The novel coronavirus (SARS-CoV-2) outbreak started in China in December 2019. The rapid transmission of the infection and its virulence forced the World Health Organization to declare the associated disease (COVID-19) an international public health emergency.
The typical clinical picture of COVID-19 in previously healthy children is a mild or even asymptomatic disease, with practically no associated mortality. It is well known that fever and respiratory symptoms, such as dry cough or dyspnea, are the most frequently observed. However, as knowledge of COVID-19 has progressed, symptoms affecting any other organ or system have been described.1
Frequency of gastrointestinal (GI) symptoms, previously thought to be scarce, has increased with the progression of the pandemic. They are of special interest in the pediatric age group, especially after the first descriptions of a multisystemic inflammatory syndrome (MIS-C), resembling Kawasaki Disease, in which GI symptoms such as diarrhea, abdominal pain, or vomiting are prominent.2
Uncertainties about this disease are greater at the pediatric age. The objective of our study was to describe COVID-19 GI manifestations of hospitalized pediatric patients.
METHODS
Study Design
Multicenter, descriptive, observational study conducted in 15 hospitals in Spain, in COVID-19 pediatric patients admitted from March 1 to June 3, 2020.
Inclusion Criteria
- Patients between 1 month and 18 years admitted to hospitals with a COVID-19 diagnosis who met at least 1 of the following:
- - Positive real time polymerase chain reaction (PCR) for SARS-CoV-2 in nasopharyngeal swab.
- - Clinical suspicion (compatible symptoms in patients with a close contact positive for COVID-19 or respiratory infection plus compatible radiography in epidemiologic situation of community transmission or MIS-C2) and positive ELISA IgG or IgM for SARS-CoV-2.
Data Collection
Data were collected anonymously. Participating hospitals received a unique site code and investigators gave an additional identification code to each patient. Investigators in charge of analysis were not able to identify individual patients based on those data.
The following data were retrieved from the electronic medical records of the admitted patients.
- (1) Epidemiologic data: gender, date of birth, date of admission, age, date of hospital discharge, and length of hospital stay.
- (2) Clinical data: history of chronic disease, treatment with immunomodulators, admission to pediatric intensive care unit, GI and extradigestive symptoms, and specific COVID-19 treatment received (lopinavir-ritonavir, remdesivir, tocilizumab, azithromycin, other antibiotics, steroids, hydroxychloroquine, or immunoglobulins).
Reasons for admission were divided into 2 categories: those related to clinical complications derived from COVID-19 infection (respiratory failure, shock, MIS-C, etc.) and those related to previous underlying conditions or clinical complications not related to COVID-19 (surgical pathology, other infections, etc).
- (3) Analytical determinations at admission
Carried out with automated methods at each center by certified labs: lymphocyte and platelet count, aspartate aminotransferase (AST), alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, total and direct bilirubin, lactate dehydrogenase, total proteins, albumin, ferritin and acute phase reactants: C-reactive protein (CRP) and procalcitonin (PCT).
Hypertransaminasemia was considered when AST and alanine aminotransferase values exceeded the upper normal limit of each laboratory. Cholestasis was considered in cases with direct bilirubin >1 mg/dL.
Statistical Analysis
Data were analyzed using Stata version 13.0. Variables with normal distribution were reported as mean and standard deviation, while those that did not meet the normality requirements as median and interquartile range. Categorical variables were expressed as percentages. Two-tailed t tests were used for comparison of means between groups. χ2 tests were used to compare proportions. A stepwise logistic regression analysis was used to calculate the risk of pediatric intensive care unit admission. A P value <0.05 was deemed statistically significant.
Study protocol was approved by the Ethics Regional Committee (reference number 2020.205).
RESULTS
One hundred twenty patients were initially included. Ten patients were withdrawn for age younger than 1 month, 6 due to absence of data, and 3 additional cases with clinical suspicion were discarded by negative PCR and serology. Finally, 101 fulfilled all the inclusion criteria: 91 patients (90.1%) had a positive PCR for SARS-CoV-2; 6 (5.9%) met the clinical suspicion criteria and had a negative PCR, negative IgM, and positive IgG serology; and 4 (4.0%) had clinical suspicion, negative PCR, positive IgG, and IgM serology. A general description of the sample is displayed in Table 1.
