The current coronavirus disease 2019 (COVID-19) outbreak is a global emergency with a fast rate of spread, a high mortality rate, and major disruptions. The disease began in the second part of 2019 as a pneumonia infection with an unknown cause that was detected in Wuhan, Hubei Province, China. On January 12, 2020, the pathogen was promptly isolated and given the name 2019 Novel Coronavirus (2019-nCoV) [1].

The disease is caused by novel beta-coronavirus that is 75-80% similar to the SARS-CoV and 40% similar to the MERS-CoV genome, the virus cause zoonotic infection, recently, it has been discovered to cause human infection [2].

Clinical characteristics of disease

The source of infection mainly those who are severely ill patient are extremely contagious than mildly symptomatic. The infection spread through respiratory droplet either directly or indirectly. Studies have demonstrate that asymptomatically infected patients or people in the incubation period shed virus, making them potential sources of infection, with no evidence of airborne infection [3].

The incubation period is 5-6 days, with around 2.5 % of patients developing symptoms within 2.2 days and 97.5 % developing symptoms within 11.5 days, the infection can be mild, moderate in intensity in most of the cases, however, the condition may progress to sever infection in about 14% of patients, patients will had dyspnea, blood oxygen saturation < 93%, PF ratio < 300, and or lung infiltrated > 50% within 24–48 hours), or in about 5% of patients the condition become critical (respiratory failure, septic shock, and/or multiorgan failure) [4].      

The clinical presentation is variable according to disease severity, studies revealed that fever, dry cough, dyspnea, and fatigue are the most presenting symptom in patients with slight differences in the prevalence according to sample size of the study, geographic differences and other factors. In a meta-analysis study, the most prevalent symptoms were fever (78%), cough (57%) and fatigue (31%) [5]. The major symptom of COVID-19 is involvement of the respiratory system, which manifests as interstitial and alveolar pneumonia. The use chest computerized tomography (CT) can detect COVID-19 pneumonia, during the prodrome phase generally patients had   pharyngitis  (sore throat) and a dry cough.

Respiratory involvement might present as minor upper respiratory tract symptoms and signs, requiring highly dependent treatment, or severe pneumonia, requiring respiratory support, independent of whether it is accompanied by bacterial sepsis [6].

COVID-19 and GIT Symptom

Studies revealed the presence of viral receptors (angiotensin-converting enzyme 2 (ACE2) protein) in part other than respiratory system, the receptors has been expressed in the vascular endothelial, renal tubular epithelium and in Leydig cells in the testes, also kidney and GI tract. The presence of those receptors give answers to cause of some of extra-pulmonary manifestations as thromboembolic event, as well as other systemic manifestation as acute renal injury, gastrointestinal (GI) symptoms, liver dysfunction and others.

The gastrointestinal (GI) tract and the hepatic system evolution in COVID-19 is becoming more widely recognized. Diarrhea, nausea, vomiting, and abdominal pain are the most prominant GI symptoms in both adult and pediatric COVID-19 patients [7]. The GI symptoms are associated with a longer disease duration with the incidence of 12-61% [8].

In systemic review study that included 43 studies, Diarrhea was developed in 11.5% of the patients, nausea and vomiting in 6.3% and abdominal pain in 2.3% [9]. Other studies suggest that the prevalence of GIT symptom is higher than expect that reach 39.6–50%, nausea (17.3%), diarrhea (12.9%), anorexia (12.2%), abdominal pain (5.8%), belching (5%) and emesis (5%) [10].

The Fecal–oral transmission of COVID-19 infection has been suggested as viral particles can survive and replicate in digestive tracts [11], its estimate that 50% of COVID- 19 patients had detectable viral RNA in the stool [12]. SARS-CoV-2 nucleic protein detected in gastric, duodenal, and rectal glandular epithelial cells mainly in severely diseased patients raising the assumption that SARS-CoV-2 presence in gastrointestinal (GI) tissue associated with unfavorable disease progression [13].

Similar to SARS-CoV, the viral entrance into enterocytes occurs through binding to angiotensin-converting enzyme 2 (ACE2) receptors on the surfaces of enterocytes. This step is followed by viral RNA and proteins replication and formation of multiple new copies of COVID-19 to infect other cells, then trigger of cytokine release which is the same mechanism of alveolar involvement [14].

