key: cord-0826249-qu99edn8
authors: Zellmer, Stephan; Hanses, Frank; Muzalyova, Anna; Classen, Johanna; Braun, Georg; Piepel, Christiane; Erber, Johanna; Pilgram, Lisa; Walter, Lorenz; Göpel, Siri; Wille, Kai; Hower, Martin; Rüthrich, Maria Madeleine; Rupp, Jan; Degenhardt, Christian; Voigt, Ingo; Borgmann, Stefan; Stecher, Melanie; Jakob, Carolin; Dhillon, Christine; Messmann, Helmut; Ebigbo, Alanna; Römmele, Christoph
title: Gastrointestinal bleeding and endoscopic findings in critically and non‐critically ill patients with corona virus disease 2019 (COVID‐19): Results from Lean European Open Survey on SARS‐CoV‐2 (LEOSS) and COKA registries
date: 2021-10-15
journal: United European Gastroenterol J
DOI: 10.1002/ueg2.12165
sha: 1ed42336dfee1e99e6c47812802e652622dd09eb
doc_id: 826249
cord_uid: qu99edn8

BACKGROUND: Corona virus disease 2019 (COVID‐19) patients are at increased risk for thromboembolic events. It is unclear whether the risk for gastrointestinal (GI) bleeding is also increased. METHODS: We considered 4128 COVID‐19 patients enrolled in the Lean European Open Survey on SARS‐CoV‐2 (LEOSS) registry. The association between occurrence of GI bleeding and comorbidities as well as medication were examined. In addition, 1216 patients from COKA registry were analyzed focusing on endoscopy diagnostic findings. RESULTS: A cumulative number of 97 patients (1.8%) with GI bleeding were identified in the LEOSS registry and COKA registry. Of 4128 patients from the LEOSS registry, 66 patients (1.6%) had a GI bleeding. The rate of GI bleeding in patients with intensive care unit (ICU) admission was 4.5%. The use of therapeutic dose of anticoagulants showed a significant association with the increased incidence of bleeding in the critical phase of disease. The Charlson comorbidity index and the COVID‐19 severity index were significantly higher in the group of patients with GI bleeding than in the group of patients without GI bleeding (5.83 (SD = 2.93) vs. 3.66 (SD = 3.06), p < 0.01 and 3.26 (SD = 1.69) vs. 2.33 (SD = 1.53), p < 0.01, respectively). In the COKA registry 31 patients (2.5%) developed a GI bleeding. Of these, the source of bleeding was identified in upper GI tract in 21 patients (67.7%) with ulcer as the most frequent bleeding source (25.8%, n = 8) followed by gastroesophageal reflux (16.1%, n = 5). In three patients (9.7%) GI bleeding source was located in lower GI tract caused mainly by diverticular bleeding (6.5%, n = 2). In seven patients (22.6%) the bleeding localization remained unknown. CONCLUSION: Consistent with previous research, comorbidities and disease severity correlate with the incidence of GI bleeding. Also, therapeutic anticoagulation seems to be associated with a higher risk of GI bleeding. Overall, the risk of GI bleeding seems not to be increased in COVID‐19 patients.

The outbreak of "severe acute respiratory syndrome corona virus 2" (SARS-CoV-2) in Wuhan, China has developed into a pandemic within a remarkably short time. By now, more than 180 million people worldwide suffered from "corona virus disease 2019" and more than 3.9 million people died. 1 Transmission of the virus occurs predominantly via droplet infection. 2 Therefore, strict isolation measures must be implemented in SARS-CoV-2 positive patients. 3 Not only the strict isolation measures and the high number of cases challenge the health systems of the affected countries, but also the occasionally severe courses with numerous complications. 4 Complications comprise pulmonary, neurological, cardiovascular as well as gastrointestinal (GI) and thromboembolic events such as mesenterial ischemia, deep vein thrombosis or pulmonary artery embolism. 3, 5 In order to prevent these events numerous guidelines for both, in-and outpatient therapy of COVID-19 patients recommend prophylaxis of thromboembolism. [6] [7] [8] Notably, oral anticoagulation as well as prophylaxis of thromboembolism leads to an increased risk of GI bleeding in hospitalized patients. [9] [10] [11] It seems therefore reasonable to assume that anticoagulation leads to gastrointestinal bleeding in COVID-19 patients also. Furthermore, other possible additional factors influencing the occurrence and frequency of GI bleeding in COVID-19 patients are neither fully recognized nor understood.

