key: cord-348835-4ocuw8uk authors: Aurelio, Mauro; Federico, De Grazia; Vincenzo, Lenti Marco; Roberto, Penagini; Roberto, Frego; Sandro, Ardizzone; Edoardo, Savarino; Franco, Radaelli; Matteo, Bosani; Stefania, Orlando; Arnaldo, Amato; Marco, Dinelli; Francesca, Ferretti; Elisabetta, Filippi; Maurizio, Vecchi; Davide, Stradella; Marco, Bardone; Lodovica, Pozzi; Laura, Rovedatti; Elena, Strada; Antonio, Di Sabatino title: Upper gastrointestinal bleeding in COVID-19 inpatients: Incidence and management in a multicenter experience from Northern Italy date: 2020-08-14 journal: Clinics and Research in Hepatology and Gastroenterology DOI: 10.1016/j.clinre.2020.07.025 sha: doc_id: 348835 cord_uid: 4ocuw8uk Abstract Background COVID-19 patients have an increased susceptibility to develop thrombotic complications, thus thromboprophylaxis is warranted which may increase risk of upper gastrointestinal bleeding (UGIB). Our aim was to evaluate incidence of UGIB and use of upper GI endoscopy in COVID-19 inpatients. Methods the medical and endoscopic management of UGIB in non-ICU COVID-19 patients has been retrospectively evaluated. Glasgow Blatchford score was calculated at onset of signs of GI bleeding. Timing between onset of signs of GI bleeding and execution, if performed, of upper GI endoscopy was evaluated. Endoscopic characteristics and outcome of patients were evaluated overall or according to the execution or not of an upper GI endoscopy before and after 24 hr. Results Out of 4871 COVID-19 positive patients, 23 presented signs of UGIB and were included in the study (incidence 0.47%). The majority (78%) were on anticoagulant therapy or thromboprophylaxis. In 11 patients (48%) upper GI endoscopy was performed within 24hr, whereas it was not performed in 5. Peptic ulcer was the most common finding (8/18). Mortality rate was 21.7% for worsening of COVID-19 infection. Mortality and rebleeding were not different between patients having upper GI endoscopy before or after 24 hr/not performed. Glasgow Blatchford score was similar between the two groups (13;12-16 vs 12;9-15). Conclusion Upper GI bleeding complicated hospital stay in almost 0.5% of COVID-19 patients and peptic ulcer disease is the most common finding. Conservative management could be an option in patients that are at high risk of respiratory complications. Outbreak of the novel severe acute respiratory distress syndrome coronavirus 2 (SARS- infection, leading to coronavirus 2019 disease (COVID-19) is dramatically growing worldwide and declared an official pandemic by WHO on March 11, 2020 [1] . The first COVID-19 case was detected in Italy on February 20th 2020 and at the time of the writing of the paper more than 230000 cases were diagnosed with 31936 deaths. COVID-19 ranges from an asymptomatic course or mild flu-like syndrome to a severe viral pneumonia with respiratory failure [2, 3] . No specific treatment is currently available and different classes of drug have been used in hospitalized patients (i.e antiviral agents, glucocorticoids, monoclonal antibodies and antimalarial drugs) [4] . Recent evidence suggests that COVID-19 patients have an increased susceptibility to develop venous thromboembolism, which may be a poor prognostic factor [5] . Therefore thromboprophylaxis is formally recognized as a pivotal treatment [6, 7] . Risk and incidence of upper gastrointestinal bleeding (UGIB) in COVID-19 patients is unknown, and at the moment only two case series (one without endoscopy data) [8, 9] and two case reports are reported in literature [10, 11] . Moreover, hospitalized patients frequently have cardiovascular comorbidity and are on antiplatelet or anticoagulant drugs. A proportion of patients with a severe course of the disease are exposed to stress ulcers, like intensive-care unit (ICU) patients [12] , and this further increases the risk of UGIB. Routinely UGIB is managed by endoscopists after clinical stabilization within 24 hr, as suggested by International Guidelines [13] . The recent ESGE and ESGENA Position Statement on gastrointestinal (GI) endoscopy and the COVID-19 pandemic [14] includes GI endoscopy in the setting of UGIB within the procedures that should be performed. However, the Authors did not consider the complex clinical scenario in which bleeding complications occur. Risk of desaturation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f and cardiopulmonary complications needs to be considered in patients with UGIB [15, 16] . COVID-19 patients are probably at increased risk of respiratory worsening during endoscopy with the possible need of respiratory support escalation and transferal to ICU department which may be a critical issue during the peak of COVID-19 outbreak for poor availability of ICU beds. Thus timing of endoscopy and medical management are crucial for patients' outcome. Aim of our study is to retrospectively evaluate incidence, management and outcome of UGIB in COVID-19 patients in non-ICU of tertiary COVID-19 hospitals from Northern Italy. From