GASTROINTESTINAL COMPLICATIONS OF CORONAVIRUS DISEASE (COVID-19)

ABSTRACT 
Background:
 It is currently understood that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) directly enters target cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Accordingly, tissues with high expression levels of ACE2 are more susceptible to infection, including pulmonary alveolar epithelial cells, small intestine enterocytes, cholangiocytes, and vascular endothelial cells. Considering the atypical manifestations of COVID-19 and the challenges of early diagnosis, this review addresses the possible gastrointestinal complications of the disease. 
Method:
 The phrase “Gastrointestinal complication of COVID” was searched in the PubMed, Medline, and SciELO databases. Due to the heterogeneity of the studies included in the present review, a narrative synthesis of the available qualitative data was performed. 
Result:
 The literature search retrieved 28 articles, primarily case reports and case series, for the qualitative analysis of gastrointestinal complications of COVID-19, in addition to two retrospective cohort and one case-control. The studies focused on hemorrhagic, thrombotic, ischemic, and perforation complications, in addition to acute pancreatitis and pneumatosis intestinalis. 
Conclusion:
 There is a straight relationship between high expression levels of ACE2 in the gastrointestinal tract and its greater susceptibility to direct infection by SARS-CoV-2. So, it is important to consider the gastrointestinal infection manifestations for early diagnosis and treatment trying to avoid more serious complications and death.

Organization declared a public health emergency of international concern, described as a pandemic, on March 11, 2020 47 . As of early January 2021, Johns Hopkins University (Baltimore, MD, USA) confirmed 92,240,036 cases globally, of which 1,975,707 were fatal 17 .
Since September 2020, the world has witnessed a "second wave" of COVID-19, associated not only with an increase in the number of cases, but also with the emergence of new SARS-CoV-2 variants 12,15 .
The primary symptoms of COVID-19 include fever, dry cough, dyspnea, fatigue, myalgia, and headache 45 . Although poorly related to the disease, extrapulmonary symptoms have also been documented since the beginning of the pandemic, with gastrointestinal symptoms being the most relevant. Some patients experience gastrointestinal manifestations in the early stages of the disease, including nausea, vomiting, diarrhea, abdominal pain, and anorexia 8,28,31,37,45 .
It is currently understood that SARS-CoV-2 can directly infect target cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Accordingly, tissues with high expression levels of this receptor are more susceptible to infection. Tissues with higher receptor concentrations include pulmonary alveolar epithelial cells, small intestine enterocytes, cholangiocytes, and vascular endothelial cells 1,8,18,20,31,38,46 . ACE2 acts to regulate the inflammatory response, and its distribution in abdominal organs possibly explains the extrapulmonary symptoms experienced by some patients. Cellular alteration(s) result in intestinal and hepatic inflammation, as well as alteration(s) to the intestinal microbiota 1,21 .
Furthermore, gastrointestinal and respiratory comorbidities can increase the severity of the disease. However, gastrointestinal symptoms can be underdiagnosed because they usually manifest in the early stages of disease and are self-limited, thus making it difficult to correlate them with a diagnosis of COVID-19 20 .
Considering the atypical manifestations and challenges of early diagnosis, this review addresses possible gastrointestinal complications within the current context of the COVID-19 pandemic.

Search strategy
A literature search of the PubMed, Medline, and SciELO databases was performed in November 2020 using the phrase "Gastrointestinal complication of COVID". The search was limited to articles published in English and Spanish, and filters for type of study or date were initially not used.

Screening and evidence synthesis
The literature search retrieved 587 articles. After excluding 248 duplicate articles, 339 were analyzed with regard to title and abstract, with six excluded for incompatible dates (published before 2020) and 227 for focusing on other topics.
Of the remaining 106 articles, 81 were excluded for not addressing complications, although they focused on gastrointestinal involvement in COVID-19. After a manual search of citations, an additional four articles were included for relevance.
Ultimately, 29 articles were included in the present review ( Figure 1).

Statistical analysis
Due to the heterogeneous nature of the studies included in this review, a narrative synthesis of the qualitative available data was performed.

Gastrointestinal hemorrhage
Considering the atypical manifestations of COVID-19, primary care for patients experiencing extrapulmonary symptoms can be initiated without early diagnosis to avoid more serious complications when associated with respiratory conditions. Although gastrointestinal symptoms often present early and tend to evolve in the most severe forms of the disease, they are the only symptoms of the disease in some cases 20 .
A case presented by Amarapurkar et al. 3  A retrospective study by Mauro et al. 33

Thrombosis and ischemia
Coagulation dysfunction is one of the main causes of death in patients with severe COVID-19, who are more likely to exhibit a state of hypercoagulability, with manifestations of intravascular coagulation due to local damage 10,13 . Coagulopathy, high levels of D-dimer, and fibrinogen at the time of hospital admission for COVID-19 have been associated with a poorer clinical course, and higher risk for micro-and macro-circulatory thrombosis, and a higher mortality rate in hospitalized patients 6,10 .
The absence of important predisposing factors for thromboembolic formation in a patient who developed thrombosis in the superior mesenteric artery and acute intestinal ischemia suggested and reinforced the theory that there is a causal relationship between COVID-19 and hypercoagulability 10 . In a case reported by Correa Neto et al. 13  The management of these patients should include coagulation tests, including coagulation profile, platelet count and D-dimer levels, to help determine a prognosis and dosages of anticoagulant agents, and imaging studies for early diagnosis to increase the chances for survival 10,40 . It is important to note that thrombolytic therapy should be used carefully, considering that such events can be self-limited, and that COVID-19 is also associated with thrombocytopenia and coagulopathy, with risk for developing widespread intravascular coagulation 26 . In addition, prophylaxis measures should be implemented during hospitalization and after discharge 40 . In another report, Ibrahim et al. 24

Pneumatosis intestinalis
SARS-CoV-2 uses the ACE2 receptor to enter cells and the serine protease TMPRSS2 for protein S priming. These two proteins are highly co-ex- The gas can enter the intestinal wall due to the coexistence of increased intraluminal pressure, rupture of the mucosa, and increased permeability. In addition, the excessive production of hydrogen due to bacterial growth can lead to gas oversaturation, thereby overloading diffusion capacity in the bloodstream and, consequently, leading to the formation of cysts containing gas 34 .

CONCLUSION
Considering the relationship between high expression levels of ACE2 in the gastrointestinal tract and its greater susceptibility to direct infection by SARS-CoV-2 is established, it is important to consider the various gastrointestinal manifestations and complications in these patients. The most important include gastrointestinal hemorrhage, thrombotic and ischemic events, perforation, pancreatitis and, less commonly, pneumatosis intestinalis. Therefore, when managing patients with known SARS-CoV-2 infection, or even initially without a diagnosis of COVID-19, all gastrointestinal manifestations should be considered, diagnosed, and treated early to prevent even more serious complications and death.