However, the current evidence on SARS-CoV-2 infection as a risk factor for a GI bleeding and the rate of GI bleeding in COVID-19 patients is limited. For example, Trinidade et al. described a GI bleeding rate of approximately 3% in COVID-19 patients, while factors influencing GI bleeding risk could not be identified. 12 This bleeding rate falls in the range of 1.5% to 5.5% reported in critically ill patients and thus does not appear to be increased. 13 However, several recent publications describe severe GI bleeding events associated with COVID-19. [14] [15] [16] In the present study, we provide an analysis of COVID-19 patients with GI bleeding from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) registry and the COVID-19 registry of Augsburg University Hospital (COKA). Our aim was to assess the GI bleeding rate of COVID-19 patients as well as to determine risk factors associated with higher incidence of GI bleeding. In addition, endoscopic findings will be described and analyzed.

A total of 6457 patients included in the LEOSS registry between March 2020 and February 2021 were analyzed in this study. The LEOSS registry is a prospective, multi-center cohort registry enclosing data on hospitalized COVID-19 patients having a laboratory-confirmed COVID-19 diagnosis. The LEOSS registry aims at addressing the lack of in-depth knowledge on epidemiology and clinical course of this disease. Besides sociodemographic data, the registry collects baseline characteristics, laboratory parameters and important comorbidities of the patients. The clinical course of the disease is divided into four phases related to the health state of the patient such as uncomplicated (oligo-/asymptomatic), complicated (predominantly characterized by the need for oxygen supplementation), critical (need for life supporting therapy) and recovery phase (clinical improvement, discharge). Data available in the LEOSS registry are collected in a rough form as categorical values only. In order to ensure anonymity in all steps of the analysis process, an individual LEOSS Scientific Use File (SUF) was created, which is based on the LEOSS Public Use File (PUF) principles described in Jakob et al. 17 In addition, a total of 1216 patients included in the COKA registry between February 2020 and December 2020 were analyzed.

The COKA registry is a prospective, monocentric cohort registry that collects data on patients hospitalized at University Hospital Augsburg with a COVID-19 diagnosis confirmed by a positive result of a polymerase chain reaction test. The registry collects baseline characteristics, laboratory parameters and important comorbidities as well as endoscopic findings of the patients.

The primary endpoint of the study was occurrence of gastroenterological-relevant bleeding in any phase of disease. 

The patients' characteristics are reported as absolute numbers and percentages. CCI was calculated in line with Charlson et al. 18 and CSI was calculated according to Altschul et al. 19 Both indices are reported as mean and standard deviation. The inference-statistical comparison of percentages between two and more groups was conducted using χ 2 -test or Fisher exact test when appropriate. The odds ratios of demographics, comorbidities and baseline characteristics were assessed in univariate and multivariate logistic regression models. Parsimonious logistic regression was calculated applying backwards elimination technique. The comparison of both examined indexes between the group of bleeders and non-bleeders was conducted using Mann-Whitney-U test due to missing normal distribution of the data and inequality of both groups in terms of the case numbers. The significance level was defined at p < 0.05. Data management, descriptive and inference-statistical analysis were conducted using IBM SPSS Version 27. ZELLMER ET AL.

Among 4128 cases from LEOSS registry included in the data analyses, 42.9% (n = 1771) were female ( Table 1) 

In order to compare clinical course of COVID-19 in terms of GI complications, the group of bleeders was compared to a total of patients without GI bleeding during their inpatient stay. The data of both examined patients groups are shown in Table 2 1.056-9.073) were significantly associated with a higher risk of GI bleeding ( Table 3) .

Comparison of the group of non-bleeders and bleeders revealed a significant difference in terms of CCI and CSI (Table S1) 

At baseline C-reactive protein (CRP) levels above 3 mg/L were observed in 56.5% (n = 2333) of patients with available laboratory values (Table S2 and Table 4 ). Anemia was significantly associated with occurrence of GI bleeding. 2.3% of the patients with this coagulopathy developed a bleeding, among patients without anemia it was observed only in 0.6% of cases. Furthermore, patients with prolongation of the aPTT showed a noticeably higher rate of GI bleedings in comparison to the control group. However, this difference was marginally not significant (2.5% vs. 1.2%, p = 0.77).

