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

RESUMEN

Objetivo:

Mapear la evidencia en la literatura sobre la relación entre síntomas gastrointestinales y COVID-19 en la población pediátrica.

Método:

Se trata de revisión de alcance siguiendo las recomendaciones del Instituto Joanna Briggs y PRISMA Extension for Scoping Reviews (PRISMA-ScR): Lista de verificación y explicación. La búsqueda se realizó sobre las siguientes bases: Embase, Google Scholar, PubMed, Scopus, LILACS, CINAHL, Scielo, Web of Science y Portal Biblioteca Virtual en Salud, entre julio y agosto de 2023. Se incluyeron estudios originales disponibles en su totalidad, en cualquier idioma.

Resultados:

Se eligieron 10 estudios que apuntaban a tres premisas: (1) el receptor ACE2 se encuentra en las células epiteliales del tracto gastrointestinal; (2) los síntomas gastrointestinales están mediados por el estrés y la infección está justificada por el eje cerebro-intestino; (3) desarrolla el proceso del Síndrome Inflamatorio Multisistémico en niños, afectando el tracto gastrointestinal.

Conclusión:

La síntesis de evidencia proporcionó tres supuestos que guían el origen de los síntomas gastrointestinales. La identificación de síntomas gastrointestinales en niños afectados por COVID-19 puede ayudar en el abordaje clínico y el manejo de la atención y los tratamientos.

DESCRIPTORES
Niño; Recién Nacido; Tracto Gastrointestinal; COVID-19

RESUMO

Objetivo:

Mapear as evidências na literatura acerca da relação entre sintomas gastrointestinais e a COVID-19 na população pediátrica.

Método:

Trata-se de scoping review seguindo as recomendações do Instituto Joanna Briggs e PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. A busca foi realizada nas bases: Embase, Google Acadêmico, PubMed, Scopus, LILACS, CINAHL, Scielo, Web of Science e Portal da Biblioteca Virtual em Saúde, entre julho e agosto de 2023. Foram incluídos estudos originais disponíveis na íntegra, em qualquer idioma.

Resultados:

Foram eleitos 10 estudos que apontaram para três premissas: (1) o receptor ECA 2 é encontrado nas células epiteliais do trato gastrointestinal; (2) os sintomas gastrointestinais são mediados pelo estresse e a infecção é justificada pelo eixo cérebro-intestino; (3) desenvolve o processo de Síndrome Inflamatória Multissistêmica em crianças, afetando o trato gastrointestinal.

Conclusão:

A síntese de evidências proporcionou três pressupostos os quais orientam a origem dos sintomas gastrointestinais. A identificação dos sintomas gastrointestinais em crianças acometidas por COVID-19 pode auxiliar na abordagem clínica e manejo de cuidados e tratamentos.

DESCRITORES
Criança; Recém-Nascido; Trato Gastrointestinal; COVID-19

INTRODUCTION

Global public health faces challenges with new infectious diseases and other existing diseases⁽¹⁾1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. China Novel Coronavirus Investigating and Research Team. A novel Coronavirus from patients with pneumonia in China. 2019. N Engl J Med. 2020;382(8):727–33. doi: http://doi.org/10.1056/NEJMoa2001017. PubMed PMID: 31978945.
https://doi.org/10.1056/NEJMoa2001017... . Respiratory diseases comprise a broad spectrum, affecting the structures of the upper and lower respiratory systems⁽²⁾2. Santos JNS, Alves SS, Novais AB, Vieira VC, Santos MS. Nasal and oropharyngeal colonization by Staphylococcus aureus in children and adolescents from a neighborhood in the city of Vitória da Conquista, Bahia, Brazil. Rev.Saúde. Com. 2021;17(4):1–12. doi: http://doi.org/10.22481/rsc.v17i4.8497.
https://doi.org/10.22481/rsc.v17i4.8497... , thus leading to the main causes of hospitalizations, morbidities, and mortalities in the world⁽³⁾3. Beber LCC, Gewehr DM, Cecconello L, Sulzbacher MM, Heck TG, Berlezi EM. Risk factors for respiratory diseases in Brazilian children: an integrative review. RIES. 2020;9(1):26–38. doi: http://doi.org/10.33362/ries.v9i1.1660.
https://doi.org/10.33362/ries.v9i1.1660... . In the childhood scenario, respiratory system disorders represent one of the main causes of morbidity and mortality in children under 5 years of age⁽⁴⁾4. Bhurtel R, Pokhrel RP, Kalakheti B. Acute respiratory infections among under-five children admitted in a tertiary hospital of Nepal: a descriptive cross-sectional study. JNMA J Nepal Med Assoc. 2022;60(245):17–21. doi: http://doi.org/10.31729/jnma.6889. PubMed PMID: 35199677.
https://doi.org/10.31729/jnma.6889... .

