convalescent patients is considered for those with severe disease;48 however, this treatment is controversial. For children with diarrhea, abdominal pain, nausea, vomiting, and other gastrointestinal symptoms, accompanied by low fever, attention should be paid to their epidemiological history and screening of suspected patients. Nucleic acid examination should be performed using throat swabs and anal tests. In daily life, the risk of transmission can be reduced through good hygiene practices, such as washing hands frequently, and closing the toilet lid when flushing.49
- Study limitations
The number of studies included in the meta-analysis was relatively small, with a relatively large proportion of case reports. Most studies did not report on the duration of the GI symptoms preceding the presentation. The number of patients included was relatively small and the description of the gastrointestinal tract of children in the included study was not sufficiently detailed. Therefore, it is necessary to conduct a large-scale double-blind randomized controlled study and include more research factors, such as stool frequency, stool characteristics, rate of patients with gastrointestinal symptoms and positive fecal nucleic acid test results, length of hospitalization of fecal nucleic acid-positive patients, severity of illness, and interrelation between respiratory tract sample nucleic acid and stool nucleic acid findings.
Gastrointestinal symptoms in pediatric COVID-19 are relatively common. Attention should be paid to the detection of fecal nucleic acids in children. Especially in high-risk epidemic areas, all children with digestive tract symptoms as the first diagnosis were tested for fecal nucleic acid.Fecal nucleic acid-negative status should be considered as one of the discharge standards.