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Iran J Pediatr. 2020 October; 30(5):e106935.
Published online 2020 September 23.
doi: 10.5812/ijp.106935.
Systematic Review
Gastrointestinal Manifestations and Dynamics of Liver Enzymes in
Children and Adolescents with COVID-19 Infection: A Systematic
Review and Meta-Analysis
Naghi Dara 1, Amirhossein Hosseini 1, Ali Akbar Sayyari 1, Mihnea-Alexandru Gaman2and Somaye
Fatahi 1, 3, *
1Pediatric Gastroenterology,Hepatolog y and Nutrition Research Center,Research Institute for Children’s Health, Shahid Beheshti University of Medical sciences, Tehran, Iran
2"Carol Davila" University of Medicine and Pharmacy,Bucharest, Romania
3Student Research Committee, Faculty of public health branch, Iran University of Medical Sciences, Tehran, Iran
*Corresponding author: Pediatric Gastroenterology, Hepatology and Nutrition, Research Center, Research Institute for Children’s Health, Shahid Beheshti University of
Medical Sciences, Tehran, Iran. Email: fatahis70@gmail.com
Received 2020 June 28; Revised 2020 August 01; Accepted 2020 August 08.
Abstract
Objectives: To improve the knowledge on Coronavirus Disease (COVID-19) infection, we aimed to study the prevalence of gastroin-
testinal symptoms and the dynamics of liver enzymes in children infected with COVID-19.
Methods: We performed a systematic search of all the articles published up to May 2020 in the following databases: PubMed-
MEDLINE, Scopus, and Cochrane. We chose the fixed- or random-effect model for analysis based on the I2 statistic. The included
data were analyzed to identify the prevalence of gastrointestinal symptoms (diarrhea, vomiting or nausea) and to identify the dy-
namics of liver enzymes in children and adolescents diagnosed with COVID-19.
Results: We detected an overall prevalence of all gastrointestinal symptoms of 26% (95% CI: 0.18 - 0.35). The pooled prevalence of
diarrhea and nausea/vomiting was 12% (95% CI: 0.08 - 0.16) with no heterogeneity (P = 0.19; I2= 23.53%) and 11% (95% CI: 0.05 - 0.17),
respectively. The pooled prevalence of elevated ALT and AST and LDH was 12% (95% CI: 0.07 - 0.17), 14% (95% CI: 0.10 - 0.18) and 33% (95%
CI: 0.12 - 0.54), respectively among the included studies.
Conclusions: According to our systematic review and meta-analysis, 26% of the children and adolescents diagnosed with COVID-19
present gastrointestinal symptoms. This paper has provided a comprehensive overview of the prevalence of digestive symptoms of
COVID-19 and of the liver enzymes dynamics in children and adolescents.
Keywords: Coronavirus, SARS-CoV-2, COVID-19, Gastrointestinal Symptoms, Children, Adolescents, Meta-Analysis
1. Background
The outbreak of pneumonia that emerged early in
2020 in Wuhan, Hubei province, China was identified as a
great public health challenge worldwide on January 7th (1).
The cause of the pneumonia outbreak was subsequently
detected to be a novel coronavirus (CoV) that belongs to
the beta-coronavirus lineage B (2). Due to the rapid spread
of the virus in China and other countries, the World Health
Organization (WHO) announced that the outbreak of Coro-
navirus Disease 2019 (COVID-19) constitutes a Public Health
Emergency of International Concern (3). Several reports
proposed that children are just as likely as adults to suf-
fer from COVID-19, but have a lower fatality rate and are
less likely to experience severe forms of disease. For vari-
ous reasons, such as an underestimation of the true rate
of infection and the lack of examination of children with
mild symptoms, the knowledge regarding COVID-19 in chil-
dren and adolescents is limited (4). Similarly to adults
with COVID-19, respiratory tract manifestations such as
cough and fever are the most common symptoms of the
disease in children and adolescents (5,6). Based on re-
cently published evidence, an alarmingly high prevalence
of gastrointestinal symptoms of COVID-19 has been re-
ported among children. In this regard, a study by Fang et
al estimated that the prevalence of diarrhea and/or vomit-
ing in children with COVID-19 was much higher than that
in adults (57.1% vs. 17.6%) (7).
It was subsequently documented that this virus can
bind to the angiotensin-converting enzyme 2 (ACE2) recep-
tors located in the intestinal and respiratory tracts and, via
these receptors, the virus can penetrate into epithelial cells
(8). However, an elevation of liver enzymes has been found
Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License
(http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly
cited.