Brazil presented, between 2012 and 2021, around 22,939 deaths, related to the respiratory system, in children under 10 years of age, and 62.65% of these were in the first year of life⁽⁵⁾5. Sociedade Brasileira de Pneumologia e Tisiologia. Infecções respiratórias. Brasília: SBPT; 2021 [cited 2023 Nov 22]. Available from: https://sbpt.org.br/portal/espaco-sauderespiratoria-infeccoes-respiratorias/.
https://sbpt.org.br/portal/espaco-sauder... . Furthermore, given the consequences of emerging diseases, in 2019 a new disease belonging to the Coronaviridae family was discovered, called COVID-19, which mainly affects the respiratory system⁽⁶⁾6. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–20. doi: http://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013.
https://doi.org/10.1056/NEJMoa2002032... . Given this new discovery, restrictive measures, such as social distancing, were imposed to control the spread of the virus, as there was a lack of scientific knowledge for treatment and prevention⁽⁷⁾7. Li G, De Clercq LG. Therapeutic options for the 2019 novel Coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149–50. doi: http://doi.org/10.1038/d41573-020-00016-0. PubMed PMID: 32127666.
https://doi.org/10.1038/d41573-020-00016... .

At the moment, there are six registered varieties of Coronavirus, namely 229E, OC43, NL63, HKU1, and these four cause flu-like symptoms in people; SARS-CoV (Severe Acute Respiratory Syndrome or SARS) and MERS-CoV (Middle East Respiratory Syndrome or MERS) have the ability to cause severe respiratory syndrome with high fatality rates⁽⁸⁾8. Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019;17(3):181–92. doi: http://doi.org/10.1038/s41579-018-0118-9. PubMed PMID: 30531947.
https://doi.org/10.1038/s41579-018-0118-... . SARS-CoV-2 (Coronavirus Severe Acute Respiratory Syndrome 2) is called Novel Coronavirus-Infected Pneumonia (NCIP) and is part of the betacoronavirus group that encompasses SARS-CoV. It was analyzed and confirmed in bronchoalveolar lavage and, later, genetic sequencing, Polymerase Chain Reaction (PCR) and culture were performed on the first infected patients in Wuhan, China, in 2019⁽⁹⁾9. Tan W, Zhao X, Ma XJ, Wang W, Niu P, Xu W, et al. A novel Coronavirus genome identified in a cluster of pneumonia cases: Wuhan, China 2019-2020. China CDC Wkly. 2020;2(4):61–2. doi: http://doi.org/10.46234/ccdcw2020.017. PubMed PMID: 34594763.
https://doi.org/10.46234/ccdcw2020.017... .

Therefore, at the beginning of the contamination, whole genome sequence analyses, culture of human airway epithelial cells and microscopy were carried out, considering respiratory secretions⁽¹⁾1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. China Novel Coronavirus Investigating and Research Team. A novel Coronavirus from patients with pneumonia in China. 2019. N Engl J Med. 2020;382(8):727–33. doi: http://doi.org/10.1056/NEJMoa2001017. PubMed PMID: 31978945.
https://doi.org/10.1056/NEJMoa2001017... as the predominant means of transmission of the virus. Thus, the child population is exposed to transmission of the virus, which can take place both through direct contact with infected people and through indirect contact with infected surfaces⁽¹⁰⁾10. World Health Organization. Modes of transmission of the COVID-19 virus: scientific brief. Geneva: WHO; 2020 [cited 2020 Nov 17]. Available from: https://www.who.int/news-room/commentaries/detail/modes-of-transmission-of-virus-causing-COVID-19-implications-for-ipc-precaution-recommendations.
https://www.who.int/news-room/commentari... .