Destruction of enterocyte by the infection has been suggested as cause of GIT symptom, as well as the role of Gut normal flora which can have an impact on the immune system's response and disease progression. The gut microbiota can affect pulmonary health “gut–lung axis” which is interaction between gut and lung microbes, Bacteroidaceae, Prevotellaceae, Rikenellaceae, Lachnospiraceae, and Ruminococcaceae bacteria are abundant in the colon, but Bacteroidetes, Firmicutes, and Proteobacteria are more prevalent in the lungs [4].

GIT Bleeding in COVID 19

GIT bleeding is common condition that carry high morbidity and mortality with high incidence rate in critically ill patients. Gastrointestinal bleeding that be divided into two categories according to source of bleeding: upper and lower sources of bleeding. The ligament of Treitz or the suspensory ligament of the duodenum, is the anatomic mark that that distinguishes upper and lower bleeds. Hematemesis or melena are resulted from bleeding starting above the Treitz ligament, whereas hematochezia is result from bleeding that originates below the ligament. Upper GIT can be fresh blood, but when the blood mixed with stomach contents is known as hematemesis. Melena is a dark, black, and tarry feces with a distinct odor as a result of hemoglobin ingestion by GIT enzyme activity and intestinal bacteria, the flow of bright red blood through the rectum is known as hematochezia [15].

Increasing the cases of COVID infection and GIT symptom has been associated with increased number of GIT bleeding with variable prevalence among studied population, the difference in prevalence can be related to definitions of GIB (clinical, anatomical and endoscopic), usage of ulcer prophylaxis, presence of comorbidities and the severity of COVID-19 infection. However, the real number of GI bleeding patients is highl yunderestimated, as a result of endoscopic departmental protocols alteration as well as higher endoscopic thresholds, with more conservative treatment being used during the pandemic.

Studies reported the occurrence of gastrointestinal bleeding in COVID-19 patients with variable proportion 2-13% in hospitalized patients [13], other study state that Hospitalized COVID 19 patients at higher risk of bleeding due to several causes as usage of corticosteroids, antithrombotic agent and mechanical ventilation [16].

In hospitalized patients on therapeutic anticoagulation, the incidence of mortality rate due to GIB is 2–12%. The use of anti-coagulant drugs has been increased due to increase thromboembolic events, including deep venous thrombi, pulmonary emboli, and cerebrovascular events [14]. Some hospitals protocols recommended use of anticoagulation in case of clinical suspicion for deep vein thrombosis (DVT) or pulmonary embolism.

Gadiparthi et al. [17] case series study in which the admitted COVID patients had higher Glasgow Blatchford bleeding score and had a high risk of gastrointestinal bleeding (GIB) that needed intervention, and those who had bleeding dead eventually due to respiratory failure, that support theory of bleeding is developed in severely ill patients.

In retrospective review done on admitted COVID patients to Jabber Al-Ahmad Al-Sabah hospital in Kuwait due to bleeding events, result revealed that 28% of admitted patients had GIT bleeding [18]. Other study reported that GI bleeding was observed in 4-13.7% among severely affected patients [19].

When bleeding is evident in COVID-19, it might lead to a misdiagnosis and a clinical assessment that is not suitable. Different types of bleeding detected in patients, however, GI bleeding and intracranial hemorrhage (ICH) are the most prevalent types of sever bleeding that have been reported [12,20].

In multicenter case-control study, Gastric or duodenal ulcers was the most prevalent cause of upper GIB in 80% of included patient while rectal ulceration was responsible for 50% of lower GIB. Most of bleeding events occurred during the hospitalization, not as presenting symptom of infection, suggesting that bleeding is occur due administered drug (prophylaxis anti-coagulant) or due to severe infection (ICU patients) [21].

GIB can be catastrophic for elderly individuals with concomitant conditions, despite the fact that The majority of people with GIB problems, both upper and lower can be managed successfully. The use of systemic anticoagulation raise the risk of GIB which estimated annually by 4.5–8% [22]. The number of COVID-19 patients exacerbated by GIB is expected to rise in the coming months as more care centers that use intermediate dosage, therapeutic dose, or extended duration anticoagulation strategies.