March 1st to April 30 th 2020, COVID-19-positive patients with signs of UGIB were retrospectively included in our study from six academic and two non-academic hospitals in Northern Italy (Como, Legnano, Milan "Ca' Granda", Milan "Sacco", Monza, Novara, Padua and Pavia). Two Centers are also referral for Liver Transplantation (Milan "Ca' Granda" and Padua). Medical history, in particular use of antiplatelet and/or anticoagulant, was acquired. Patients who had overt signs of acute UGIB (i.e. haematemesis, tarry stool or coffee ground vomitus) with a positive diagnosis of COVID-19 infection (positive real-time PCR obtained with nasopharyngeal swab or bronchoalveolar lavage) were eligible to be included in the study. We excluded patients who were younger than 18 years of age, pregnant, or moribund from terminal course of COVID-19, and those who were already admitted to ICU. We decided to exclude from the study patients admitted to ICU Departments because during COVID-19 outbreak the majority of them were intubated and therefore the management and decision on timing of endoscopy was not influenced by the risk of the procedure or sedation. Upper GI endoscopy, when needed, was performed by experienced endoscopists. Endoscopic bleeding findings were classified accordingly. Gastroduodenal ulcers with active bleeding or with nonbleeding visible vessels (i.e. Forrest Ia, Ib and IIa), gastroesophageal varices with active or recent stigmata of bleeding and other source of active bleeding were treated by the endoscopists accordingly to guidelines [13, 17] . If the endoscopic management was unsuccessful, a radiological or surgical treatment was proposed. Endoscopic characteristics and outcome of patients were evaluated overall or according to the execution or not of an upper GI endoscopy within and after 24 hr. Data are expressed as median with IQ range. Chi-square test with Fisher test and Mann-Whitney test were used when appropriate. March 13th 2020, and all patients provided written informed consent for the anonymized use of their data for research purposes, within the respect of their privacy. Among 4871 COVID-19-positive patients, we enrolled 23 cases (18 males; 75 yrs; IQR 64-78) with UGIB in non-ICU Departments (prevalence 0.47%). One Center (Como) did not report any case of upper GI bleeding out of 410 COVID-19 positive patients. Prevalence among Centers was homogeneous being always lower than 1% and ranging from 0.1% to 0.9%. All 23 patients had a confirmed diagnosis of COVID-19 by nasopharyngeal swab. Clinical characteristics and biochemical data are detailed in Table 1 . In particular 15 out of 23 patients (65%) had two or more comorbidities (78% hypertension or chronic heart disease, 48% diabetes and 9% cirrhosis). Seven patients (30%) were on antiplatelet therapy, and three of them were also taking at home direct oral anticoagulant. A total of 18 patients (78%) were on anticoagulant therapy at the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 At onset of GI bleeding all but one patient were treated with intravenous bolus of proton pump inhibitor. One patient was treated before endoscopy with vasoactive agent for suspicious of variceal bleeding. GBS at onset of bleeding was 13 (range 10-16). Upper GI endoscopy was performed in 18 patients. Endoscopic findings and treatments are detailed in Table 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f haematemesis. In one patient it was not executed for a severe respiratory worsening that lead to patients' death after 24 hr. In the other four patients (three with severe respiratory involvement) conservative treatment with PPI iv, anticoagulant withdrawal and blood transfusions lead to stabilization of haemoglobin values and resolution of bleeding. Clinical characteristics were similar between the two groups (see table 1 ). Rebleeding rate was not different between patients having upper GI endoscopy within or after 24 hr (2/11 vs 1/7 episodes). Need for endoscopic treatment was more common in patients in whom upper GI endoscopy was performed before 24 hr (6 vs 1 patients, p=0.08) although GBS score was similar between the two groups (13;12-16 vs 12;9-15, p=NS). Interestingly, C-reactive protein was higher in the group of patients where upper GI endoscopy was not performed or after 24 hr (4.5 mg/dl; 4-6.3 vs 11 mg/dl; 8.8-16.9). As expected, haemoglobin levels were lower in the group where upper GI endoscopy was performed within 24hr (8.3g/dl; 7.6-8.9 vs 10.7 g/dl; 8.9-12.5, p=0.03). Eighteen patients were discharged. Mortality rate was 21.7 % (five patients). All of them have died for worsening of COVID-19 infection, and one of them had a rebleeding that was successfully treated with radiological embolization. Patients who underwent to upper GI endoscopy before 24 hr or after 24hr/not performed have similar mortality rate (2 vs 3 patients). This is the first study, to the best of our knowledge, that evaluated the incidence and the endoscopic characteristics of UGIB in COVID-19 patients. All the