key: cord-0863702-3fx5ykuy
authors: Ashktorab, Hassan; Russo, Tiziano; Oskrochi, Gholamreza; Latella, Giovanni; Massironi, Sara; Luca, Martina; Chirumamilla, Lakshmi G.; Laiyemo, Adeyinka O.; Brim, Hassan
title: Clinical and Endoscopic Outcomes in COVID-19 Patients with Gastrointestinal Bleeding
date: 2022-03-10
journal: Gastro Hep Adv
DOI: 10.1016/j.gastha.2022.02.021
sha: 6641c6e9774dbd76fd5664abe090ff346b18bfbf
doc_id: 863702
cord_uid: 3fx5ykuy

Background & Aims Over 404 million people worldwide have been infected with COVID-19, 145 million in the United States (77 million) and Europe (151 million) alone (as of Feb. 10th, 2022). This paper aims to analyze data from studies reporting Gastrointestinal bleeding (GIB) and/or endoscopic findings in COVID-19 patients in Western countries. Methods We conducted a systematic review of articles on confirmed COVID-19 cases with GIB in Western countries published in PubMed and Google Scholar databases from June 20th, 2020, to July 10th, 2021. Results A total of 12 studies reporting GIB and/or endoscopic findings in 808 COVID-19 patients in Western countries were collected and analyzed. Outcomes and comorbidities were compared with 18,179 non-GIB COVID-19 patients from Italy and the United States. As per our study findings the overall incidence of GIB in COVID-19 patients was found to be 0.06%. When compared to non-GIB cohort, death rate was significantly high in COVID-19 patients with GIB (16.4% vs. 25.4%, p<0.001, respectively). Endoscopic treatment was rarely necessary, and blood transfusion was the most common GIB treatment. Most common presentation in GIB patients is melena (n=117, 47.5%). Peptic, esophageal, and rectal ulcers were the most common endoscopic findings in upper (48.4%) and lower endoscopies (36.4%), respectively. The GIB cohort had worse outcomes and higher incidence of hypertension (61.1%), liver disease (11.2%), and cancer (13.6%) when compared with non-GIB cohort. Death was strongly associated with hypertension (p<0.001, r=0.814), hematochezia (p<0.001, r=0.646) and EGD (p<0.001, r=0.591) in COVID-19 patients with GIB. Conclusion Overall, the incidence of GIB in COVID-19 patients is similar to that estimated in the overall population with melena being the most common presentation. The common endoscopic findings in GIB COVID-19 patients were ulcers, esophagitis, gastritis, and colitis. Patients with GIB were more prone to death than non-GIB COVID-19 patients.

SARS-CoV-2 virus has infected over 404 million people worldwide, many of them developed the coronavirus disease-2019 (COVID-19) 1 . SARS-CoV-2 associates with a wide variety of manifestations, partly because there are several variants in the world due to mutations but also because of geographic and population's specificities and differences. The most common COVID-19 symptoms are fever, cough, dyspnea, sore throat, rhinorrhea, anosmia, dysgeusia, fatigue, and myalgia 2 . However, gastrointestinal (GI) symptoms (nausea, diarrhea, vomiting, abdominal pain, and anorexia) are also commonly reported 2, 3 . A specific GI manifestation that has been identified in 3-12% of COVID-19 patients is gastrointestinal bleeding (GIB) 4-6 .

Coagulopathy is a major concern in COVID-19 patients 7 . Endothelial dysfunction and hypercoagulability are likely associated with a strong immune response of the host towards the virus, which generates a cytokine storm and subsequent complications 7 . Therefore, anti-coagulants and thromboprophylaxis are frequently used in the treatment of COVID-19. Coagulopathies, adoption of anti-coagulant therapies, and other viral effects make COVID-19 patients more prone to develop gastrointestinal bleeding 6 . In particular, the virus is thought to cause both direct and indirect damage, via a "double-hit" mechanism 8 . Direct damage refers to the GI mucosal injury with consequent immune response and inflammation, and indirect damage is the subsequent hypoxic stress that stems from coagulopathy 9 . Little is known about the underlying conditions that increase the risk of developing GIB.

In normal circumstances, it is recommended that patients developing upper GI bleeding (UGIB) undergo endoscopy within 24 hours from presentation 9 . However, the COVID-19

pandemic has led to several changes in the allocation of resources and performance of such procedures, both to free health care providers to deal with patients infected by the virus and to J o u r n a l P r e -p r o o f 6 limit the risk of infection in health care facilities. A study from Northern Italy reported that most of the endoscopic procedures that were supposed to take place in March 2020 were either postponed or cancelled 10 . Another study from central Italy reported similar findings, with the number of patients admitted for urgent upper endoscopy in March-May 2020 dropping 50% from the same period pre-lockdown 11 . Finally, a nation-wide Italian study showed a statistically significant decrease in upper and lower endoscopies during the COVID-19 pandemic, mainly due to patients avoiding exposure to the virus in hospital settings 12 . Consequently, post-UGIB endoscopy survival was shown to be reduced during the COVID-19 pandemic 13 .