The epidemiological and clinical characteristics of children infected with SARS-CoV-2 may be asymptomatic, presenting mild symptoms such as fever, cough, runny nose, headache, nausea, vomiting, and diarrhea(¹¹11. Park JY, Han MS, Park KU, Kim JY, Choi EH. First pediatric case of coronavirus disease 2019 in Korea. J Korean Med Sci. 2020;35(11):e124. doi: http://doi.org/10.3346/jkms.2020.35.e124. PubMed PMID: 32193905.
https://doi.org/10.3346/jkms.2020.35.e12... ,¹²12. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational Cohort study. Lancet. 2020;395(10239):1771–8. doi: http://doi.org/10.1016/S0140-6736(20)31103-X. PubMed PMID: 32410760.
https://doi.org/10.1016/S0140-6736(20)31... ,¹³13. Brodin P. Why is COVID-19 so mild in children? Acta Paediatr. 2020;109(6):1082–3. doi: http://doi.org/10.1111/apa.15271. PubMed PMID: 32212348.
https://doi.org/10.1111/apa.15271... ,¹⁴14. Wang J, Wang D, Chen GC, Tao XW, Zeng LK. SARSCoV-2 infection with gastrointestinal symptoms as the first manifestation in a neonate. Chin J Contemp Pediatr. 2020;22(3):211–4. doi: http://doi.org/10.7499/j.issn.1008-8830.2020.03.006. PubMed PMID: 32204755.
https://doi.org/10.7499/j.issn.1008-8830... ), or serious impairment, such as respiratory failure, pneumonia, and multiple organ failure(¹⁵15. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32–40. doi: http://doi.org/10.1148/radiol.2020200642. PubMed PMID: 32101510.
https://doi.org/10.1148/radiol.202020064... ,¹⁶16. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel Coronavirus in Wuhan. Lancet. 2020;395(10223):497–506. doi: http://doi.org/10.1016/S0140-6736(20)30183-5. PubMed PMID: 31986264.
https://doi.org/10.1016/S0140-6736(20)30... ). Among the symptoms presented by children, fever is the most common one; however, gastrointestinal symptoms have a high incidence in this population. Around 90% of care provided to the pediatric population with exposure to or diagnosis of COVID-19 presented gastric or intestinal manifestations(¹⁷17. Wan Y, Li J, Shen L, Zou Y, Hou L, Zhu L, et al. Enteric involvement in hospitalised patients with COVID-19 outside Wuhan. Lancet Gastroenterol Hepatol. 2020;5(6):534–5. doi: http://doi.org/10.1016/S2468-1253(20)30118-7. PubMed PMID: 32304638.
https://doi.org/10.1016/S2468-1253(20)30... ,¹⁸18. Puoti MG, Rybak A, Kiparissi F, Gaynor E. Borrelli. SARS-CoV-2 and the gastrointestinal tract in children. Front Pediatr. 2021;9(617980):617980. doi: http://doi.org/10.3389/fped.2021.617980.
https://doi.org/10.3389/fped.2021.617980... ,¹⁹19. Feldstein LR, Tenforde MW, Friedman KG, Newhams M, Rose EB, Dapul H, et al. Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19. JAMA. 2021;325(11):1074–87. doi: http://doi.org/10.1001/jama.2021.2091. PubMed PMID: 33625505.
https://doi.org/10.1001/jama.2021.2091... ). However, in some cases, only gastric and intestinal manifestations are observed, and there is an absence of respiratory manifestations⁽²⁰⁾20. Villapol S. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. JDR Clin Trans Res. 2020;226:57–69. doi: http://doi.org/10.1016/j.trsl.2020.08.004. PubMed PMID: 32827705.
https://doi.org/10.1016/j.trsl.2020.08.0... . Tests carried out showed negative nasopharyngeal results and positive rectal swab, thus indicating that the gastrointestinal tract can release the virus and consequently fecal-oral transmission may be possible⁽²¹⁾21. Ding S, Liang TJ. Is SARS-CoV-2 also an enteric pathogen with potential fecal-oral transmission? A COVID-19 virological and clinical review. Gastroenterology. 2020;159(1):53–61. doi: http://doi.org/10.1053/j.gastro.2020.04.052. PubMed PMID: 32353371.
https://doi.org/10.1053/j.gastro.2020.04... .

In this regard, the pediatric population may only develop gastrointestinal symptoms, without presenting other clinical manifestations⁽²²⁾22. Penninger JM, Grant MB, Sung JTY. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection. Gastroenterology. 2021;160(1):39–46. doi: http://doi.org/10.1053/j.gastro.2020.07.067. PubMed PMID: 33130103.
https://doi.org/10.1053/j.gastro.2020.07... . Furthermore, gastric and intestinal involvement is associated with greater severity of the disease⁽²⁰⁾20. Villapol S. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. JDR Clin Trans Res. 2020;226:57–69. doi: http://doi.org/10.1016/j.trsl.2020.08.004. PubMed PMID: 32827705.
https://doi.org/10.1016/j.trsl.2020.08.0... . It was found that SARS-CoV-2 is capable of replicating intestinal epithelial cells, thus developing tissue injuries and an increase in a large number of innate immune cells, triggering a deregulated hyperinflammatory response(²³23. Kaushik S, Aydin SI, Derespina KR, Bansal PB, Kowalsky S, Trachtman R, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection (MIS-C): a multi-institutional study from New York City. J Pediatr. 2020;224:24–9. doi: http://doi.org/10.1016/j.jpeds.2020.06.045. PubMed PMID: 32553861.
https://doi.org/10.1016/j.jpeds.2020.06.... ,²⁴24. Chiu JS, Lahoud-Rahme M, Schaffer D, Cohen A, Samuels-Kalow M. Kawasaki disease features and myocarditis in a patient with COVID-19. Pediatr Cardiol. 2020;41(7):1526–8. doi: http://doi.org/10.1007/s00246-020-02393-0. PubMed PMID: 32542549.
https://doi.org/10.1007/s00246-020-02393... ).