Dara N et al.
in children, as well as adults, but a reason for this change in
laboratory findings is still unclear (3,9). Although COVID-
19 is thought to be less severe in children than in adults, it
should be noted that, in some instances, children and ado-
lescents are more vulnerable than adults. Also, gastroin-
testinal and liver disorders can prolong the hospital stay
and lead to treatment complications (8,10-12).
In this systematic review and meta-analysis, we have
analyzed the prevalence of gastrointestinal symptoms and
the dynamics of liver enzymes in children with COVID-19,
based on the reported cases up to date. Comprehending
the gastrointestinal manifestations of COVID-19 in this age
group is important for a better identification of children
and adolescents with possible COVID-19 infection and for a
better therapeutic management of these cases, thus limit-
ing the spread of this virus worldwide.
2. Methods
2.1. Search Strategy
The present study was conducted in accordance with
the PRISMA [preferred reporting items for systematic re-
view and meta-analysis] guidelines (13). We carried out
a comprehensive systematic search in PubMed/MEDLINE,
Web of Science, SCOPUS and Embase from inception until
May 2020 without using time or language restrictions. The
following keywords were used in combination with the
wild-card ‘*’ and Medical Subject Heading (MeSH) terms:
(“2019-nCoV- 2” OR “coronavirus” OR “COVID-19” OR “SARS-
CoV-2” OR “nCoV” OR “novel coronavirus” OR “coronavirus
2019”) and (“child*” OR “Adolescent*” OR “Pediatrics*”) AND
(“abdominal pain” OR “Nausea” OR Vomiting” OR “Fecal
incontinence” OR “Gastrointestinal Diseases” OR “Diges-
tive System Diseases” OR “Esophageal Diseases” OR “Gas-
troesophageal Reflux” OR “GERD” OR “Constipation”). Ad-
ditionally, the reference lists of the articles retrieved and
related review studies were also hand-screened to identify
eligible publications that our search might have omitted.
2.2. Study Selection
After excluding duplicate articles, two authors inde-
pendently reviewed the titles, the abstracts or the full-
text of the retrieved studies to detect eligible publica-
tions. Finally, original studies were included in the
present meta-analysis if they met the following crite-
ria: (1) the articles were case reports/case series, prospec-
tive/retrospective cohort studies, case-control studies, or
randomized controlled trials; (2) the studies enrolled pedi-
atric/children/adolescents (aged < 18 years); and (3) the ar-
ticles reported digestive symptoms or dynamics of liver en-
zymes (ALT, AST and LDH). Duplicate data, studies with un-
clear information, studies involving animals, reviews and
studies whose corresponding author did not offer any feed-
back after several emails were excluded.
2.4. Data Extraction
Twoindependent researchers reviewed the data and an
additional reviewer resolved any disagreements between
the two. The following information was collected: au-
thor, year of publication, country, study date, age, disease
severity, participants’ gender, presence of fever, respira-
tory symptoms, digestive symptoms (diarrhea, vomiting
or nausea and abdominal pain) and elevation of ALT, AST
and LDH.
2.5. Data Synthesis and Statistical Analysis
The statistical analysis was conducted using RevMan
V.5.3 software and STATA version 12.0 (Stata Corp, College
Station, TX, USA). The prevalences of gastrointestinal symp-
toms and elevated liver enzymes were expressed as propor-
tions and 95% confidence intervals (95% CI) using the ran-
dom effects model, and presented as Forest plot. .Hetero-
geneity was examined using the I-squared (I2) statistic, in
which the source of heterogeneity was determined if the
I2value was > 50% (4). We assessed the presence of publi-
cation bias using the formal Egger’s test (14).
3. Results
Appendix 1 in Supplementary File shows a flowchart
of the study selection process and reasons for exclud-
ing articles. Following the systematic search, 574 pub-
lications from the aforementioned electronic databases
were retrieved. After excluding duplicate studies, a total
of 469 publications remained. Then, we reviewed the ti-
tle/abstract of the remaining studies, and excluded 417 ar-
ticles which did not meet the inclusion criteria. A total of
52 articles was retrieved during the secondary screening
(by full-text). Of these, 33 studies were discarded since they
did not include data of interest. Finally, 19 studies (1,10-12,
15-29) met the eligibility criteria and were included in the
quantitative meta-analysis.
3.1. Study Characteristics
The characteristics of the pooled studies are presented
in Table 1. All studies were conducted in China except for
one publication (11) whose authors were from Malaysia.
All articles were published between January 1st and March
10th, 2020. In total, 415 participants were included in our
pooled study. The median age of the patients was 6.2 years,
and 53.7% of them were males. A number of thirteen (10-
12,15-17,19,21,24-28) studies reported mild to moderate
manifestations of the disease, while four studies (18,20,22,
2 Iran J Pediatr. 2020; 30(5):e106935.
Dara N et al.