In the complicated phase of disease, the share of patients with abnormal laboratory blood values was increased (Table 3) In the patient group with anemia the proportion of GI bleeding was significantly higher in comparison to those with normal hemoglobin levels (0.4% vs. 1.9%, p < 0.01; Table 4 ). This tendency applies also to aPTT levels: Patients with longer aPTT developed GI bleeding more frequently. Patients in the critical phase exhibit higher proportions of the abnormal blood values with a notably higher rate of patients with anemia 71.8% (n = 507; Table S3 ). In the critical phase increased intestinal bleeding rates were associated with platelets disorders (p = 0.034) and abnormal aPTT levels (p = 0.023; Table 4 ). Patients having increased INR levels also showed a higher rate of GI bleedings (6.5% vs. 3.2%), however, this difference was not significant (p = 0.072).

In the complicated phase the majority of patients received anticoagulation with low-molecular-weight heparin (LMH) 51.5% 

Thirty-one (2.5%) COVID-19 patients in the COKA registry developed a GI bleeding (Table 6 ). Females were 38.7% and the mean age The present study has notable strengths. Firstly, the data used for analysis are from the LEOSS registry comprising patients with confirmed COVID-19 diagnosis from different medical centers across Europe. Secondly, the data includes relatively large number of GI bleeding events, which makes the findings more generalizable.

However, the study also has several limitations worth mentioning.

Firstly, as the data were taken from a registry, some variables show a high proportion of missing data; a total of 2329 (36.1%) out of 6457 cases had to be excluded from the analysis. This is a major limitation of our study. Secondly, the information of an endoscopic examination of the GI bleeders has not been obtained in the LEOSS registry.

However, this shortcoming could be partially compensated by detail T A B L E 6 (Continued) In conclusion, the data presented in this study suggest that the incidence of GI bleeding in COVID-19 patients does not differ compared to non-COVID-19 patients in similar settings or in other clinical scenarios. In critical stage of disease, being on therapeutic dose of anticoagulation was associated with a significant increase the risk of GI bleeding.

Hospital Dortmund gGmbH (Martin Hower), University Hospital Jena (Maria Madeleine Ruethrich)

Hospital Passau (Martina Haselberger), Tropical Clinic Paul-Lechler Hospital Tuebingen

Kielstein)

The LEOSS study infrastructure group: Jörg Janne Vehreschild

Sandra Fuhrmann (University Hospital of Cologne)

Open access funding enabled and organized by Projekt DEAL

An interactive web-based dashboard to track COVID-19 in real time

COVID-19) outbreak: what the department of endoscopy should know

Empfehlungen des RKI zu Hygienemaßnahmen im Rahmen der Behandlung und Pflege von Patienten mit einer Infektion durch SARS-CoV-2; 2021

Covid-19-implications for the health care system

Ischemic gastrointestinal complications of COVID-19: a systematic review on imaging presentation

American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19

Clinical Practice guideline: recommendations on inpatient treatment of patients with COVID-19

Antithrombotic therapy in patients with COVID-19. NIH COVID-19 treatment guidelines

American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients

Management of anticoagulation in patients with acute gastrointestinal bleeding

Gastrointestinal bleeding in hospitalized COVID-19 patients: a propensity score matched cohort study

Prophylaxis against upper gastrointestinal bleeding in hospitalized patients

A case of COVID-19 complicated by massive gastrointestinal bleeding

A severe coronavirus disease 2019 patient with high-risk predisposing factors died from massive gastrointestinal bleeding: a case report

Peptic ulcer disease as a common cause of bleeding in patients with coronavirus disease 2019

Design and evaluation of a data anonymization pipeline to promote Open Science on COVID-19

A new method of classifying prognostic comorbidity in longitudinal studies: development and validation

A novel severity score to predict inpatient mortality in COVID-19 patients

COVID-19 in cancer patients: clinical characteristics and outcome-an analysis of the LEOSS registry

Charlson comorbidity index score and risk of severe outcome and death in Danish COVID-19 patients

Charlson Comorbidity Index and a composite of poor outcomes in COVID-19 patients: a systematic review and meta-analysis

Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial

Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents

Chronic kidney disease and risk for gastrointestinal bleeding in the community: the atherosclerosis risk in communities (ARIC) study

Gastrointestinal bleeding and endoscopic findings in critically and non-critically ill patients with corona virus disease 2019 (COVID-19): results from Lean European Open Survey on SARS-CoV-2 (LEOSS) and COKA registries

The authors express our deep gratitude to all study teams supporting the LEOSS study. The LEOSS study group contributed at least 5 per mille to the analyses of this study: University Hospital Regensburg

All authors declare that they have no conflict of interest.

The study was conducted in accordance with the Declaration of 

Data available on request from the authors.

https://orcid.org/0000-0002-5747-9150Siri Göpel https://orcid.org/0000-0002-7666-4634Kai Wille https://orcid.org/0000-0002-7682-8563