Therefore, there is a need to review the clinical approach used to treat gastrointestinal symptoms in the pediatric population, as the digestive system is often not associated with SARS-CoV-2 viral infection⁽²⁵⁾25. Oba J, Carvalho WB, Silva CA, Delgado FA. Gastrointestinal manifestations and nutritional therapy during COVID-19 pandemic: a practical guide for pediatricians. Einstein. 2020;18:eRW5774. doi: http://doi.org/10.31744/einstein_journal/2020RW5774. PubMed PMID: 32667418.
https://doi.org/10.31744/einstein_journa... . Healthcare professionals should pay attention to acute gastrointestinal manifestations in the child population, considering COVID-19 as a differential diagnosis(²⁶26. Pontes GCL, Vasques KDBR, Oliveira KS. Manifestações gastrointestinais em pacientes pediátricos com infecção por Coronavírus no Brasil: uma revisão integrativa. Pará Res Med J. 2021;5:1–7. doi: http://doi.org/10.4322/prmj.2021.004.
https://doi.org/10.4322/prmj.2021.004... ,²⁷27. Lee PI, Hsueh PR. Multisystem inflammatory syndrome in children: a dysregulated autoimmune disorder following COVID-19. J Microbiol Immunol Infect. 2023;56(2):236–45. doi: http://doi.org/10.1016/j.jmii.2023.01.001. PubMed PMID: 36720670.
https://doi.org/10.1016/j.jmii.2023.01.0... ), as there are extrapulmonary symptoms of COVID-19, involving the gastrointestinal system, recently detected. They are a cause for concern among health professionals who care for this population(²⁸28. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020;158(6):1831–1833.e3. doi: http://doi.org/10.1053/j.gastro.2020.02.055. PubMed PMID: 32142773.
https://doi.org/10.1053/j.gastro.2020.02... ,²⁹29. Li LY, Wu W, Chen S, Gu JW, Li XL, Song HJ, et al. Digestive system involvement of novel Coronavirus infection: prevention and control infection from a gastroenterology perspective. J Dig Dis. 2020;21(4):199–204. doi: http://doi.org/10.1111/1751-2980.12862. PubMed PMID: 32267098.
https://doi.org/10.1111/1751-2980.12862... ).

Given this context, this study is warranted by the need to know and compile data on gastrointestinal symptoms in children, to provide data for clinical practice, thus reinforcing rapid diagnosis for the pediatric population. In addition, the digestive system can be a potential route of infection transmission by the new Coronavirus, and research on this topic can provide scientific evidence to support care for children with COVID-19. Thus, this study aimed at mapping the evidence in the literature about the relationship between gastrointestinal symptoms and COVID-19 in the pediatric population.

METHOD

Design of Study

This is a scoping review, which aims to map the current evidence available in the literature, as well as to present the main concepts in the area and show the gaps in knowledge available, allowing the exploration of new research⁽³⁰⁾30. Peters MDJ, Marnie C, Tricco AC, Pollock D, Munn Z, Alexander L, et al. Updated methodological guidance for the conduct of scoping reviews. JBI Evid Synth. 2020;18(10):2119–26. doi: http://doi.org/10.11124/JBIES-20-00167. PubMed PMID: 33038124.
https://doi.org/10.11124/JBIES-20-00167... . Scoping reviews are complex studies, as they involve methodological rigor, and must be developed with independent evaluation involving at least two reviewers and following protocols⁽³¹⁾31. Pollock D, Davies EL, Peters MDJ, Tricco AC, Lyndsay A, McInerney P, et al. Undertaking a scoping review: a practical guide for nursing and midwifery students, clinicians, researchers, and academics. J Adv Nurs. 2021;77(4):2102–13. doi: http://doi.org/10.1111/jan.14743. PubMed PMID: 33543511.
https://doi.org/10.1111/jan.14743... . This study was built based on the recommendations of the Joanna Briggs Institute (JBI) Review Manual and the PRISMA extension – Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation(³²32. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018;169(7):467–73. doi: http://doi.org/10.7326/M18-0850. PubMed PMID: 30178033.
https://doi.org/10.7326/M18-0850... ,³³33. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Qualidade metodológica de estudos de séries de casos: uma introdução ao instrumento de avaliação crítica JBI. JBI Evid Synth. 2020;18(10):2127–33. doi: http://doi.org/10.1186/s12874-018-0611-x. PubMed PMID: 33038125.
https://doi.org/10.1186/s12874-018-0611-... ). The research protocol has been published⁽³⁴⁾34. Desconsi D, Araujo JP, Zani AV. Relação de sintomas gastrointestinais e a infecção por COVID-19 na população pediátrica: protocolo scoping review. Arq Ciênc Saúde UNIPAR. 2023;27(5):2601–11. doi: http://doi.org/10.25110/arqsaude.v27i5.2023-029.
https://doi.org/10.25110/arqsaude.v27i5.... and registered with Open Science Framework with identifier https://doi.org/10.17605/OSF.IO/G59AB.

