Relationship between gastrointestinal symptoms and COVID-19 infection in the pediatric population: a scoping review

Desconsi, Denise; Araujo, Juliane Pagliari; Furtado, Marcela Demitto; Pimenta, Rosângela Aparecida; Zani, Adriana Valongo

doi:10.1590/1980-220X-REEUSP-2023-0365en

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REVIEW • Rev. esc. enferm. USP 58 • 2024 • https://doi.org/10.1590/1980-220X-REEUSP-2023-0365en copy

Relationship between gastrointestinal symptoms and COVID-19 infection in the pediatric population: a scoping review

Relación entre síntomas gastrointestinales e infección por COVID-19 en la población pediátrica: revisión del alcance

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To map the evidence in the literature about the relationship between gastrointestinal symptoms and COVID-19 in the pediatric population.

Method:

This is a scoping review following the recommendations of the Joanna Briggs Institute and PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. The search was carried out on the following bases: Embase, Google Scholar, PubMed, Scopus, LILACS, CINAHL, Scielo, Web of Science and Virtual Health Library Portal, between July and August 2023. Original studies available in full, in any language, were included.

Results:

Ten studies were chosen that pointed to three premises: (1) the ACE2 receptor is found in the epithelial cells of the gastrointestinal tract; (2) gastrointestinal symptoms are mediated by stress and infection is justified by the gut-brain axis; (3) it develops the process of Multisystem Inflammatory Syndrome in children, affecting the gastrointestinal tract.

Conclusion:

The synthesis of evidence provided three assumptions which guide the origin of gastrointestinal symptoms. The identification of gastrointestinal symptoms in children affected by COVID-19 can assist in the clinical approach and management of care and treatments.

DESCRIPTORS
Child; Infant; Newborn; Gastrointestinal Tract; COVID-19

Base	Search Strategy	Results found
EMBASE	#1 child OR newborn AND “gastrointestinal tract” AND COVID-19 #2 child OR newborn OR infant AND “gastrointestinal tract” AND COVID-19 #3 infant premature OR child OR infant OR newborn AND “gastrointestinal tract” AND “SARS-CoV-2 infection”	110 78 79
Google Scholar	#1 infant premature OR child OR infant OR newborn AND “gastrointestinal tract” AND “SARS-CoV-2 infection” #2 lactente AND trato gastrointestinal AND infecção por SARS-CoV-2	2128 236
PubMed	#1 child OR newborn AND “gastrointestinal tract” AND COVID-19 #2 infant premature OR child OR infant OR newborn AND “gastrointestinal tract” AND “SARS-CoV-2 infection”	1866 1089
Scopus	#1 child OR newborn AND “gastrointestinal tract” AND COVID-19 #2 child OR newborn OR infant AND “gastrointestinal tract” AND COVID-19 #3 infant premature OR child OR infant OR newborn AND “gastrointestinal tract” AND “SARS-CoV-2 infection”	340 74 05
LILACS	#1 criança AND recém-nascido AND COVID-19 #2 criança OR recém-nascido AND COVID-19 #3 neonato AND trato gastrointestinal AND COVID-19 #4 criança recém-nascida AND trato gastrointestinal AND COVID-19 #5 recém-nascido AND aparelho gastrointestinal AND doença por Coronavírus 2019 #6 recém-nascido OR prematuro AND trato gastrointestinal AND COVID-19 #7 neonato OR recém-nascido AND trato gastrointestinal AND COVID-19 #8 recém-nascido OR criança AND tubo digestório AND infecção por SARS-CoV-2 #9 lactente AND trato gastrointestinal AND infecção por SARS-CoV-2 #10 lactente OR prematuro AND trato gastrointestinal AND COVID-19	35 0 0 0 1 0 3 0 4 0
CINAHL	#1 child AND “gastrointestinal tract” AND COVID-19 #2 child OR newborn OR infant AND “gastrointestinal tract” AND COVID-19 #3 newborn AND “gastrointestinal tract” AND COVID-19 #4 newborn AND “gastrointestinal tract” OR “digestive tube” AND COVID-19	16 120 1 80
Scielo	#1 infant premature OR child OR infant OR newborn AND “gastrointestinal tract” AND “SARS-CoV-2 infection” #2 child OR newborn OR infant AND “gastrointestinal tract” AND COVID-19 #3 child OR newborn AND “gastrointestinal tract” AND COVID-19	0 0 0
Web of Science	#1 child AND “gastrointestinal tract” AND COVID-19	77
VHS	#1 child AND “gastrointestinal tract” AND COVID-19 #2 infant premature OR child OR infant OR newborn AND “gastrointestinal tract” AND “SARS-CoV-2 infection” #3 child OR newborn OR infant AND “gastrointestinal tract” AND COVID-19	89 16 37