In this review, we analyze and discuss the results of studies including mainly patients from western countries that report GIB and endoscopic findings in COVID-19 patients. We report the current consensus and available information on different types of treatments, and investigate the differences in underlying conditions and outcomes between COVID-19 patients with and without GIB. Selection and identification of relevant literature: Using the listed inclusion and exclusion criteria, we first sorted the GI bleeding and endoscopy COVID-19 studies by title and abstract; then we compiled the papers by relevance and conducted a new selection process by a thorough review of the data (Fig. 1) . We incorporated studies that reported GI bleeding and/or endoscopic findings in COVID-19 patients. Then we selected articles on non-GIB COVID-19 patients from Italy and the United States for comparison. From the selected papers, tables were generated for each dataset on Microsoft Excel. These tables included the following information for each study (when available): general information about the study (year, location, hospital or city, state and country, publication date), confirmed cases, GI bleeding (general, upper, lower), indication to gastroscopy/GI bleeding manifestation (melena, hematochezia, anemia, hematemesis, etc.), number and type of endoscopies, main upper and lower endoscopy findings, COVID-19 treatments, GI bleeding treatments, outcome (re-bleeding, hospitalizations, ICU transfers, deaths), respiratory support (supplemental oxygen, non-invasive ventilation/CPAP, intubation), general signs and symptoms, GI symptoms, comorbidities. We compared clinical manifestations, J o u r n a l P r e -p r o o f comorbidities, treatment, and outcomes between COVID-19 patients with GIB vs. non-GIB

Inclusion criteria: The following inclusion criteria were adopted to validate article selection: any study including patients with confirmed diagnosis of COVID-19 (PCR positive) with specified gastrointestinal bleeding or endoscopic findings; any study with 5 or more patients; any study with all or the majority of patients from Western countries; no distinction with regard to sex, age, severity of disease, inpatient or outpatient management, data collection date, treatment and outcome. Confirmed diagnosis of COVID-19 (RT-PCR) patient without GIB are included for comparison with GIB patients.

The following exclusion criteria were adopted to filter out incomplete data: studies where cases were not confirmed by PCR; studies with less than 5 patients; studies which did not distinguish between COVID-19 with GIB and COVID-19 patients without GIB; systematic reviews and meta-analyses. Studies from Eastern countries were also excluded to have more homogeneous data.

The collected data was used to calculate the most common endoscopic findings in the included COVID-19 patients' studies. Different GIB presentations, common symptoms, comorbidities, treatment strategies, respiratory support, and outcomes were combined and analyzed by weighted analysis methods where applicable. Variables reported in only one study were excluded from statistical analysis. Correlation coefficients were calculated together with regression analysis to establish associations between comorbidities and mortality. The effect of symptoms was reported using weighted analysis where weights were related to the size of the reported study. Differences in comorbidities and outcome between COVID-19 patients with and without GI bleeding were computed. SPSS (SPSS Inc., Chicago, IL, USA) was used for this analysis.

J o u r n a l P r e -p r o o f

The studies reporting GIB included a total of 808 patients (Table 1) . Six of these studies reported the incidence of patients with GIB in their overall COVID-19 population which amounts to 0.06%.

Within the selected 808 patients with endoscopic findings from the 12 studies, 92.7% displayed GIB. Not all studies specified the type or presence of GIB. Among 633 patients, the bleeding was localized in the upper GI tract in 66.0% (418) of patients, and in the lower GI tract in 24.8% (157).

The remaining 9.2% (58) had unspecified GIB location.

From the 808 patients in all the studies reporting GIB, the mean age was 69.7 years compared to 62.3 in the control group (Tables 1 and 2 ). The control population consists of a large general COVID-19 cohort of which the characteristics are presented in Table 2 (Non-GIB cohort). In the GIB cohort, 62.4% were males and 37.6% were females, while the distribution in the control cohort was 52.6% and 47.4%, respectively. In the GIB cohort, men are older than in the control group (p<0.001).

GIB was strongly correlated with GI symptoms, diabetes, cancer, hypertension, and heart disease but not with anti-coagulants Several symptoms, comorbidities, and treatments were associated with GIB. Positive associations were found with diarrhea (p<0.001, r=0.884), loss of taste (p<0.001, r=0.791), nausea (p<0.001, r=0.734), and vomiting (p<0.001, r=0.651). Negative associations with shortness of breath (p<0.001, r=-0.770) and fever (p<0.001, r=-0.524) were noted. As for comorbidities, positive correlations were found between GIB and diabetes (p<0.001, r=0.915), cancer (p<0.001, r=0.844), hypertension (p<0.001, r=0.754), and cardiac disease (p<0.001, r=0.714).