Centers came from Regions (six in Lombardy, one in Piedmont and one in Veneto) that had the highest incidence of SARS-CoV-2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f outbreak in Italy [18] . We reported an incidence of 0.47% in COVID-19 patients who were admitted in non-ICU Department. Reported incidence in literature of UGIB in hospitalized patients is different among studies and varies in consideration of diagnostic definition, the prophylaxis prescribed, the publication era and type of admission department [19] . It is certainly known that the incidence is higher in critically ill patients admitted to the ICU ranging from 1.5% to 5.5% [20, 21] compared to non-critically ill patients in whom the incidence varies from 0.005% [22] to 0.4% [23] ; hospital admission incidence for UGIB was reported around 0.3% [24] . Our reported incidence is in line with the rate of patients not admitted to the ICU. However, COVID-19 inpatients need to be considered as a group of critically ill patients. Indeed, in our cohort the majority had at least two comorbidities (78%) and the majority of them had a significant respiratory involvement (69%). Moreover, during COVID-19 outbreak availability of ICU beds was poor and therefore many patients were managed in non-ICU departments although they had many criteria for admission to the ICU. Therefore, incidence of UGIB in COVID-19 patients is not as high as expected, given the significant comorbidity and the widespread of thromboprophylaxis. Median age in our cohort was 75 years, confirming previously published data showing that UGIB predominantly afflicts elderly patients with comorbidities in a hospital setting [25] . Anticoagulant therapy and thromboprophylaxis are recognized risk factors for upper GI bleeding in hospitalized patients with an OR in a multivariate analysis of 2.6 and 1.7 respectively; the OR increases to 3.2 if anticoagulation is associated with a single antiplatelet agent [26] . In our retrospective study we did not have data about the overall use of anticoagulant therapy or thromboprophylaxis in all COVID-19 patients. However given the progressive evidence on the risk of thrombosis in this category of patients [5] , thromboprophylaxis was progressively and early started in COVID-19 patients. Italian agency of drugs inserted on 11th of April enoxaparin as a recommended off-label therapy in patients with acute respiratory failure and/or reduced mobility [27] . This type of management is confirmed in our report where 78% of patients were in anticoagulant therapy or thromboprophylaxis that was started during hospital stay in 48% of them. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f Although the diffuse use of LMWH, incidence of UGIB remained low. About endoscopic findings, peptic alterations were the most common finding (44% active ulcers and 22% diffuse erosive or hemorrhagic gastritis)in agreement with a case series. Despite the participation in our study of two referral Centers for liver transplantation and one center being the referral for infectious disease in Milan with a high number of cirrhotic patients in follow up, only one patient developed variceal bleeding from a gastroesophageal varice. It must be remarked that we did not know which is the incidence of COVID-19 infection in cirrhotic patients. Our percentage of endoscopic findings are in line with the ones reported in literature as a cause for non-variceal UGIB [28] and therefore we cannot speculate on a causative effect of COVID-19 on GI bleeding. One of the aims of our study was to evaluate which was the management of UGIB in this novel systemic disease. We interestingly found that almost half of the enrolled patients (52%) performed the endoscopy after 24hr and five of them were managed conservatively with resolution of bleeding and stabilization of haemoglobin values, except in one case where endoscopy was not performed for a progressive respiratory worsening that lead to patients' death. We compared the two category of patients (endoscopy within 24hr vs endoscopy after 24hr or not performed), and we found similar clinical characteristics in terms of comorbidities, respiratory support and GBS. As expected, we observed a trend towards a higher number of pathologic findings needing endoscopic treatment in the group that performed upper GI endoscopy within 24 hr (6 vs 1, p=0.08). However, we found a similar outcome considering mortality and rebleeding rate, although endoscopic treatment is known not to be always associated with a better outcome [29] . We have to point out that the decision to group patients that performed endoscopy after 24hr with those who did not was arbitrary and related to the assumption of a wait-and-see approach. Noteworthy, c-reactive protein values were higher in patients where endoscopy was performed after 24hr. It is known from the literature that higher c-reactive protein values at admission are associated with worse outcome in COVID-19 patients [30] . Despite this significant