Gastrointestinal symptoms in children
The respiratory system appears to be the main target of SARS-CoV-2; however, numerous evidence supports the fact that the gastrointestinal tract and the liver may also be involved both in children as well as in adults.4 This involvement can be associated with isolated modifications of some laboratory parameters (for example, liver enzymes) or with overt symptoms. In adults, the reported incidence of diarrhea varies from 2% to 50% of cases, and the overall percentage of diarrhea was estimated to be 10.4%.5
In children, the available data are sparse, however gastrointestinal symptoms, including nausea, vomiting, diarrhea, and abdominal pain, seem to occur frequently. Diarrhea and vomiting have been reported in about 8-9% of cases, reaching more than 20% in some studies (Table 1). Therefore, although COVID-19 in children seems to have a milder course than in adults and respiratory symptoms are less frequently reported, the incidence of gastrointestinal symptoms is similar to that observed in adults.
Unfortunately, both in adult and pediatric studies, the characteristics of diarrhea are not usually reported, and information related to the total number of evacuations, consistency of the stools, and duration of symptoms is poor. On one study, diarrhea appeared 1 to 8 days after the onset of the disease, with a median of 3.3 days.4Watery diarrhea appears to be more frequently reported. Bloody diarrhea, probably associated with SARS-CoV-2 colitis, has been described only in one adult patient so far.6 Few adult cases of esophagitis are also reported.7
Some children presented with diarrhea or vomiting as the first symptom of the disease, even before or in the absence of respiratory manifestations. For example, there are some case reports of infants or older children who developed fever and diarrhea as the only or main manifestation of the disease.8 Thus, it is currently discussed whether, in the course of an epidemic, diagnostic tests for SARS-CoV-2 in children presenting with diarrhea alone or associated with fever should be considered.9 Furthermore, the fact that, in some cases, gastrointestinal symptoms may precede systemic and respiratory ones support the hypothesis that the gastrointestinal system represents a possible route of viral invasion and transmission.
In adult case-series, gastrointestinal symptoms have been reported to be associated with more severe disease.7,10 In a systematic review, diarrhea was found to be more common in patients with severe forms of COVID-19 than those with the non-severe disease (5.8% vs. 3.5%, respectively) and patients with diarrhea, nausea and vomiting were more likely to develop acute respiratory distress or to require mechanical ventilation compared to patients without gastrointestinal symptoms (6.76% vs. 2.08%, p = 0.034). However, other studies did not confirm this finding with gastrointestinal symptoms occurring at a similar rate in patients with severe and not-severe forms.10 The discrepancies among study results may be influenced by several factors, including the variable proportion of patients with diarrhea observed in the various studies and by the fact that some antiviral drugs, likely used in more severe cases, include diarrhea as a possible adverse event (e.g., lopinavir/ritonavir). To date, a possible correlation between the presence of diarrhea and the severity of COVID-19 does not seem to be found in children.4 In a recent Chinese study on 244 SARS-CoV-2 infected children, authors compared disease severity between 34 (13.9%) children with at least one gastrointestinal symptom (diarrhea, nausea, vomiting, abdominal pain, decreased feeding) with those without gastrointestinal involvement. Patients with gastrointestinal symptoms were younger (14 vs. 86 months; p<0.05) and were more likely to have a fever on admission (70.6% vs. 35.7%, p<0.05), but no other significant differences were found between the two groups, including respiratory symptoms, the duration of RT-PCR positivity for SARS-CoV-2 and lung radiology findings.11
As regards liver involvement, a modest increase in liver enzymes is well described in the pediatric population, with varying percentages among studies, ranging from 13% to 50%. In two pediatric studies reporting two datasets in Italy and China, overall including over 270 children, increased serum levels of aspartate aminotransferase (> 50 U/L) (20.4-50% of cases) were more frequently observed than increased in alanine aminotransferase serum levels (> 45 U/L) (13-35% of cases).12 This data, together with the fact that the increase in transaminases is often associated with the increase in creatine kinase and lactic dehydrogenase serum levels, suggests that hypertransaminasemia may be an expression of myositis than liver damage in many cases.4
However, in children, a severe increase ​​in serum liver enzymes is considered a warning sign. This recommendation is mainly based on data obtained from adult studies that report increased serum liver enzymes being more frequent in severe COVID-19 cases (40-60%) than in mild or asymptomatic forms (18-25%).4 Abnormal bilirubin levels may also occur, although to a lesser extent than increases in alanine aminotransferase and aspartate aminotransferase.
The pathogenesis of liver damage in adults is complex ad related to direct viral invasion, systemic inflammation, hepatic ischemia, and hypoxia. Liver involvement may be part of multiorgan failure in the context of a multisystem inflammatory disorder. Moreover, pre-existing liver disease and drug-related liver toxicity may play a role.13
ACE-2 expression may be enriched in cholangiocytes, indicating that SARS-CoV-2 might directly bind to these cells to dysregulate liver function. Gamma-glutamyltransferase, a biomarker for cholangiocyte injury, has been elevated in 30 (54%) of 56 patients with COVID-19 in one adult study.13
In pediatrics, however, it should be bared in mind that severe COVID-19 forms are exceptional and in children with SARS-CoV-2 infection and abnormalities in liver function tests, investigation for possible etiologies of liver or muscle damage other than SARS-CoV-2 should be considered.4