TABLE 1. -
Epidemiologic, Clinical, and Laboratory Characteristics of the Sample
| Characteristics |
All Cases
N = 101 |
Gastrointestinal Symptoms |
P
|
| Yes (n = 58) |
No (n = 43) |
Age
median (interquartile range) |
9.4 (3.0–12.2) |
9.0 (5.2–11.9) |
9.8 (0.9–12.7) |
0.777 |
| Age group, n (%) |
|
|
|
|
| <2 |
25 (24.8) |
11(19.0) |
14(32.6) |
0.128 |
| 2–10 |
28 (27.7) |
20(34.5) |
8(18.6) |
|
| >10 |
48 (47.5) |
27(46.6) |
21(48.8) |
|
| Sex, n (%) |
|
|
|
|
| Male |
58(57.4) |
36(62.1) |
2(51.2) |
0.273 |
| Female |
43 (42.6) |
22(37.9) |
21(48.8) |
|
| Immunosuppressive therapy, n (%) |
10 (9.9) |
4 (6.9) |
6(14.0) |
0.240 |
| Underlying medical condition, n (%) |
33 (32.67) |
8 (13.79) |
25 (58.14) |
<0.001 |
| Cardiac |
3 (2.97) |
0 (0) |
3(6.98) |
|
| Gastrointestinal |
3 (2.97) |
2 (3.45) |
1(2.33) |
|
| Hematologic |
4 (3.96) |
1 (1.72) |
3(6.98) |
|
| Nephropathy |
2 (1.98) |
0 (0) |
2(4.65) |
|
| Neurologic |
3 (2.97) |
1 (1.72) |
2(4.65) |
|
| Oncologic |
6 (5.94) |
3 (5.17) |
3(6.98) |
|
| Rheumatic |
1 (0.99) |
0 (0) |
1(2.33) |
|
| Preterm birth |
1(0.99) |
0 (0) |
1(2.33) |
|
| Psychiatric |
4 (3.96) |
0 (0) |
4(9.30) |
|
| Respiratory |
3 (2.97) |
1 (1.72) |
2(4.65) |
|
| Other |
3 (2.97) |
0 (0) |
3(6.98) |
|
| Reason for admission, n (%) |
|
|
|
<0.001 |
| Non clinical |
26 (26) |
9(15.5) |
17(39.5) |
|
| Clinical |
75 (74) |
49 (84.5) |
26 (60.5) |
|
| Respiratory |
30 (29.7) |
16 (27.59) |
14(32.56) |
|
| Bacteremia/sepsis |
9 (8.9) |
9 (15.52) |
0 (0) |
|
| Cardiocirculatory(myocarditis) |
5 (5.0) |
2 (3.45) |
3 (6.98) |
|
| MIS-C |
11 (10.9) |
11 (18.97) |
0 (0) |
|
| Protracted fever |
8 (7.9) |
2 (3.45) |
6 (13.95) |
|
| Neurologic |
6 (5.9) |
4 (6.90) |
2 (4.65) |
|
| Digestive |
5 (5.0) |
5 (8.62) |
0 (0) |
|
| Others |
1 (1.0) |
0 (0) |
1(2.33) |
|
| PICU admission, n (%) |
30 (29.7) |
23 (39.7) |
7 (16.3) |
0.011 |
Length of stay
median (interquartile range) |
N = 94
5 (3–10) |
N = 56
7 (3–10) |
N = 38
5 (2–10) |
0.174 |
| Initial symptom, n (%) |
|
|
|
|
| Fever |
60 (61.86) |
36 (62.07) |
24 (61.54) |
<0.001 |
| Gastrointestinal |
14 (14.43) |
14 (24.14) |
0 (0) |
|
| Cough |
10 (10.31) |
3 (5.17) |
7 (17.95) |
|
| Respiratory distress |
8 (8.25) |
1 (1.72) |
7 (17.95) |
|
| Thoracic pain |
1 (1.03) |
1 (1.72) |
0 (0) |
|
| Headache |
3 (3.09) |
3 (5.17) |
0 (0) |
|
| Psychiatric |
1 (1.03) |
0 (0) |
1 (2.56) |
|
| Gastrointestinal symptoms, n (%) |
|
|
|
|
| Abdominal pain |
35 (34.7) |
|
|
|
| Nausea/vomiting |
35 (34.7) |
|
|
|
| Diarrhea |
33 (32.7) |
|
|
|
| At least 1 of the previous |
58 (57.4) |
|
|
|
| Extraintestinal symptoms, n (%) |
|
|
|
|
| Fever |
82 (81.2) |
50 (86.2) |
32 (74.4) |
0.134 |
| Respiratory |
60 (59.4) |
32 (55.2) |
28 (65.1) |
0.314 |
| Headache |
17 (16.8) |
11 (19.0) |
6 (14.0) |
0.448 |
| Odynophagia |
7 (6.9) |
5 (8.6) |
2 (4.7) |
0.437 |
| Myalgia |
10 (9.9) |
8 (13.8) |
2 (4.7) |
0.128 |
| Skin rash |
11 (10.9) |
9 (15.5) |
2 (4.7) |
0.083 |
| Anosmia |
4 (4.0) |
2 (3.5) |
2 (4.7) |
0.759 |
| Laboratory values |
|
|
|
|
| median (interquartile range) |
|
|
|
|
| Lymphocytes (cells/µL) n = 94 |
1710 (790–2990) |
N = 57 1500 (670–2800) |
N = 37 2300 (890–2990) |
0.577 |
| Platelets (×109/L) n = 93 |
243 (146–330) |
N = 57, 228 (146–330) |
N = 36, 244 (119–348) |
0.801 |
| AST (UI/L) n = 76 |
33 (24–47) |
N = 45, 36 (26–56) |