23) reported evidence of severe symptoms. Two papers did
not provide enough information regarding the severity of
COVID-19 (1,29). Among the studies that reported disease
severity, severe disease accounted for 1.8% - 100% in Lu et
al. (20) and Qiu et al. (10) studies , respectively. We defined
the clinical types of COVID-19 in pediatric patients based on
Qiu’s et al. (10) study. Other variables include treatment
schedule and medications and duration of hospital stay
are completely presented in Table 1.
3.2. Meta-Analysis
Based on data from 17 studies with a total of 407 par-
ticipants, we detected an overall prevalence of gastroin-
testinal symptoms (diarrhea, nausea/vomiting, abdominal
pain and constipation) in children with COVID-19 of 26%
[95% CI: 0.18 - 0.35 with significant heterogeneity noted
among the included studies (P < 0.001; I2= 67.66%)]. For
the individual digestive symptoms, 15 studies with 391 par-
ticipants reported the prevalence of diarrhea, 10 with 191
participants reported the prevalence of nausea/vomiting,
and 2 reported the prevalence of abdominal pain. The
pooled prevalence was: diarrhea = 12% (95% CI: 0.08 - 0.16)
with no heterogeneity (P = 0.19; I2= 23.53%) among the in-
cluded studies (Figure 1A) and nausea/vomiting = 11% (95%
CI: 0.05 -0.17) with no heterogeneity among the included
studies (P = 0.06; I2= 47.65%) (Figure 1B).
Regarding the individual elevation in liver enzymes,
the pooled prevalence of elevated ALT levels in 293 partici-
pants was 12% (95% CI: 0.07 - 0.17) (Figure 2A) with no het-
erogeneity (P = 0.24; I2= 24.03%) among the included stud-
ies, of elevated AST levels in 284 participants was 14% (95%
CI: 0.10 - 0.18) with no significant heterogeneity among the
included studies (P = 0.65; I2= 0.0%) (Figure 2B), and of el-
evated LDH levels in 144 participants was 33% (95% CI: 0.12
- 0.54) (Figure 2C) with a high heterogeneity among the in-
cluded studies (P < 0.001; I2= 90.88%). The results, includ-
ing data regarding the heterogeneity of the variables, are
shown in Table 2.
3.3. Publication Bias
The evaluation of publication bias by visual inspection
of the funnel plot and Egger’s test demonstrated some ev-
idence for publication bias in the meta-analysis of diges-
tive symptoms (diarrhea and nausea/vomiting) of COVID-
19 in children (P < 0.001) (Appendix 2 in Supplementary
File). However, the results of the meta trim and fill analysis
found no study. Egger’s linear regression test for elevated
ALT (P = 0.20), AST (P = 0.11) and LDH (P = 0.82) revealed no
publication bias (Appendix 3 in Supplementary File).
4. Discussion
To this date, the increasing number of articles have
documented an involvement of the digestive system in
children and adolescents with COVID-19. The pooled preva-
lence of all gastrointestinal symptoms (diarrhea, nau-
sea/vomiting, abdominal pain and constipation) was 26%.
Diarrhea was the most common gastrointestinal manifes-
tations (12%), followed by nausea/vomiting (11%). Abdomi-
nal pain/discomfort was reported only in two studies. We
also observed that some children and adolescents with
COVID-19 had elevated levels of ALT (12%), AST (14%) and LDH
(33%) during the course of the illness. Although diarrhea
is one of the most common gastrointestinal symptoms of
COVID-19, the presence of abdominal pain and constipa-
tion should not be ignored.
Emerging evidence suggests that, as the severity of
the disease increases, digestive symptoms become more
pronounced. Based on the evidence coming from adults,
about 10% of patients with COVID-19 presented with diges-
tive symptoms alone without respiratory manifestations.
Unfortunately, this feature delays the diagnosis of COVID-
19 and enables the rapid spread of the disease in the popu-
lation especially in children (9). Moreover, subjects with di-
gestive symptoms have an increased risk of critical illness,
and can progress to acute respiratory distress syndrome
(30,31).
The digestive symptoms of COVID-19 in children and
adolescents were various, and included diarrhea, vomit-
ing, abdominal pain and constipation. There is little evi-
dence regarding the histopathological changes which can
affect the digestive system of the patients with COVID-
19. For example, segmental dilatation and stenosis of the
small intestine has been seen in an 85-year-old man diag-
nosed with COVID-19 (32). However, it is uncertain whether
this finding was related to COVID-19 or merely incidental.
Thus, further research is needed to clarify gastrointestinal
involvement in COVID-19.