Authors	Objective	Population	Design of study
Xu et al.⁽³⁵⁾35. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020;26(4):502–5. doi: http://doi.org/10.1038/s41591-020-0817-4. PubMed PMID: 32284613. https://doi.org/10.1038/s41591-020-0817-...	To report the initial epidemiological and clinical features of SARS-CoV-2 infection tested for evidence of viral excretion through the gastrointestinal and respiratory tracts.	Children aged 0 to 18.	Case report
Miller et al.⁽³⁶⁾36. Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis KG. 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. 2020;159(4):1571–1574 e2. doi: http://doi.org/10.1053/j.gastro.2020.05.079. PubMed PMID: 32505742. https://doi.org/10.1053/j.gastro.2020.05...	To evaluate the prevalence and presentations of gastrointestinal symptoms derived from pediatric multisystem inflammatory syndrome related to COVID-19.	Children between 7 months and 20 years old.	Retrospective
Giacomet et al.⁽³⁷⁾37. Giacomet V, Barcellini L, Stracuzzi M, Longoni E, Folgori L, Leone A, et al. Gastrointestinal symptoms in severe COVID-19 children. J Pediatr Infect Dis. 2020;39(10):e317–20. doi: http://doi.org/10.1097/INF.0000000000002843. PubMed PMID: 32932333. https://doi.org/10.1097/INF.000000000000...	To describe the results of a preliminary analysis of a cohort of pediatric patients hospitalized with COVID-19 with a focus on mode of presentation, presence of comorbidities, disease severity, and early outcome.	Children between 1 and 18 years old.	Multicenter retrospective
Dooki et al.⁽³⁸⁾38. Dooki ME, Mehrabani S, Sorki H, Nikpour M, Tabatabaie M, Mohammadi M, et al. COVID-19 and digestive system in children: a retrospective study. Arch Iran Med. 2020;23(11):782–6. doi: http://doi.org/10.34172/aim.2020.104. PubMed PMID: 33220697. https://doi.org/10.34172/aim.2020.104...	To determine the presentations of gastrointestinal and liver injuries in children admitted with COVID-19 infection to Amirkola Children’s Hospital.	Children between 2 months and 18 years old.	Retrospective
Souza et al.⁽³⁹⁾39. Souza AL, Matos F, Flintz R, Marliere R, Presti M, Falconiere C. Manifestações gastrointestinais como apresentação inicial da COVID-19 em pediatria. Residência Pediátrica. 2020;10(3):1–3. doi: http://doi.org/10.25060/residpediatr-2020.v10n3-366. https://doi.org/10.25060/residpediatr-20...	To highlight gastrointestinal manifestations as the initial presentation of SARS-CoV-2, through the analysis of pediatric patients followed in the pediatric intensive care unit of an emergency hospital, diagnosed with COVID-19.	Children aged 0 to 14.	Retrospective
Lo Vecchio et al.⁽⁴⁰⁾40. Lo Vecchio A, Garazzino S, Smarrazzo A, Venturini E, Poeta M, Berlsese P, et al. Factors associated with severe gastrointestinal diagnoses in children with SARS-CoV-2 infection or multisystem inflammatory syndrome. JAMA Netw Open. 2021;4(12):e2139974. doi: http://doi.org/10.1001/jamanetworkopen.2021.39974. PubMed PMID: 34928354. https://doi.org/10.1001/jamanetworkopen....	To describe the clinical, radiological and histopathological characteristics of children with COVID-19 presenting severe gastrointestinal manifestations.	Children under 18.	Multicenter retrospective cohort
Berni Canani et al.⁽⁴¹⁾41. Berni Canani R, Comegna M, Paparo L, Cernera G, Bruno G, Strisciuglio C, et al. Age-related differences in the expression of most relevant mediators of SARS-CoV-2 infection in human respiratory and gastrointestinal tract. Front Pediatr. 2021;9:697390. doi: http://doi.org/10.3389/fped.2021.697390. PubMed PMID: 34395341. https://doi.org/10.3389/fped.2021.697390...	To evaluate the expression of the most relevant mediators of SARS-CoV-2 infection: ACE2, ACE1, TMPRSS2 and NRP1, in the upper respiratory tract and small intestine of children.	Children aged 1 to 10.	Prospective observational
Farello et al.⁽⁴²⁾42. Farello G, Di Lucia A, Fioravanti A, Tambucci B, Stagi R, Gaudino S. Analysis of the impact of COVID-19 pandemic on functional gastrointestinal disorders among paediatric population. Eur Rev Med Pharmacol Sci. 2021;25(18):5836–42. doi: http://doi.org/10.26355/eurrev_202109_26802. PubMed PMID: 34604975. https://doi.org/10.26355/eurrev_202109_2...	To assess the impact of the COVID-19 pandemic on the prevalence of functional gastrointestinal disorders in Italian children and adolescents.	Children between 10 and 17 years old.	Cross-sectional with case report
Stepan et al.⁽⁴³⁾43. Stepan MD, Cioboata R, Vintilescu SB, Vasile CM, Osman A, Ciolofan MS, et al. Pediatric functional abdominal pain disorders following COVID-19. Life. 2022;12(4):509. doi: http://doi.org/10.3390/life12040509. PubMed PMID: 35455000. https://doi.org/10.3390/life12040509...	To investigate the functional disorders of abdominal pain in preschool children affected by a viral infection, according to the most recent diagnostic criteria.	Children aged 4 to 6 years.	Retrospective, observational descriptive and analytical
Vasichkin et al.⁽⁴⁴⁾44. Vasichkina E, Kofeynikova O, Fetisova S, Starshinova AY, Sheyanova E, Vershinina T, et al. Severe course of COVID-19 and long-COVID-19 in children: difficulties in diagnosis. Life. 2023;13(3):781. doi: http://doi.org/10.3390/life13030781. PubMed PMID: 36983936. https://doi.org/10.3390/life13030781...	To report clinical cases that demonstrate difficulties in diagnosing polyorganic disorders in children infected by SARS-CoV-2 at different periods of the disease.	Children aged 7 and 12.	Case report