Data Sources and Research Strategy

To construct this review, nine databases were accessed through the Periodical Portal of the Coordination for the Improvement of Higher Education Personnel (CAPES), including: Excerpta Medica data BASE (Embase), Google Scholar, PubMed, Scopus, Latin American and Caribbean Literature in Health Sciences (LILACS), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scielo, Web of Science, and the Virtual Health Library (VHL) website.

The review question was formulated according to the acronym PCC (Population, Concept and Context), with Population (P) being child, newborn, infant; Concept (C), gastrointestinal tract; Context (C), COVID-19. The research question was therefore: What is the relationship between gastrointestinal symptoms and COVID-19 in the pediatric population?

Moreover, MeSH (Medical Subject Headings), DeCS (Health Sciences Descriptors), and CINAHL Headings descriptors were used, together with boolean operators AND and OR. The search strategy presentation in each database is described in Chart 1.

Data Collection and Extraction

Data collection took place in July and August 2023. The eligibility criteria were primary studies and technical notes addressing the topic of gastrointestinal symptoms and COVID-19 and that answered the research question. Furthermore, no language or publication date limitations were established, considering the lack of studies related to the topic. Also, studies addressing newborns (NB), infants, children and adolescents, or adults in the same study were included, using data only from the pediatric population. Duplicate studies were counted once.

The studies were analyzed by two independent reviewers, who carried out an in-depth reading considering the eligibility criteria. A third reviewer was called in to resolve differences and thus avoid the risk of bias. All information, as well as captured studies, were stored in electronic spreadsheets and in analytical tables where the information was exposed for better interpretation and comparison of productions, thus allowing the description of the evidence.

After reading the titles and abstracts, the pre-selected studies underwent data analysis and mapping. For this, the Review Manual of the JBI⁽²³⁾23. Kaushik S, Aydin SI, Derespina KR, Bansal PB, Kowalsky S, Trachtman R, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection (MIS-C): a multi-institutional study from New York City. J Pediatr. 2020;224:24–9. doi: http://doi.org/10.1016/j.jpeds.2020.06.045. PubMed PMID: 32553861.
https://doi.org/10.1016/j.jpeds.2020.06.... was used, which consisted of careful reading and classification of texts extracting the results. A manual search took place by checking the list of references of the studies included in the review. This search yielded articles that were included in the final amount. This search aimed to find studies that were not identified in the databases.

The following data were extracted from the studies: authors/year, objective, population, main gastrointestinal symptoms, tests performed, association of gastrointestinal symptoms with COVID-19.

Summary of Results

In the selected studies, a descriptive analysis of the variables was carried out, with critical analysis and discussion. The main characteristics of the selected studies were organized and presented in summary charts, containing the most important information, responding to the objective of the study, such as main gastrointestinal symptoms, tests performed and association of gastrointestinal symptoms.

Ethical Aspects

This scoping review was carried out considering the ethical aspects regarding the authorship of the articles researched and selected, with all authors being duly cited. As it is a study performed exclusively with scientific texts, approval by a Research Ethics Committee is not required.

RESULTS

The search strategies allowed us to find a total of 6,484 publications, of which 172 were duplicates, 27 were not freely accessible, and 5,924 were outside the topic of this review. A total of 218 studies was selected for title and abstract reading and, after this process, 27 were selected for full reading, with 191 being excluded for not answering the objective and research question. Therefore, six studies were chosen to compose the present review. Additionally, the bibliographic references of these studies were explored and, after considering the eligibility criteria again, four more publications were added to compose the results, totaling 10 articles (Figure 1).

The studies included were published in 2020 (n = 05), 2021 (n = 03), 2022 (n = 01) and 2023 (n = 01), in different countries such as Italy (n = 03), United States of America (n = 1), Brazil (n = 01), Iran (n = 01), Romania (n = 01), China (n = 01), and Russia (n = 2). As for the language of publication, English was predominant.

In Chart 2 the authors, year of publication, main objective of the study, population, and type of study adopted in the articles that made up this research are demonstrated.

Chart 3 presents the main gastrointestinal symptoms, the tests carried out during the contagion period and the association of symptoms with COVID-19 presented by the populations of the selected studies.

The findings pointed to three premises, which present possible explanations of the clinical conditions and the clarification of the symptoms presented by the pediatric population, namely: the first premise points to the ACE 2 receptor (Angiotensin Converting Enzyme 2) which is found in the epithelial cells of the gastrointestinal tract and SARS-CoV-2 enters the cells via this route, giving rise to gastric manifestations. The second premise refers to gastrointestinal symptoms that are mediated by stress and the mental health of the pediatric population in the pandemic has suffered long-term repercussions. Thus, infection by the virus can be justified by the brain and intestine axis where the viral infection is triggered, generating destabilization of structures. The third premise is that COVID-19 develops the process of Pediatric Multisystem Inflammatory Syndrome (MIS-P), affecting the gastrointestinal tract and triggering symptoms such as diarrhea, vomiting, nausea, and abdominal pain (Figure 2).