Endoscopic procedures were performed for varied reasons (Table 1 ). Only 9 out of the 12 studies reporting GIB also reported information regarding endoscopies. Most procedures were carried out due to GIB. The known GIB manifestations and reasons for endoscopy were melena (47.5%), hematochezia (37.8%), anemia (21.0%), hematemesis (16.7%), diarrhea (8.1%), and coffeeground emesis (7.8%) (Fig.2 ). Performed endoscopic procedures were esophagogastroduodenoscopy (EGD) (81.7%), colonoscopy (20.9%), Endoscopic retrograde cholangiopancreatography (ERCP) (9.2%), sigmoidoscopy (8.7%), and enteroscopy (3.8%).

The upper and lower endoscopies revealed a wide spectrum of findings (Table 1) . The upper endoscopy findings were the following: peptic ulcer (48.4%), esophagitis or esophageal ulcer (17.6%), erosive or hemorrhagic gastritis (16.6%), gastropathy or duodenopathy (9.9%), Mallory-Weiss tears (6.3%), esophageal varices (5.5%), and Dielafuoy lesions (2.9%) while 23% of upper endoscopies had no abnormal findings (Fig. 3a) . As for the lower endoscopies, the most reported findings were rectal ulcer (36.4%), hemorrhagic, lymphocytic, or microscopic colitis (30.7%), colon ischemia (29.8%), diverticular bleeding or diverticulosis (25.0%), hemorrhoids (15.6%), and blood without source (11.7%; Fig. 3b ). In 20.5% of cases, no abnormal findings were identified.

In the cohort of 808 GIB patients, endoscopic treatment (in the form of cautery, clips and others) was only performed in 6% of the cases (Table 1 ). In the remaining 94%, treatment for bleeding was either medical only or not performed. The most frequent non-endoscopic treatments for GI bleeding were the following: transfusions (55.2%), proton pump inhibitor (47.7%), vasopressor support (44.9%), H2 receptor blockers (15.2%), and interventional radiology (8.9%; Fig. 4 ).

Different kinds of COVID-19 treatments were also reported as follows: azithromycin or other antibiotics (71.2%), anti-coagulants, low molecular weight heparin, or thromboprophylaxis (59.6%), hydroxychloroquine (52.1%), steroids (43.5%), anti-platelets (43.3%), Remdesivir (11.6%), and Tocilizumab (11.4%; Supplementary Fig.1 ).

The GIB cohort and the control cohort had different incidences of comorbidities (Fig. 5a) (Fig. 5b) . There was also a 5.9% incidence of re-bleeding in the GIB cohort. All these differences in outcomes were significant (p<0.001).

Death was positively associated with hypertension, EGD, and hematochezia in GIB patients

Several associations with death were found in the GIB cohort. Among all the comorbidities, death was strongly associated with hypertension (p<0.001, r=0.814). Other strong positive correlations with death were EGD (p<0.001, r=0.591), and hematochezia (p<0.001, r=0.646).

J o u r n a l P r e -p r o o f

Gastrointestinal bleeding (GIB) has been identified in some COVID-19 patients as a GI manifestation. In this systematic review, we analyzed the findings of 12 studies which reported GIB and endoscopic findings in COVID-19 patients. These studies included 808 patients. The data retrieved from the GIB cohort was compared with a control group consisting of 18,179 COVID-19 mostly hospitalized patients. GIB was found to have an incidence of about 0.06% in COVID-19 patients. This rate was calculated from the studies from which we extracted and constructed our GIB cohort. This rate is slightly greater than the incidence in the overall population, which is estimated around 0.05% (0.06% for upper GIB and 0.03% for lower GIB ) 15 .

In our cohort, as in the overall population, bleeding in the upper GI tract occurred more often than in the lower GI tract. Because not all the analyzed studies provided a specific subdivision of upper and lower GIB, we could not calculate an exact ratio, but from the available data it is approximately 7:3. Additionally, males were found to be more susceptible to GIB than females. This is also confirmed by the studies, which state that both upper and lower GIB are more common in men than women 15, 16 . As such, it seems unlikely that COVID-19 affects GIB or its upper/lower distribution since the profile in the general population fits the one in the GIB COVID-19 cohort.

It is worth noting however that COVID-19 associates with coagulopathies and veinous thromboembolism and that many patients receive anti-coagulants as part of their treatment regimen. While anti-coagulants' use is known to associate with bleeding disorders, including in the GI tract, such an association was not confirmed in our cohort. Consequently, neither COVID-19 nor anti-coagulants' use can be suspected to be causative of GIB in the analyzed cohort.