N = 31, 29 (21–39) |
0.432 |
| ALT (UI/L) n = 79 |
24 (14–40) |
N = 48, 24 (15–45) |
N = 31, 20 (14–37) |
0.490 |
| GGT (UI/L) n = 61 |
21 (14–45) |
N = 37, 25 (14–50) |
N = 24, 20 (14–43) |
0.442* |
| Alkalyne phosphatase (UI/L) n = 55 |
135 (104–228) |
N = 32, 134 (107–186) |
N = 23, 151 (100–240) |
0.952 |
| Total protein (g/dL) n = 58 |
6.4 (6.0–7.2) |
N = 34, 6.4 (5.9–7.2) |
N = 24, 6.3 (6.1–7.2) |
0.501 |
| Albumin (g/dL) n = 60 |
3.7 (3.3–4.3) |
N = 35, 3.5 (2.9–4.0) |
N = 25, 3.9 (3.5–4.5) |
0.034 |
| Total bilirubin(mg/dL) n = 54 |
0.5 (0.32–0.66) |
N = 34, 0.5 (0.31–0.60) |
N = 20, 0.5 (0.33–0.77) |
0.687* |
| Direct bilirrubin (mg/dL) n = 15 |
0.36 (0.25–0.60) |
N = 6, 0.44 (0.12–0.60) |
N = 9, 0.35 (0.27–0.44) |
0.814* |
| LDH (UI/L) n = 69 |
318 (230–372) |
N = 41, 322 (276–440) |
N = 28, 275 (213–359) |
0.119* |
| Ferritin (ng/mL) n = 48 |
290 (111–1118) |
N = 33, 372 (158–1277) |
N = 15, 167 (79–383) |
0.065* |
| CRP (mg/dL) n = 78 |
3.3 (0.6–18.3) |
N = 46, 13.9 (1.58–20.6) |
N = 32, 0.9 (0.2–5.2) |
0.004 |
| PCT (ng/mL) n = 59 |
0.23 (0.09–2.82) |
N = 36, 1.78 (0.11–3.64) |
N = 23, 0.12 (0.04–0.26) |
0.015* |
*Non parametric test Mann Whitney-Wilcoxon test.
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; GGT, gamma-glutamyl transpeptidase; LDH, lactate dehydrogenase; MIS-C, multisystem inflammatory syndrome in children; PCT, procalcitonin; PICU, pediatric intensive care unit.
Gastrointestinal symptoms were the first manifestation of the disease in 14% of the cases. Twenty-five patients showed GI symptoms in the absence of respiratory symptoms.
Mild elevation of liver enzymes was observed in 29 patients (40%) but only 9% of the subjects exceeded 2 times the upper reference value.
Patients with digestive symptoms tended to have higher CRP and PCT levels and received antibiotics, Lopinavir-ritonavir, corticosteroids, and immunoglobulins more frequently (Table 1).
Those patients admitted to the PICU (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/E149) had a higher frequency of digestive symptoms, headache, myalgia, and rashes, as well as higher CRP, PCT, ferritin and AST values, and lower albumin, proteins, and platelets. Adjusted by age, gender, immunosuppressive therapy, and previous underlying conditions, patients with GI symptoms had a higher risk of PICU admission (OR 5.90, 95% confidence interval: 1.67–20.83, P = 0.006). Results of the multivariate analysis are detailed in Table (Supplemental Digital Content 2, https://links.lww.com/INF/E150).
DISCUSSION
Digestive symptoms usually appear early during the course of COVID-19, even before the onset of fever or respiratory symptoms. The first published case of confirmed SARS-CoV-2 infection in the United States had a 2-day history of nausea, vomiting, and diarrhea before the onset of respiratory symptoms.3 In our study, GI symptoms were the third in frequency, behind fever and respiratory symptoms, affecting more than half of the patients. Moreover, they were the first manifestation of the disease in 14% of the patients. One in every 4 patients admitted to hospital showed digestive symptoms in the absence of respiratory signs. These data suggest that COVID-19 may initially resemble acute infectious gastroenteritis of any etiology, a circumstance that could lead to a diagnostic delay in the pediatric age range.