Remarkably, fever and cough are still the most com-
mon symptoms of the disease (16). Several reports indi-
cate that the occurrence of gastrointestinal symptoms in-
creases with the severity of COVID-19. However, as reported
in a recent study, patients with gastrointestinal symptoms
are less likely to be treated and most likely to be discharged
versus patients without gastrointestinal symptoms, prob-
ably because there is insufficient knowledge regarding the
possible gastrointestinal involvement in COVID-19 (33). On
the other hand, Han et al. (16) stated that one of the rea-
sons for the high prevalence of gastrointestinal symptoms
in children with COVID-19 was their hospitalization for a
longer period of time versus children without gastroin-
testinal symptoms. Therefore, it is not clear whether the
Iran J Pediatr. 2020; 30(5):e106935. 3
Dara N et al.
A B
Overall (I^2 = 23.53%, p = 0.19)
Xin (2020)
Han (2020)
Qiu (2020)
Wang (2020)
Xia lu (2020)
Shen (2020)
see (2020)
Study
Sun (2020)
Chen (2020)
Zhang (2020)
Tang (2020)
Lu (2020)
Xu (2020)
Ji (2020)
Xia (2020)
0.12 (0.08, 0.16)
0.15 (0.04, 0.42)
0.29 (0.08, 0.64)
0.06 (0.02, 0.18)
0.10 (0.03, 0.25)
0.67 (0.21, 0.94)
0.22 (0.06, 0.55)
0.25 (0.05, 0.70)
ES (95% CI)
0.38 (0.14, 0.69)
0.33 (0.14, 0.61)
0.12 (0.05, 0.27)
0.08 (0.02, 0.24)
0.09 (0.05, 0.14)
0.30 (0.11, 0.60)
0.50 (0.09, 0.91)
0.15 (0.05, 0.36)
100.00
4.20
1.57
17.01
11.45
0.63
2.32
0.99
Weight
1.56
2.40
10.84
11.70
26.62
2.14
0.38
6.18
%
0.12 (0.08, 0.16)
0.15 (0.04, 0.42)
0.29 (0.08, 0.64)
0.06 (0.02, 0.18)
0.10 (0.03, 0.25)
0.67 (0.21, 0.94)
0.22 (0.06, 0.55)
0.25 (0.05, 0.70)
ES (95% CI)
0.38 (0.14, 0.69)
0.33 (0.14, 0.61)
0.12 (0.05, 0.27)
0.08 (0.02, 0.24)
0.09 (0.05, 0.14)
0.30 (0.11, 0.60)
0.50 (0.09, 0.91)
0.15 (0.05, 0.36)
100.00
4.20
1.57
17.01
11.45
0.63
2.32
0.99
Weight
1.56
2.40
10.84
11.70
26.62
2.14
0.38
6.18
%
.25 .5 .75 1
Prevalence
Diarrhea (%)
Overall (I^2 = 47.65%, p = 0.05)
Zhang (2020)
Li (2020)
Qiu (2020)
Sun (2020)
Wang (2020)
Tang (2020)
Tan (2020)
Xin (2020)
Study
Han (2020)
Xia (2020)
0.11 (0.05, 0.17)
0.12 (0.05, 0.27)
0.67 (0.30, 0.90)
0.06 (0.02, 0.18)
0.50 (0.22, 0.78)
0.06 (0.02, 0.21)
0.08 (0.02, 0.24)
0.10 (0.02, 0.40)
0.08 (0.01, 0.33)
ES (95% CI)
0.29 (0.08, 0.64)
0.10 (0.03, 0.30)
100.00
13.84
2.36
17.92
2.75
16.44
14.51
7.48
10.30
Weight
2.93
%
11.47
0.11 (0.05, 0.17)
0.12 (0.05, 0.27)
0.67 (0.30, 0.90)
0.06 (0.02, 0.18)
0.50 (0.22, 0.78)
0.06 (0.02, 0.21)
0.08 (0.02, 0.24)
0.10 (0.02, 0.40)
0.08 (0.01, 0.33)
ES (95% CI)
0.29 (0.08, 0.64)
0.10 (0.03, 0.30)
100.00
13.84
2.36
17.92
2.75
16.44
14.51
7.48
10.30
Weight
2.93
%
11.47
.25 .5 .75 1
Prevalence
Nausea/ Vomiting (%)
Figure 1. This figure shows the pooled estimate of the prevalence of gastrointestinal symptoms [(A) diarrhea and (B) nausea/vomiting] in children and adolescents with
COVID-19
Table2. Pooled Prevalence of GI Symptom and Liver Enzymes in Children and Adolescents COVID-19
Variable Pooled Value 95% CI I2(%) P Within Group
All GI symptom 17 (26) 0.18 - 0.35 67.66 < 0.001
Diarrhea 15 (12) 0.08 - 0.16 23.53 0.19
Nausea/vomiting 10 (11) 0.05 - 0.17 47.65 0.06
Elevated ALT 8 (12) 0.07 - 0.17 24.03 0.24
Elevated AST 8 (14) 0.10 - 0.18 0.0 0.65
Elevated LDH 10 (33) 0.12 - 0.54 90.88 < 0.001
high prevalence of gastrointestinal symptoms of COVID-
19 children is due to long-term hospital treatment or to a
higher expression of ACE2 in the gastrointestinal tract or
to different functions of ACE2 between children and adults
(6). Undoubtedly, further studies involving children with
COVID-19 are needed to confirm this hypothesis.