DISCUSSION

This scoping review covers gastrointestinal manifestations in the pediatric population resulting from COVID-19 infection and the mechanism by which the virus is capable of causing the disorder. COVID-19 is a systemic disease, which has been presenting gastrointestinal symptoms(²²22. Penninger JM, Grant MB, Sung JTY. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection. Gastroenterology. 2021;160(1):39–46. doi: http://doi.org/10.1053/j.gastro.2020.07.067. PubMed PMID: 33130103.
https://doi.org/10.1053/j.gastro.2020.07... ,³⁷37. 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... ) in the pediatric population as initial symptoms, which differentiates it from adults who, in general, have a high prevalence of respiratory symptoms⁽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... . The average number of pediatric patients who developed only gastrointestinal symptoms and no respiratory symptoms is 33.5%(²²22. Penninger JM, Grant MB, Sung JTY. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection. Gastroenterology. 2021;160(1):39–46. doi: http://doi.org/10.1053/j.gastro.2020.07.067. PubMed PMID: 33130103.
https://doi.org/10.1053/j.gastro.2020.07... ,³⁷37. 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... ). In this regard, the symptoms presented by the pediatric population diagnosed with COVID-19 are: diarrhea, anorexia, vomiting, nausea, abdominal pain and gastrointestinal bleeding(³⁶36. 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... ,⁴⁵45. Tian Y, Rong L, Nian W, He Y. gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;51(9):843–51. doi: http://doi.org/10.1111/apt.15731. PubMed PMID: 32222988.
https://doi.org/10.1111/apt.15731... ,⁴⁶46. Hormati A, Shahhamzeh A, Afifian M, Khodadust F, Ahmadpour S. Can COVID-19 present unusual GI symptoms? J Microbiol Immunol Infect. 2020;53(3):384–5. doi: http://doi.org/10.1016/j.jmii.2020.03.020. PubMed PMID: 32249184.
https://doi.org/10.1016/j.jmii.2020.03.0... ).

Of these symptoms, diarrhea was identified as the main sign in the absence of respiratory findings, in 22% of cases⁽⁴⁵⁾45. Tian Y, Rong L, Nian W, He Y. gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;51(9):843–51. doi: http://doi.org/10.1111/apt.15731. PubMed PMID: 32222988.
https://doi.org/10.1111/apt.15731... and its onset is described from 01 to 08 days after the onset of the disease, and with an average of 03 to 06 days, with a watery, yellowish characteristic and with a frequency of three to nine bowel movements per day(⁴⁷47. Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J, 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(5):766–73. doi: http://doi.org/10.14309/ajg.0000000000000620. PubMed PMID: 32287140.
https://doi.org/10.14309/ajg.00000000000... ,⁴⁸48. Lu X, Zhang L, Du H, Zhang J, Li Y, Qu J, et al. Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-2 infection in children. N Engl J Med. 2020;382(17):1663–5. doi: http://doi.org/10.1056/NEJMc2005073. PubMed PMID: 32187458.
https://doi.org/10.1056/NEJMc2005073... ). Therefore, fecal-oral transmission should be considered, even if there are no gastrointestinal symptoms, thus preventing the spread of the virus through this route(³⁵35. 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-... ,⁴⁹49. Xing Y-H, Ni W, Wu Q, Li W-J, Li G-J, Wang W-D, et al. Prolonged viral shedding in feces of pediatric patients with Coronavirus disease 2019. J Microbiol Immunol Infect. 2020;53(3):473–80. doi: http://doi.org/10.1016/j.jmii.2020.03.021. PubMed PMID: 32276848.
https://doi.org/10.1016/j.jmii.2020.03.0... ,⁵⁰50. Jin X, Lian JS, Hu HJ, Gao J, Zheng L, Zhang LZ, et al. Epidemiological, clinical and virological characteristics of 74 cases of Coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020;69(6):1002–9. doi: http://doi.org/10.1136/gutjnl-2020-320926. PubMed PMID: 32213556.
https://doi.org/10.1136/gutjnl-2020-3209... ).