Despite the fact that respiratory failure is responsible for more than 70% of deaths in COVID 19, bleeding is responsible for 6% of deaths. Another study revealed that 7.1% of COVID patients died because of GI bleeding [23]. As mentioned before, gastrointestinal bleeding is a rare symptom of COVID-19 infection that might emerge as hematemesis or melena. However, gastrointestinal bleeding is more deadly than other gastrointestinal symptoms [24].

Possible Causes of Bleeding

Several theories have been suggested to explain the development of bleeding in COVID patients: some state that prolonged tissue hypoxia will trigger necrosis and mucosal injury, then ulceration and GI hemorrhage according to Liu et al. [25], the same study state that using of anticoagulant induce thrombocytopenia and GIT bleeding. The use rectal tubes is account to cause lower GIT bleeding, These catheterization techniques are extensively used to divert liquid or semiliquid stool, reducing the risk of perianal skin breakdown, nosocomial infections, and nursing labor, however, bleeding complications from prolonged indwelling intra-rectal catheterization is not commonly underreported [26]. Other studies state to take precaution to presence of large internal hemorrhoids or a history of lower GIB when using these devices in COVID-19 patients and who are on anticoagulant.

In Martin et al. [21] study that detected 3 cases of rectal ulcers who were on rectal tubes and concurrent anticoagulation, despite the fact that no statistically significant association between rectal tube usage with GIB with an OR of 30.4.

Older age, previous history of GIB, chronic renal impairment, H. pylori infection, simultaneous use of antiplatelet medications, and preexisting gastrointestinal tract lesions are all factors that should be considered in patients starting anticoagulants. The risk of GIB rises as risk factors rises [27]. However, some controversies are presented regarding the presentation of GIT in COVID-19 patients, Hematemesis episodes or black stools that resemble melena can be caused by certain conditions (pulmonary embolism, myocardial infarction, and renal failure) and medications (iron supplements, bismuth subsalicylate, and meals like blood soup) [28].

Other mechanism of GIB is Cytokine disturbance, SARS-CoV-2-infected cells cause huge number of inflammatory mediators and chemokines are released, causing neutrophil aggregation. Neutrophils had antiviral effect and produce cytokines, and chemokines promoting immune cells accumulation. However, in COVID infection a disturbance in immune system is developed in some cases which lead to increase release of IL-1B, IFN- т, IP-10, and monocyte chemotactic protein 1 (MCP-1) expression, known as cytokines storms. High level of those markers will contribute to increase vascular injury, RDS, DIC and fulminant multi-organ failure [29]. Increase the proinflammatory mediators in ACE2 cells is attributed to mucosal damage and bleeding.

Management of Git Bleeding

The management upper GIT commonly done by stabilizing patients hemodynamically then endoscopic assessment and management. Stabilizing patients include adequate resuscitation, proton pump inhibitor (PPI) therapy and blood transfusion if needed.

Most COVID 19 patients are managed conservatively, as endoscopies are high-risk aerosol-generating procedures. However, according to Current guidelines recommended endoscopic exploration within 24 hours within acute attack of upper GIB within 24 hours after proper bowel preparation. Other guidelines prefer to stratificate bleeding as variceal or non-variceal in origin, and performing upper endoscopy within 24 h of non-variceal upper GI bleeding as variceal causes of bleedings stop spontaneously without any treatment.

It's necessary to weigh the risks and advantages of procedures, to safeguard providers with personal protective equipment (PPE), and to estimate the risk of critical illness as peri-procedural respiratory decompensation due to anaesthesia, cardiorespiratory function deterioration peri- and post-procedure that may require endotracheal intubation and mechanical ventilation. Endoscopists are left with insufficient information to make decisions on whether the risks of endoscopy disadvantages may outweigh the advantages due to a lack of research on endoscopy's diagnostic and therapeutic advantages in COVID patients. It's important to note that decision of endoscopy and time should be individualized, using a risk scores as the clinical Rockall score or the Glasgow- Blatchford score can be helpful [30].