Unlike Fang et al.’s (7) study, the prevalence of gastroin-
testinal symptoms such as diarrhea and vomiting in chil-
dren with COVID-19 did not differ much from the preva-
lence of these conditions in adults, as reported in a recent
meta-analysis (2). This finding might be due to the greater
number of pooled studies that included in their meta-
analysis more digestive symptoms of COVID-19 in adults
than in the present meta-analysis. Another difference in
the incidence of digestive symptoms of COVID-19 among
children and adults was the high prevalence of anorexia
in adults. Anorexia was not reported in any of the studies
included in our meta-analysis and this difference between
children and adults with COVID-19 should warrant further
research on the topic.
In addition to the influence of gastrointestinal involve-
ment on COVID-19 prognosis, patients with COVID-19 are
also at risk of liver function abnormalities (9). As our meta-
analysis showed, a percentage of children and adolescents
with COVID-19 experienced increased levels of liver en-
zymes, mainly ALT and AST, accompanied by a notable el-
evation of LDH levels especially in patients with severe
forms of the disease.
Liver dysfunction was characterized by a slight incre-
ment in hepatocyte-related enzymes, including ALT, AST
and LDH levels (34,35). Total bilirubin was also reported
to be slightly increased in a few patients (16,29). At the mo-
ment, no mechanisms have been identified linking COVID-
19 and liver damage. Most probably, the dysfunction of the
4 Iran J Pediatr. 2020; 30(5):e106935.
Dara N et al.
A B
C
Overall (I^2 = 24.03%, p = 0.24)
Cai (2020)
Tang (2020)
Study
Sun (2020)
Han (2020)
Xia (2020)
Xu (2020)
Qiu (2020)
Lu (2020)
0.12 (0.07, 0.17)
0.10 (0.02, 0.40)
0.12 (0.04, 0.29)
ES (95% CI)
0.50 (0.22, 0.78)
0.14 (0.03, 0.51)
0.25 (0.11, 0.47)
0.10 (0.02, 0.40)
0.06 (0.02, 0.18)
0.12 (0.08, 0.18)
100.00
6.45
12.89
Weight
2.02
3.51
6.22
6.45
25.07
37.40
%
0.12 (0.07, 0.17)
0.10 (0.02, 0.40)
0.12 (0.04, 0.29)
0.50 (0.22, 0.78)
0.14 (0.03, 0.51)
0.25 (0.11, 0.47)
0.10 (0.02, 0.40)
0.06 (0.02, 0.18)
0.12 (0.08, 0.18)
100.00
6.45
12.89
2.02
3.51
6.22
6.45
25.07
37.40
.25 .5 .75 1
Prevalence
Elevated ALT (%)
Overall (I^2 = 0.00%, p = 0.65)
Tang (2020)
Han (2020)
Tan (2020)
Study
Cai (2020)
Shen (2020)
Qiu (2020)
Lu (2020)
Xu (2020)
0.14 (0.10, 0.18)
0.12 (0.04, 0.29)
0.43 (0.16, 0.75)
0.20 (0.06, 0.51)
ES (95% CI)
0.20 (0.06, 0.51)
0.22 (0.06, 0.55)
0.08 (0.03, 0.22)
0.14 (0.10, 0.20)
0.20 (0.06, 0.51)
100.00
10.45
1.17
2.56
Weight
2.56
2.14
19.33
59.23
%
2.56
0.14 (0.10, 0.18)
0.12 (0.04, 0.29)
0.43 (0.16, 0.75)
0.20 (0.06, 0.51)
0.20 (0.06, 0.51)
0.22 (0.06, 0.55)
0.08 (0.03, 0.22)
0.14 (0.10, 0.20)
0.20 (0.06, 0.51)
100.00
10.45
1.17
2.56
2.56
2.14
19.33
59.23
2.56
.25 .5 .75 1
Prevalence
Elevated AST (%)
Overall (I^2 = 90.88%, p = 0.00)
Study
Han (2020)
Tang (2020)
Shen (2020)
Cai (2020)
Zhang (2020)
Sun (2020)
Wang (2020)
Xu (2020)
Tan (2020)
Xing (2020)
0.33 (0.12, 0.54)
ES (95% CI)
0.29 (0.08, 0.64)
0.46 (0.29, 0.65)
0.11 (0.02, 0.43)
0.30 (0.11, 0.60)
0.82 (0.66, 0.92)
0.63 (0.31, 0.86)
0.07 (0.02, 0.23)
0.20 (0.06, 0.51)
0.10 (0.02, 0.40)
0.33 (0.06, 0.79)
100.00
Weight
9.13
10.77
10.63
%
9.75
11.32
9.12
11.52
10.17
10.83
6.76
0.33 (0.12, 0.54)
0.29 (0.08, 0.64)
0.46 (0.29, 0.65)
0.11 (0.02, 0.43)
0.30 (0.11, 0.60)
0.82 (0.66, 0.92)
0.63 (0.31, 0.86)
0.07 (0.02, 0.23)
0.20 (0.06, 0.51)
0.10 (0.02, 0.40)
0.33 (0.06, 0.79)
100.00
9.13
10.77
10.63
9.75
11.32
9.12
11.52
10.17