ID	Main gastrointestinal symptoms	Tests carried out	Association of gastrointestinal symptoms with COVID-19
Xu et al.⁽³⁵⁾35. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020;26(4):502–5. doi: http://doi.org/10.1038/s41591-020-0817-4. PubMed PMID: 32284613. https://doi.org/10.1038/s41591-020-0817-...	Diarrhea (30%).	Tomography, blood count and RT-PCR.	Positive real-time RT-PCR results were observed in rectal swabs of children, which remain detectable after nasopharyngeal swabs become negative, suggesting that the GI tract may release virus and fecal-oral transmission may be possible.
Miller et al.⁽³⁶⁾36. Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis KG. 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. 2020;159(4):1571–1574 e2. doi: http://doi.org/10.1053/j.gastro.2020.05.079. PubMed PMID: 32505742. https://doi.org/10.1053/j.gastro.2020.05...	Nausea (29.5%), vomiting (29.5%), and abdominal pain (29.5%).	PCR, erythrocyte sedimentation rate, albumin, ALT, AST, Ultrasound, resonance.	SARS-CoV-2 triggers the process of Multisystem Inflammatory Syndrome in Children and subsequent symptoms arising from this inflammation affect the GI tract.
Giacomet et al.⁽³⁷⁾37. Giacomet V, Barcellini L, Stracuzzi M, Longoni E, Folgori L, Leone A, et al. Gastrointestinal symptoms in severe COVID-19 children. J Pediatr Infect Dis. 2020;39(10):e317–20. doi: http://doi.org/10.1097/INF.0000000000002843. PubMed PMID: 32932333. https://doi.org/10.1097/INF.000000000000...	Vomiting (22%), diarrhea (9.4%), and abdominal pain (6.3%).	Radiography.	The GI tract is a target for SARS-CoV-2 due to the expression of angiotensin-converting enzyme 2 being one of the main receptors for the virus.
Dooki et al.⁽³⁸⁾38. Dooki ME, Mehrabani S, Sorki H, Nikpour M, Tabatabaie M, Mohammadi M, et al. COVID-19 and digestive system in children: a retrospective study. Arch Iran Med. 2020;23(11):782–6. doi: http://doi.org/10.34172/aim.2020.104. PubMed PMID: 33220697. https://doi.org/10.34172/aim.2020.104...	Anorexia (83.3%), nausea (38.9%), vomiting (38.9%), diarrhea (33.3), and abdominal pain (33.3).	ALT, AST, ALP, prothrombin, thromboplastin, TTP, INR, Albumin, Direct and Total Bilirubin, PCR, Sedimentation Rate, Erythrocytes, Tomography, Radiography, and Ultrasonography.	The interaction between ACE2 and the SARS-CoV-2 virus may occur due to the receptors being present in the gastrointestinal system, as well as to a cytokine storm and dysregulation of the intestinal flora through immunological mechanisms.
Souza et al.⁽³⁹⁾39. Souza AL, Matos F, Flintz R, Marliere R, Presti M, Falconiere C. Manifestações gastrointestinais como apresentação inicial da COVID-19 em pediatria. Residência Pediátrica. 2020;10(3):1–3. doi: http://doi.org/10.25060/residpediatr-2020.v10n3-366. https://doi.org/10.25060/residpediatr-20...	Fever (100%), abdominal pain (30%), and jaundice (15%).	Ultrasound, PCR-RT and blood count.	The emergence of gastrointestinal symptoms is due to the Coronavirus entering cells that use the ACE2 enzyme receptor. The receptor is found in large quantities in lung cells, but also in epithelial cells of the esophagus, ileum and colon.
Lo Vecchio et al.⁽⁴⁰⁾40. Lo Vecchio A, Garazzino S, Smarrazzo A, Venturini E, Poeta M, Berlsese P, et al. Factors associated with severe gastrointestinal diagnoses in children with SARS-CoV-2 infection or multisystem inflammatory syndrome. JAMA Netw Open. 2021;4(12):e2139974. doi: http://doi.org/10.1001/jamanetworkopen.2021.39974. PubMed PMID: 34928354. https://doi.org/10.1001/jamanetworkopen....	Diarrhea (87.7%), vomiting (60%), nausea (28.6%), anorexia (28.6%), pain and abdominal distension (20.3%).	Ferritin, ALT, Abdominal ultrasound, intra-abdominal fluid/tissue samples.	SARS-CoV-2 has direct action on cells, due to the abundant expression of ACE2 and TMPRSS2 binding receptors on the surface of enterocytes, facilitating the entry of RNA into the cell. The GI tract is a potential target of immune-mediated inflammatory response by SARS-CoV-2.