Regarding LGIB, in normal situations patients needed colonoscopy after proper bowel preparation, Colonoscopy for lower gastrointestinal bleeding (LGIB) is considered urgent by the American Gastroenterological Association. Many considerations, this decision is influenced by factors such as personnel availability and personal protective equipment (PPE). An active respiratory infection (as COVID-19) also increases the risk of sedation- related procedures. According to a recent paper that revealed successful conservative management in six patients with upper GI bleeding, COVID-19 patients with LGIB are regarded a rare presentation (UGIB) [24].

Unlike UGIB, there is no widely acknowledged risk stratification score for LGIB. As a result, deciding when to intervene for LGIB is more ambiguous. Colonoscopies performance in LGIB have no bearing on mortality of patients, the death is more related to respiratory cause than LGIB. During the pandemic, the focus should be on patient- relevant outcomes. While LGIB may cause anxiety in both the patient and the physician, colonoscopy is unlikely to improve patient-important outcomes in patients who are hemodynamically stable and have no current bleeding.

COVID-19 patients' mortality risk is linked to respiratory failure severity rather than LGIB. The pulmonary defect increase risk of intra-procedural complications, limitation of PPE, and minimize unnecessary exposure for the endoscopy team should all be considered when deciding whether to do a colonoscopy or msnaged conservatively. In the majority of cases, cautious management of COVID-19 patients with LGIB appears to be a reasonable strategy, according to the findings.

In order to decrease risk of GI bleeding, Proton-pump inhibitors (PPI) were selected due to its ability to reduce gastric acid secretion, promote ulcer healing, and reduce risk of ulcer recurrence. According to Ray et al. [31] study state that PPI co-administration with anti- coagulant medications had a protective role in decreasing risk of GIB, PPI co-therapy with warfarin reduce risk of upper GIB by 24% in compare to those without PPI co- therapy.

Cavaliere et al. [24] publish a case serial study that describe 6 COVID-19 patients who presented upper gastrointestinal bleeding with the possible management method in the light of the pandemic, Patients were treated conservatively with blood transfusions and proton pump inhibitors (PPIs), and the researchers concluded that COVID-19 patients with bleeding should not undergo endoscopy.

In Mauro et al. [32] study which is cross sectional study to evaluate incidence of UGIB and the management using medical and endoscopic method. The study included 4871 COVID-19 positive patients in which only 23 presented of UGIB, the majority were on anticoagulant therapy or thromboprophylaxis. 11 out of 23 patients upper endoscopy, There was no statistical difference in the risk of death or re-bleeding between patients who received an endoscopy and those who were treated conservatively.

In a research, 11 patients with COVID-19 from two Boston tertiary care hospitals who developed LGIB were investigated. They were managed in Intensive care units. No endoscopic procedures were performed, despite the fact that one patient had interventional radiology-guided embolization. Within 48 hours, no re-bleeding occurred in ten of the patients. Anticoagulation was used in eight of the patients, and it was restarted in seven of them throughout hospitalization with no evidence of re-bleeding. None of the patients' antiplatelet drugs were withdrawn. There was no need for a blood transfusion in any of the 11 individuals. Three patients died from COVID-19-related complications rather than LGIB-related complications, while the remainder of patients were treated conservatively [33].

It’s necessary to note the limited evidence on the benefits of endoscopic procedures. While multiple studies have shown that conservative care alone can stop bleeding, there is little evidence to support either invasive or conservative treatment and its effect on 30- day outcomes.

The study of Shalimar et al. [34] retrospective analysis, included 1342 COVID-19 patients from the duration of April to July 2020, only 24 (1.8%) of included patients had GIB, only one had LGB. All patients were managed conservatively using vasoconstrictors- somatostatin and terlipressin as well as use of proton pump inhibitors and antibiotics. Packed red blood cells (PRBCs), fresh frozen plasma (FFPs) and platelets were used. Only one patient required endoscope, while those who had conservative management and followed for 5 days had no rebleeding event or death. It's worthy to mention that 22 of included patients had features of liver cirrhosis.

GIB bleeding is a rare symptom in COVID 19, however, if not managed properly can be fatal. Increasing number of severely infected patients, coagulations events, uses of NSAIs and anticoagulant raise number of reported GIB case. According to reviewed studies and articles, its prefer to managed UGIB or LGIB conservatively, and made the decision of endoscopy or colonoscopy individualized, taking in account risk and benefits patient gaining from chosen method.

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