10.83
6.76
.25 .5 .75 1
Prevalence
Elevated LDH (%)
Figure 2. This figure shows the pooled estimate of the prevalence of elevated (A) ALT, (B) AST and (C) LDH in children and adolescents with COVID-19
liver is related to the viral infection of liver cells, to sys-
temic inflammation and/or linked to drug toxicity (36).
Moreover, according to a recent report, liver biopsy
specimens collected from a 50-year-old man with COVID-
19 exhibited moderate microvesicular steatosis and mild
lobular and portal activity (37,38). In that study, it was
assumed that the liver injury could have been caused by
either SARS-CoV-2 infection or by drug toxicity. On the
other hand, Fan et al. (38) reported no statistical differ-
ences between patients with normal liver function and ab-
normal liver function in terms of medications taken be-
fore hospitalization. Interestingly, patients with elevated
liver enzymes spent more time in the hospital and re-
ceived more lopinavir/ritonavir prescriptions after admis-
sion compared to patients with normal liver function. In
this context, it is difficult to identify the clear cause of the
elevation of liver enzymes in patients with COVID-19, and
especially in children where the number of studies is lim-
ited (38).
4.1. Strength and Limitations
The primary strength of our study was that this meta-
analysis provided a comprehensive overview of the preva-
lence of digestive symptoms and elevated liver enzymes
among children and adolescents, far beyond the available
evidence in 19 different studies. The evidence base avail-
able before our meta-analysis lacked a summative and con-
sensual assessment, and thus a quantitative assessment
Iran J Pediatr. 2020; 30(5):e106935. 5
Dara N et al.
was needed, which we have provided in this report. There
are also a few limitations worth considering. We analyzed
articles with different study designs, e.g. brief communi-
cations (19), or in some studies gastrointestinal symptoms
of COVID-19 might have been under-reported. Thus, un-
fortunately, we were unable to extract sufficient informa-
tion from these studies. We have also not been able to ac-
curately extract information such as percent of patients
with GI presentation who have respiratory symptoms or
the mortality percentage in patient with GI from the ar-
ticles, so it seems that these issues will be considered in
future studies. Although our meta-analysis allowed for a
large number of studies and participants to be analyzed,
it is difficult to generalize our findings and to hypothesize
the possible mechanisms involved in the development of
gastrointestinal symptoms in COVID-19 in children.
5. Conclusion
The major finding of this review was the presence of
gastrointestinal symptoms in 26% of the children and ado-
lescents diagnosed with COVID-19. This review has pro-
vided a comprehensive overview of the prevalence of di-
gestive symptoms of COVID-19 and elevated liver enzymes
among children and adolescents, far beyond the evidence
available until now from singular studies.
Supplementary Material
Supplementary material(s) is available here [To read
supplementary materials, please refer to the journal web-
site and open PDF/HTML].
Footnotes
Authors’ Contribution: S. F., and N. D. designed research;
N. D. and AK. S. conducted research; S. F. analyzed data; and
N. D., MA. G. and AH. H. wrote the paper. S. F. had primary
responsibility for final content. All authors read and ap-
proved the final manuscript.
Conflict of Interests: None.