Regardless of age, in the first published COVID-19 series, the proportion of patients with GI symptoms was lower than 10%.1 However, as the pandemic spread, this prevalence has increased.4 A study, including hospitalized adult patients, showed that GI symptoms increased from 19% in those cases admitted between January and early February 2020 to 43% in those admitted between the end of February and March.5 This increase may not only be due to the growing awareness of clinicians allowing the recognition of nonrespiratory symptoms but also to the presence of new mutations that may enable the increase of the viral tropism for the GI tract.
The presence of GI symptoms in COVID-19 affected adults is associated to more severe disease.6 In a series of 232 adult patients, those with diarrhea had a higher risk of ICU admission (OR 4.95) regardless of age, sex, or associated comorbidities.5 Our data are in concordance with those results: the presence of GI symptoms and more specifically nausea and vomiting were associated with an increased risk of admission to the PICU, independently of other confounding factors.
COVID-19 infection in children shows unique features. All published series agree on its usual mildness, with a high proportion of asymptomatic patients and very low mortality. However, an association between SARS-CoV-2 infection and the appearance of a very serious clinical picture, called pediatric multisystem inflammatory syndrome, has been described.2,7 Pathophysiology of MIS-C is still unclear. In a recent case series, children with MIS-C had significantly higher SARS-CoV-2 binding and neutralizing antibodies than children with COVID-19 or Kawasaki Disease. MIS-C might be different from other syndromes with similar clinical appearances, with features including an age at onset greater than 7 years, diffuse cardiovascular involvement and elevated quantitative SARS-CoV-2 binding and neutralizing antibodies.8
Gastrointestinal symptoms are increasingly recognized to be associated with the presentation of MIS-C. In 2 recently reported series of 35 and 44 pediatric patients with MIS-C, more than 80% showed some type of digestive involvement.9,10 In our study, 11 patients with MIS-C were included, all of them showing GI symptoms.
Our study has several strengths. It is a multicenter study, involving 15 hospitals in Spain, one of the most impacted countries during the pandemic in Europe. As a consequence, our sample is probably the largest published in pediatric hospitalized patients with COVID-19.
As a limitation of the study, we want to acknowledge the fact that although the development of the project started early in the course of the pandemic in Spain, the majority of the data were retrospectively retrieved.
In conclusion, gastrointestinal symptoms are frequent in COVID-19 pediatric patients admitted to hospital. These symptoms are also predictive of severity, regardless to other confounding factors.
ACKNOWLEDGMENTS
We want to acknowledge the work of Spanish Society of Gastroenterology Hepatology and Pediatric Nutrition members who participated in this study: Elena Balmaseda Serrano, Antonio Rosell Camps, José Ramón Alberto Alonso, José Ignacio García Burriel, Myriam Herrero Alvarez, Jorge Martinez Perez, Nuria Puente Ubierna, Johanna Marcela Martinez Osorio, Andres Bodas Pinedo, Cristina Molinos Norniella, and David Perez Solis.
REFERENCES
1. Guan WJ, Ni ZY, Hu Y, et al.; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
2. WHO. Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. Available from:
https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19. Accessed June 17, 2020.
3. Holshue ML, DeBolt C, Lindquist S, et al.; Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382:929–936.
4. Pan L, Mu M, Yang P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol. 2020;115:766–773.
5. Wan Y, Li J, Shen L, et al. Enteric involvement in hospitalised patients with COVID-19 outside Wuhan. Lancet Gastroenterol Hepatol. 2020;5:534–535.
6. Jin X, Lian JS, Hu JH, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with
gastrointestinal symptoms. Gut. 2020;69:1002–1009.
7. Jiang L, Tang K, Levin M, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020S1473-3099(20)–30651-4. doi: 10.1016/S1473-3099(20)30651-4. [Epub ahead of print]
8. Rostad CA, Chahroudi A, Mantus G, et al. Quantitative
SARS-CoV-2 serology in children with Multisystem Inflammatory Syndrome (MIS-C). Pediatrics. 2020.
9. Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global
SARS-CoV-2 pandemic. Circulation. 2020. doi: 10.1161/CIRCULATIONAHA.120.048360. [Epub ahead of print]
10. Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis K. G.
Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children that is related to coronavirus disease 2019: a single center experience of 44 cases. Gastroenterology. 2020S0016-5085(20)–34753-3. doi: 10.1053/j.gastro.2020.05.079. [Epub ahead of print]