The findings of the selected studies pointed to three premises about the relationships between COVID-19 and gastrointestinal symptoms in the pediatric population. The first assumption to be addressed is that there is intestinal impairment caused by the COVID-19 virus, as the ACE2 receptor is the cellular link for SARS-CoV-2⁽⁵¹⁾51. Villanueva MC, Herrera MF, Godoy M. Manifestaciones gastrointestinales y hepáticas de COVID-19 en niños. Rev Chil Pediatr. 2020;91(4). doi: http://doi.org/10.32641/rchped.v91i4.2484.
https://doi.org/10.32641/rchped.v91i4.24... . An example of this is that the glycoprotein spike belonging to SARS-CoV-2 binds to the extracellular part of ACE2 in host cells, providing high levels of expression of the ACE2 receptor(⁴⁰40. 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.... ,⁵²52. Liang W, Feng Z, Rao S, Xiao C, Xue X, Lin Z, et al. Diarrhoea may be underestimated: a missing link in 2019 novel Coronavirus. Gut. 2020;69(6):1141–3. doi: http://doi.org/10.1136/gutjnl-2020-320832. PubMed PMID: 32102928.
https://doi.org/10.1136/gutjnl-2020-3208... ).

The ACE2 receptor enzyme has an important function in regulating intestinal homeostasis. After this influence of the virus on cells occurs, the receptor’s activities are interrupted in the gastrointestinal tract, generating evident differences in its expression and causing gastrointestinal manifestations(³⁸38. 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... ,³⁹39. 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... ).

Although the expression of SARS-CoV-2 mediators acts in different locations, such as in the intestinal epithelium and nasal epithelium, ACE1 and ACE2 are more expressed at the intestinal level in children than in adults, which explains why the pediatric population presents more evident gastrointestinal symptoms compared to adults⁽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... . In addition, transmembrane serine protease 2 (TMPRSS2), which also initiates the protein spike and acts as a co-receptor for SARS-CoV-2, is predominantly found in adults; neuropilin 1 (NRP1) has a high capacity to enhance infection in cells at the nasal level, another explanation for respiratory symptoms being more pronounced in the adult population⁽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... .

The second premise found in the results of this review is that functional gastrointestinal disorders may arise from symptomatic disorders without organic abnormalities, with psychosomatic origins⁽⁵³⁾53. Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O, et al. Assessment of SARS-CoV-2 in human semena cohort study. Int J Fertil Steril. 2020;114(2):233–8. doi: http://doi.org/10.1016/j.fertnstert.2020.05.028. PubMed PMID: 32650948.
https://doi.org/10.1016/j.fertnstert.202... , that is, stress-sensitive disorders, which are gastrointestinal pathologies with multifactorial pathophysiology, the main cause being dysregulation of the gut-brain axis⁽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... .

It is believed that the pandemic led to changes in children’s routines, and several safety measures were taken to combat the virus, one of which was social distancing, which contributed to the manifestation of mental illnesses⁽⁵⁴⁾54. Holtmann G, Shah A, Morrison M. Pathophysiology of functional gastrointestinal disorders: a holistic overview. Dig Dis. 2017;35(1, Suppl 1):5–13. doi: http://doi.org/10.1159/000485409. PubMed PMID: 29421808.
https://doi.org/10.1159/000485409... . The main gastrointestinal findings related to functional gastrointestinal disorders are cyclic vomiting syndrome, functional constipation⁽⁵⁵⁾55. Boronat AC, Ferreira-Maia AP, Matijasevich A, Wang YP. Epidemiology of functional gastrointestinal disorders in children and adolescents: a systematic review. World J Gastroenterol. 2017;23(21):3915–27. doi: http://doi.org/10.3748/wjg.v23.i21.3915. PubMed PMID: 28638232.
https://doi.org/10.3748/wjg.v23.i21.3915... , aerophagia, and abdominal pain⁽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... .

In this sense, following the premises set out in the studies, there is the third condition, the association of gastrointestinal symptoms caused by SARS-CoV-2 and Pediatric Multisystem Inflammatory Syndrome, highlighted by fever and bleeding, being evidenced in more severe presentations of the disease(²⁷27. Lee PI, Hsueh PR. Multisystem inflammatory syndrome in children: a dysregulated autoimmune disorder following COVID-19. J Microbiol Immunol Infect. 2023;56(2):236–45. doi: http://doi.org/10.1016/j.jmii.2023.01.001. PubMed PMID: 36720670.
https://doi.org/10.1016/j.jmii.2023.01.0... ,³⁶36. 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... ,⁵⁶56. Dipasquale V, Passanisi S, Cucinotta U, Cascio A, Romano C. Implications of SARS-COV-2 infection in the diagnosis and management of the pediatric gastrointestinal disease. Ital J Pediatr. 2021;47(1):71. doi: http://doi.org/10.1186/s13052-021-01020-9. PubMed PMID: 33761992.
https://doi.org/10.1186/s13052-021-01020... ). It can be observed that patients who were detected with the COVID-19 virus had gastrointestinal symptoms along with rashes, elevated inflammatory markers, and myocardial involvement⁽⁵⁷⁾57. Kostik MM, Bregel LG, Avrusin IS, Efremova OS, Belozerov KE, Dondurei EA, et al. Heart involvement in multisystem inflammatory syndrome, associated with COVID-19 in children: the retrospective multicenter cohort data. Front Pediatr. 2022;10:829420. doi: http://doi.org/10.3389/fped.2022.829420. PubMed PMID: 35311051.
https://doi.org/10.3389/fped.2022.829420... . Imaging exams are also complementary to intestinal inflammation resulting from MIS-P⁽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... .