Funding/Support: Pediatric Gastroenterology, Hepatol-
ogy and Nutrition Research Center, Research Institute for
Children’s Health, Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
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Table1. Characteristics of Eligible Studies
Author
(year)
Country Study
Date
No. Age
(Mean or
Median
[±1 SD
or
Range)
Male (%) Disease Severity a
, No. (%)
Treatment
Schedule and
Medications
Dura-
tion of
Admis-
sion
Time
Fever,
No. (%)
Respiratory
Symptoms, No.
(%)
All GI
Symp-
toms b,
No. (%)
Diar-
rhea, No.
(%)
Nausea/
Vomit-
ing, No.
(%)
Abdomi-
nal Pain/
Discom-
fort, No.
(%)
ALT, U/L
Elevated,
No. (%)
AST, U/L
Elevated,
No. (%)
LDH, U/L
Elevated,
No. (%)
Lu China January
28 to
February
26, 2020
171 7 (1d-15
years)
104 (61) Severe type :3 (1.8); NA NA 55(32) Cough:83 (49);
Pharyngitis: 79
(46); Nasal
congestion:9 (5);
Rhinorrhea: 13 (8);
Tachypnoea:49
(29); Pneumonia 113
(64.9)
15 (9) 15 (9) NA NA 21 (12) 25 (150 NA
Qiu China January
17 to
March 1,
2020
36 8 years 13 (36) Mild type:17 (47);
Moderate type:19
(52);
General; support
therapy;
monitoring of
lung, liver,kidney,
and; myocardial
functions; active
control over high
fever; oxygen
uptake if necessary;
interferon alfa and
lopinavir-ritonavir
14 (3,
10-20)
4 (11) Cough:7 (19);
Pharyngitis: 4 (11);
Tachypnoea:1 (3);
Sore throat:2 (6);
4 (12) 2(6) 2 (6) NA 2 (6) 3 (8) NA
Zhang China January 1
to
February
25, 2020
34 5 (1-6)
years
14 (41) NA; antibiotictherapy
antiviral therapy
interferon-α
nebulization
corticosteroid
therapy; Oxygen
inhalation
3 (2-4);
between
admis-
sion and
recover
from
fever
26 (76) Cough:20 (59);
Tachypnoea:3 (9);
8 (24) 4(12) 4 (12) NA NA NA 28 (82)
Wang China January
25 to
February
21, 2020
31 6
months-
17
years
15 (50) Asymptomatictype
in 4 cases (13%),
Mild type in 13 cases
(42%), and
Common type in 14
cases (45%)
Interferon;
Oseltamivir;
Ribavirin; Arbidol;
Lopinavir
NA 20 (64.5) Cough: 14 (45); Sore
throat: 2 (6.4)
5 (16) 3 (10) 2 (6.4) NA Both 6
(22)
2 (8)
Tang China January
16 to
February
8, 2020
26 7 years 17 (65) Mild type:8 (31);
Ordinary:18 (69);
Oseltamivir,
ribavirin,
interferon, kaletra
and traditional
Chinese medicine
13.6±1.03 11(42) Cough:12(46);
Rhinorrhea: 2 (8);
4 (16) 2 (8) 2 (8) NA 3(12) 3 (12) 12 (46)
Xia China January
23 to
February
8, 2020
20 2 years
(1.5 mon)
13 (65) Mild type:100 (20); Based on Protocol
for COVID-19 (Fifth
Revised Edition)”
distributed by the;
National Health
Commission
12.9 days
(8-20)
12 (60) Cough:13 (65);
Nasal discharge: 3
(15); Sore throat: 1
(5); Tachypnea:2
(10)
5 (25) 3 (15) 2 (10) NA ;5 (25) ; NA NA
Xin China January
17 to
February
29, 2020
13 7.9 years 4 (30) Mild type:7 (53);
Common type:5
(38); Severe type:1
(7)
Interferon;
Ribavirin; Arbidol;
Lopinavir
13 6 (46) Cough: 5(38); Nasal
discharge: 3 (15);
Throat discomfort:
2 (15); Tachypnea:2
(10)
4 (30) 2(15) 1(7) 1 (7) NA NA NA
Chen China 11-Feb-20 12 14.50
(9.25-
15.75)
years
6 (50) Mild pneumonia:10
case; asymptomatic
infection: 2 cases
Interferon;
Ribavirin;
Lopinavir
NA 7 (58.3) Cough: 9 (75);
Upper airway
symptom: 2 (16.7)
4 (33.3) 4 (33.3) NA NA NA NA NA
Tan China January
27 to;
March 10
10 7 years 3 (30) Mildtype:10 (100) Empirical
antibiotic therapy
2 4(40) Cough: 3 (30);
Convulsion:1 (10)
2 (20) NA 1(10) 1 (10) NA 2 (20) 1 (10)
8 Iran J Pediatr. 2020; 30(5):e106935.
Dara N et al.