Since upper GIB was more common than lower GIB, it follows that the most common type of endoscopy was EGD and the most common bleeding presentation was melena, which mainly occurs when the bleeding lesions are located above the ligament of Treitz 15, 17 . Hematemesis, J o u r n a l P r e -p r o o f which was the fourth most common presentation in the papers included in the study, confirms that the bleeding is mostly located in the upper GI tract and that the hemorrhage is large, often leading to the loss of large amounts of blood and ultimately to anemia 17 Steroids' use was positively associated with GIB, a finding consistent with the previous study by Narum et al. 21 . Interestingly, among all the patients who exhibited GIB and/or underwent endoscopy, only 6% required an endoscopic treatment. This means that 94% of the patients fully recovered with medical treatment or no treatment at all. The medical treatments mostly consisted of blood transfusions, proton pump inhibitors, and vasopressor support, which are used routinely to deal with blood loss and to reduce stomach acid production, whether or not a COVID-19

background is present 22 .

Overall, the GIB cohort exhibited worse outcomes than the control group. This is reflected by the higher incidence of ventilation, intubations, ICU transfers, and deaths. Furthermore, our analysis showed a direct correlation between death and both EGD (p= 0.000, r=0.591) and hematochezia (p=0.0001, r= 0.646). It was reported that patients undergoing endoscopy secondary to upper GIB in the COVID-19 era (regardless of whether or not they are infected) were more likely to die than before the pandemic 13 . These results were attributed to two main factors: patients'

avoidance of hospitals to reduce exposure to virus during the pandemic and hospital staff and resources relocation to respond to more severe COVID-19 cases, thus leading to a reduction and delay in endoscopic procedures, leading to the exacerbation of patients' conditions 13 .

The reduced survival in GIB patients could also be linked to comorbidities. According to our analysis, in the GIB cohort, death was positively associated with hypertension. Hypertension was found to be directly correlated with GIB, and more prevalent in the GIB cohort than in the control group. According to a recent meta-analysis, high blood pressure was independently J o u r n a l P r e -p r o o f associated with increased mortality in COVID-19 patients 23 . A specific mechanism connecting hypertension with COVID-19-related death was not identified. Of note, many anti-hypertensive drugs can increase the expression of ACE2, thus increasing the number of entry points for the virus. By contrast, other researchers proposed a diametrically opposite reasoning, stating that hypertensive patients might have reduced ACE2 expression, which would lead to a higher concentration of angiotensin upon binding with SARS-CoV-2, and consequent COVID-19 development 23 .

Other variables that were associated with GIB or had a higher incidence in the GIB cohort were GI symptoms (diarrhea, nausea, vomiting), loss of taste, diabetes, liver disease, cancer, and heart disease. Diabetes has been associated with increased incidence of GI bleeding in diabetic ketoacidosis patients 24 . Patients with liver cirrhosis are known to be at higher risk of GIB from different lesions, including gastroesophageal varices, which were identified in this analysis 25 .

Same goes for cancer patients, who are often subjects to GIB 26 . Of note, the studies included in the analysis did not specify the types of cancer detected in their cohorts. Finally, heart disease is normally considered a risk factor for GIB because these patients take anti-coagulants or antiplatelets medications 27, 28 . However, in our data analysis, no correlation between the use of anticoagulants/anti-platelets and GIB was found.

The main limitation of this study is certainly the heterogeneity of the data reported in the included studies. Indeed, all collected data was in aggregated format. This means that calculations reporting associations between variables, such as correlations with GIB and death, have a more potential statistical error than would be yielded by an analysis of de-identified single patients' data. In conclusion, we found that the incidence of GIB in COVID-19 patients is similar to that estimated in the overall population, with men being more susceptible than women and melena being the most common presentation. Nonetheless, patients with GIB were more likely to die than non-GIB COVID-19 control patients. Common endoscopic findings in GIB COVID-19 patients were ulcers, esophagitis, gastritis, and colitis. GIB was not found to be associated with anticoagulants' use. There was a higher incidence and association of GI symptoms, diabetes, heart disease, hypertension, liver disease and cancer in the GIB cohort. The latter three were positively associated with death in the GIB cohort.

Disparities of the National Institutes of Health under Award Number G12MD007597. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 

Coffee-ground emesis - 39 Incerti et al. 40 Schettino et al. 41 Colaneri et al. 42 Aghemo et al. 43 Vena et al. 44 Total % (N) J o u r n a l P r e -p r o o f Figure 5 : Comparing comorbidities, outcomes and respiratory support between GIB and Non-GIB patients exposed to COVID-19 A. Differences in comorbidities among the gastrointestinal bleeding and non-GIB patients. B. Differences in respiratory support and outcomes among gastrointestinal bleeding (GIB) and non-GIB patients exposed to COVID-19.

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We appreciate for the work, invaluable and enthusiastic support of all healthcare providers in this COVID-19 pandemic. We also would like to thank the funding agency.