Another issue imposed is that Long COVID-19, which is the second long-term infection caused by SARS-Cov-2, can develop polyorganic disorders(⁵⁸58. Sedik RNM. The clinical course and outcomes of SARS-CoV-2 virus infection in children: a 24-week follow-up study in Sulaimaniyah, Iraq. BMC Pediatr. 2023;23(1):303. doi: http://doi.org/10.1186/s12887-023-04111-0. PubMed PMID: 37330479.
https://doi.org/10.1186/s12887-023-04111... ,⁵⁹59. Satterfield BA, Bhatt DL, Gersh BJ. Cardiac involvement in the long-term implications of COVID-19. Nat Rev Cardiol. 2022;19(5):332–41. doi: http://doi.org/10.1038/s41569-021-00631-3. PubMed PMID: 34686843.
https://doi.org/10.1038/s41569-021-00631... ). It can be observed that reinfection is capable of generating some respiratory damage (21.2%), nervous disorders (16%), integumentary tissue (15%), gastrointestinal tract (13%), cardiovascular system (11%), as well as possible psychiatric symptoms (10%) and pathologies of the intestinal system (9%)⁽⁶⁰⁾60. Arutyunov GP, Tarlovskaya EI, Arutyunov AG, Belenkov NY, Konradi AO, Lopatin YM, et al. International register “Dynamics analysis of comorbidities in SARS-CoV-2 survivors” (AKTIV SARS-CoV-2): analysis of predictors of short-term adverse outcomes in COVID-19. Angiol Sosud Khir. 2021;26(4):4470. doi: http://doi.org/10.15829/1560-4071-2021-447.
https://doi.org/10.15829/1560-4071-2021-... . Long COVID-19 is directly associated with the causes of MIS-P. Due to the persistence of the virus⁽⁵⁷⁾57. Kostik MM, Bregel LG, Avrusin IS, Efremova OS, Belozerov KE, Dondurei EA, et al. Heart involvement in multisystem inflammatory syndrome, associated with COVID-19 in children: the retrospective multicenter cohort data. Front Pediatr. 2022;10:829420. doi: http://doi.org/10.3389/fped.2022.829420. PubMed PMID: 35311051.
https://doi.org/10.3389/fped.2022.829420... , some symptoms can be expected in up to three months or more. Therefore, observation of patients must be carried out at future levels, even when detection of the virus by occupational diagnostic methods is negative⁽⁶⁰⁾60. Arutyunov GP, Tarlovskaya EI, Arutyunov AG, Belenkov NY, Konradi AO, Lopatin YM, et al. International register “Dynamics analysis of comorbidities in SARS-CoV-2 survivors” (AKTIV SARS-CoV-2): analysis of predictors of short-term adverse outcomes in COVID-19. Angiol Sosud Khir. 2021;26(4):4470. doi: http://doi.org/10.15829/1560-4071-2021-447.
https://doi.org/10.15829/1560-4071-2021-... .

This way, special attention is required for patients who have gastrointestinal symptoms and a history of exposure to or infection with SARS-CoV-2, as data suggest that contact with the virus triggers MIS-P, and gastrointestinal symptoms are signs of this condition⁽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... .

It should be highlighted that the results presented contribute to formulating strategies for caring for this population, giving emphasis and importance to gastrointestinal symptoms when reported. Some limitations were found, such as the inclusion of only studies available in full and free of charge, which may have led to the exclusion of studies relevant to the proposed synthesis. Additionally, nine databases were used, which also limits the number of sources reviewed, and may result in the exclusion of potential studies that could contribute to elucidating the findings. There were also no procedures used to evaluate the evidence found.

CONCLUSION

The gastrointestinal symptoms presented by the pediatric population are diarrhea, anorexia, vomiting, nausea, abdominal pain, and gastrointestinal bleeding, with diarrhea being the most prevalent symptom in this age group. The identification of gastrointestinal symptoms in the pediatric population affected by COVID-19 can assist in the clinical approach and in the discussion of care and treatment management for these children.

The evidence synthesis provided three assumptions that guide the origin of the symptoms. One of them is the ACE2 receptor, which is found in the epithelial cells of the gastrointestinal tract and favors the entry of SARS-CoV-2 into the cells, causing infection and generating gastric manifestations. Also, the mental health of the pediatric population was affected by the pandemic and the restrictions imposed, causing disorders of the gut-brain axis, thus affecting gastrointestinal manifestations. Furthermore, the virus is capable of triggering gastrointestinal symptoms due to its ability to develop the process of multisystem inflammatory syndrome.

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