difference, patients had a similar outcome. Patients with haematemesis were managed earlier than 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f patients presenting other symptoms (i.e tarry stool or coffee ground vomitus) as expected and in line with guidelines [13] . The decision to postpone upper GI endoscopy or to not perform was probably related to the significant respiratory involvement (nine out of 12 patients) or to a severe systemic course of COVID-19 disease that reflected higher c-reactive protein values and that lead physicians to avoid additional factors (i.e. sedation, endoscopic procedure) that could worsen respiratory function. Moreover, in Italy during the peak of COVID-19 outbreak there was a complete saturation of ICU beds and therefore there was a trend to manage conservatively all type of complications that could result in transferal to the ICU. This type of conservative management was also described with clinical success by Cavaliere K. et al in six COVID-19 patients with UGIB [8] . Our study has also some limitations. First, the retrospective nature of the study could not have included those patients with non-significant UGIB in which endoscopist's evaluation was not requested. Therefore, the rate of UGIB in COVID-19 may be underestimated. However, in our centers endoscopists are usually consulted for minor bleedings and therefore the underestimation is, in our opinion, negligible. Second, the total number of enrolled cases is limited, thus comparative results between the two groups needs to be considered with caution. Moreover predictive analysis of UGIB on mortality or disease worsening was not possible. Based on our results we propose a simple algorithm (Fig 3) for the management of UGIB in COVID-19 patients. First, it is crucial patients' support if there are signs of hemodynamic instability with infusion of liquids and hemotransfusion, infusion of PPI and anticoagulant withdrawal. Then it is necessary to stratify respiratory involvement based on type of respiratory support. In a study by Stanley A. et al need of endoscopic treatment was predicted with a sensitivity of 80% using the GBS with a cut off ≥7 [31] . In our study all but one patients have a GBS more than 7 and therefore we did not included GBS for endoscopic risk stratification. In presence of low risk patients that are in ambient air or low flow oxygen support (type 1-2 support), upper GI endoscopy could be performed based on standard guidelines within 24hr. If patients are more critical (high flow or non-invasive positive pressure support) it is important to stratify them 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Table 1 Clinical characteristics and biochemical data of COVID-19 positive patients with upper 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 WHO Director-General's opening remarks at the media briefing on COVID-19 -11 Clinical Characteristics of Coronavirus Disease 2019 in China COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis," (in eng) Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up Management of upper GI bleeding in patients with COVID-19 pneumonia Peptic Ulcer Disease as a Common Cause of Bleeding in Patients with Coronavirus Disease Emergency endoscopic variceal band ligation in a COVID-19 patient presented with hematemesis while on mechanical ventilation Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline ESGE and ESGENA Position Statement on gastrointestinal endoscopy and the COVID-19 pandemic Pulmonary aspiration during emergency endoscopy in patients with upper gastrointestinal hemorrhage A national study of cardiopulmonary unplanned events after GI endoscopy U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients Sorveglianza Integrata COVID-19 in Italia Prophylaxis against Upper Gastrointestinal Bleeding in Hospitalized Patients Risk factors for gastrointestinal bleeding in critically ill patients Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis Gastrointestinal bleeding in the hospitalized patient: a case-control study to assess risk factors, causes, and outcome Hospital-acquired gastrointestinal bleeding outside the critical care unit: risk factors, role of acid suppression, and endoscopy findings Acid-suppressive medication use and the risk for nosocomial gastrointestinal tract bleeding Mortality rate and risk factors for gastrointestinal bleeding in elderly patients Risk factors for nosocomial gastrointestinal bleeding and use of acid-suppressive medication in noncritically ill patients Eparine a basso peso molecolare nei pazienti adulti con COVID-19 Mortality from nonulcer bleeding is similar to that of ulcer bleeding in high-risk patients with nonvariceal hemorrhage: a prospective database study in Italy Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early Comparison of risk scoring systems for patients presenting with upper gastrointestinal bleeding: international multicentre prospective study Glasgow-Blatchford score 13 (10-16) 13 (12-16) 12 (9) (10) (11) (12) (13) (14) (15)