Berni Canani et al.⁽⁴¹⁾41. Berni Canani R, Comegna M, Paparo L, Cernera G, Bruno G, Strisciuglio C, et al. Age-related differences in the expression of most relevant mediators of SARS-CoV-2 infection in human respiratory and gastrointestinal tract. Front Pediatr. 2021;9:697390. doi: http://doi.org/10.3389/fped.2021.697390. PubMed PMID: 34395341. https://doi.org/10.3389/fped.2021.697390...	Abdominal pain (90%), vomiting (90%), constipation (90%) and diarrhea (50%).	Cytology of epithelial samples, intestinal epithelial biopsy, PCR, IgG, IgM, AST, ALT, CBC.	In the small intestine, ACE2 expression is higher in children. The ACE2 receptor acts as a gateway for the virus and TMPRSS2 is used by SARS-CoV-2 to initiate the protein spike, and NRP1, a SARS-CoV-2 coreceptor, increases the virus’s ability to enter and enhances infection in host cells.
Farello et al.⁽⁴²⁾42. Farello G, Di Lucia A, Fioravanti A, Tambucci B, Stagi R, Gaudino S. Analysis of the impact of COVID-19 pandemic on functional gastrointestinal disorders among paediatric population. Eur Rev Med Pharmacol Sci. 2021;25(18):5836–42. doi: http://doi.org/10.26355/eurrev_202109_26802. PubMed PMID: 34604975. https://doi.org/10.26355/eurrev_202109_2...	Abdominal pain (13.6%), rumination (2.7%), constipation (13.6%).	Rome III Criteria (For non-organic diseases).	The COVID-19 pandemic generated anxiety in healthy people and exacerbated pre-existing mental illnesses. Social restrictions represented a threat to the mental health of children and adolescents, being a source of stress that, combined with changes in routine, generates a trigger for the appearance of episodes of abdominal pathology and the recurrence of symptoms related to irritable bowel syndrome.
Stepan et al.⁽⁴³⁾43. Stepan MD, Cioboata R, Vintilescu SB, Vasile CM, Osman A, Ciolofan MS, et al. Pediatric functional abdominal pain disorders following COVID-19. Life. 2022;12(4):509. doi: http://doi.org/10.3390/life12040509. PubMed PMID: 35455000. https://doi.org/10.3390/life12040509...	Abdominal pain (60.9%).	Rome IV Criteria (For non-organic diseases).	Functional gastrointestinal disorders are mediated by stress; psychosocial health in the pandemic has had long-term repercussions. SARS-CoV-2 infection is justified by the gut-brain axis where they are connected, providing viral infection.
Vasichkina et al.⁽⁴⁴⁾44. Vasichkina E, Kofeynikova O, Fetisova S, Starshinova AY, Sheyanova E, Vershinina T, et al. Severe course of COVID-19 and long-COVID-19 in children: difficulties in diagnosis. Life. 2023;13(3):781. doi: http://doi.org/10.3390/life13030781. PubMed PMID: 36983936. https://doi.org/10.3390/life13030781...	Suppressed appetite (100%), abdominal pain (100%), semi-liquid stools (100%).	PCR, procalcitonin, ferritin, D-dimer, x-ray, echocardiogram.	Multisystem inflammatory syndrome in children can be caused after COVID-19 and after SARS-2-CoV-2 infection and long-COVID-19, with the persistence of the virus. The presence of comorbidities is a risk factor for the development of the syndrome.

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[1] Corresponding author: Denise Desconsi, Av. Robert Koch, 60, Operária, 86038-350 – Londrina, PR, Brazil, desconsid@gmail.com