Cai China January
19 to
February
3, 2020
10 6 (3
mon-11
years
4 (40) NA; Empirical
antibiotic therapy
14 7 (70) Cough:6 (60);
Pharyngitis: 4 (40);
Nasal congestion:3
(30); Rhinorrhea: 2
(20)
NA NA NA NA 1 (10) 2 (20) 3 (30)
Xu China December
to
February
20, 2020
10 6 (2
mon-15
years
7 (70) Mildtype:10 (100) Antiviral therapy
with α-interferon
oral; spray initiated
from admission
(8,000 U, two
sprays, three times;
a day) and
zithromycin
9 6(60) Cough:5 (50);
Pharyngitis: 4 (40);
Nasal congestion:2
(20); Rhinorrhea: 2
(20)
3 (30) 3(30) NA NA 1(10) 2(200 2 (20)
Shen China January 8
to
February
19,2020
9 7.5 years 3 (33) Mild type:9 (100) Lopinavir/ritonavir;
Azithromycin;
meprednisone
18 3(33) Cough: 1 (11); Sore
throat: 1 (11)
2 (22) 2(22) NA NA NA 2 (22) 1(11)
Sun China January
24 to
February
24, 2020
8 6.81years 6 (75) Severe type :5 (62);
critically; ill:3 (37)
High-flow oxygen
therapy;
mechanical
ventilation;
Antiviral
treatments
(virazole,
oseltamivir; and
interferon).
Antibiotics,
traditional Chinese
medicine;
intravenous
glucocorticoids
and
immunoglobulin
19 6 (75) Cough: 6(75);
Unilateral
pneumonia:2 (25);
Bilateral
pneumonia:6 (75)
6 (75) 3(37) 4 (50) NA ; 4 (50) ;NA 5 (62)
Han China January
31; to
February
16, 2020
7 1.3 (0.2-13
years
4 (57.1%) Mild type:7 (100) Oxygen inhalation;
Empirical
antibiotic
treatment;
Antiviral
treatment;
Glucocorticoids
NA 5 (71.4) Cough:5 (71.4);
Shortness of
breath:3 (42.9);
Pharyngalgia: 1
(14.3)
4 (57.1) 2(28) 2 (28) NA 1(14.3) 3 (42.9) 2 (28)
Liu China January 7
to
January
15, 2020
6 3 years 2 (33) Severe type :1 (16) Pooled immune
globulin from
healthy donors.
Antiviral agents,
antibiotic agents,
and supportive;
therapies
7.5 (5-13) 6 (100) Cough: 6 (100); 4(66) NA 4 (66) NA NA NA NA
see Malaysia until end
of
February,
2020
4 6.4 years 3 (75) Mildtype: 4(100) None of the
children required
treatment with
anti-virals
10.3 2(50) Cough: 2 (50);
Runny nose:1 (25);
Wheeze:1. (25)
1 (25) 1 (25) NA NA NA NA NA
Xia lu China 3 7.2years 1 (33) Mildtype:3 (100) NA 10 3 (100) Cough: 1(33); nasal
congestion: 2 (66);
rhinitis: 2 (66)
2 (66) 2 (66) NA NA NA NA NA
Xing China January
23 to
February
5, 2020
3 5 (1-6)
years
2 (66) Mildto moderate
type:3 (100)
Oral Ribavirin and
traditional Chinese
23 3 (100) NA NA NA NA NA NA NA 1(33)
Ji China January
25 to
February
3, 2020
2 12 years 2 (100) Mild type:2 (100) Symptomatic
treatment; Oral
probiotic
NA 0 (0) pharyngeal
congestion:1 (50)
1 (50) 1(50) NA NA NA NA NA
Abbreviations: SD, standard deviation; IQR, interquartile range; GI, gastrointestinal; NA, not available; No, number; ALT, alanine aminotransferase (normal range 0 - 42 U/L); AST,aspartate aminotransferase (normal range 0 - 37 U/L); LDH,
Lactate dehydrogenase (normal range 0 - 225 U/L)
aSevere disease was defined as the American Thoracic Society and Infectious Disease Society of America guidelines for community-acquired pneumonia, need of ICU admission, and death.
bIf all gastrointestinal symptoms were not reported and the number of events of any individual GI symptoms was less than one, it was regarded as “not available” and was excluded from the meta-analysis of all gastrointestinal symptoms.
However,this study was still included in the meta-analysis of individualgastrointestinal symptom if theproportion of patientswith that symptom was reported.
Iran J Pediatr. 2020; 30(5):e106935. 9
