Introduction

A proportion of patients who contracted a severe COVID-19 infection suffer from post-acute disease.

Aims & Methods

In order to understand the role of the gut-liver axis in this setting, we compared a large panel of patient reported outcomes and biomarkers related to respiratory symptoms, gastrointestinal and health-related quality of life, routine blood work, gut permeability, innate and adapted immune response as well as the intestinal microbiome and metabolome of patients who previously suffered from severe COVID-19 disease (sCOV, n=21) to patients after mild COVID-19 disease (mCOV, n=10) in a crosssectional study.

Results

sCOV patients were studied on average 318 days after the infection, mCOV patients after 221 days (p=0.013) and even after this period of recuperation, sCOV patients reported lower general health (p=0.026), physical functioning (p<0.01) and more lower-airways symptoms (p=0.031) in validated questionnaires compared to mCOV patients. In general, sCOV patients were older (p=0.031), had more comorbidities (p=0.02), higher BMI (p<0.01), and higher rate of arterial hypertension (p=0.023) although being physically more active (p=0.035), had lower serum albumin (p<0.01), total protein (p<0.01), serum calcium (p=0.02), and estimated glomerular filtration rate (p=0.022), but higher fasting glucose levels (p<0.01) compared to mCOV patients. Increased serum diamine oxidase levels (p=0.017) indicated increased intestinal permeability, impaired neutrophil function with impaired directedness of chemotaxis (p=0.035), and lower ROS production in response to E. coli (p<0.01) indicated a dysfunction of the innate immune system. Higher of effector memory cells (p=0.009), terminally differentiated effector memory cells (0.035), CD3+ CD4+ T - cells (p=0.013) and CD45RA negative memory cells (p=0.028) and on the other hand and lower marginal zone B cells (p=0.021), central memory cells (p=0.024), immature T helper cells (p=0.031) and CD161 positive cytotoxic T cells (p=0.04) in sCOV compared to mCOV patients indicated an altered adaptive immune response. Gut microbiome sequencing revealed lower microbial richness (p<0.01) and reorganization of Ruminococcaceae and Lachnospiraceae families, potentially a long-term sequelae of the acute disease. Serum metabolome analysis showed higher glycoprotein to supramolecular phospholipid composite ratio (p<0.05), indicating inflammation, and lower levels of small-medium sized HDL particles (p<0.05) in sCOV patients. Stool metabolome analysis showed lower glycine and lactulose levels (p<0.05), and higher asparagine (p<0.001) and glycocholic acid (p<0.01) levels in sCOV patients. Multi-omics factor analysis showed higher VLDL particle number and predicted higher glucose and mannose metabolism capacity in sCOV patients.

Conclusion

This study highlights the differences in biomarkers of the gut-liver axis in patients who previously had severe COVID-19 disease. The gut-liver axis may be a potential source of biomarkers and a therapeutic target in COVID-19 disease.

Disclosure

AH and VS received speaker honoraria and research grants from Institut Allergosan

Introduction

Several studies have found that the course of infection by COVID-19 virus is often associated with varying degrees of hepatic damage, but the occurrence and its risk factors is yet to be mapped. The aim of the study was first, to determine the prevalence of liver injury in patients hospitalized for COVID19 infection. Second, to compare the groups with severe and critical course of COVID19. Third, to identify independent risk factors of several types of liver injury in the group of critically ill patients.

Aims & Methods

During several waves of the pandemic, we collected data about cases hospitalized for COVID-19 pneumonia in two groups: severe course, group 1 and critical course with mechanical ventilation, group 2. We recorded basic demographic parameters, comorbidities and their chronic treatment, clinical status and laboratory findings at admission, administered treatment and evolution of hepatic tests during hospitalization, maximum levels of ALT, ALP, and bilirubin. We defined liver injury according to the Common terminology criteria for adverse events v.5.0: ALT > 5 times the upper limit of normal (ULN, cytolytic damage 2nd degree), ALT > 3 times and bilirubin > 2 times ULN (Hy's law), ALP > 5 times ULN (cholestatic damage 2nd degree). In the group 2, we also identified independent risk factors for individual adverse events.

Results

345 patients had available data, 58. 3 % were men, with a median age of 66 years, a the Charlson comorbidity index of 4. 0, BMI of 28.4, with an initial CRP of 97 mg/l, an oxygen saturation of 91. 5 %, and leukocytes 7.7 x10.9/l.
There were 201 patients in group 1 and 144 patients in group 2. Group 2 differed significantly (p < 0.001) from group 1 in median age (61.5 vs. 71 years), proportion of men (70 vs. 49.8%), comorbidity index (2 vs. 6), initial CRP (117 vs. 86.8 mg/l), by entry ALT (0.75 vs. 0.49) and AST (1.0 vs. 0.77ukat/l), but not by a history of liver disease or cirrhosis (11.1 vs. 15.5 % and 2.1 vs. 3.0 %). In group 2, all defined events of liver injury were significantly more frequent (P<0.001): elevation of ALT > 5xULN (39.4 vs. 5%), Hy's law (30.3 vs. 3%), ALP > 5xULN (26.5 vs. 2%).
In group 2, the independent risk factors for ALT elevation > 5xULN were: entry AST (OR 1.75), aminoglycoside antibiotics (OR=4.28), methylprednisolone (OR=2.7), tigacycline (OR=3.06) and mean erythrocyte volume (OR=0.92). Hy's law risk factors were: history of hepatopathy (OR=3.3), aminoglycoside antibiotics (OR=4.04), caspofungin (OR=3.43) and linezolid (OR=3.07). Risk factors for ALP > 5xULN were: methylpredisolone (OR=4.1), level of fibrinogen on admission (OR=1.45), number of types of antibiotics administered (OR=1.41) and albumin on admission (OR=0.86).

Conclusion

Adverse events of liver injury among critically ill patients with COVID-19 were 8 to 12 times more frequent compared to patients with a severe course. The risk factors were mainly the initial state of the liver (history of hepatopathy, AST, albumin), methylprednisolone and selected antimicrobial drugs.

Clinical Case Summary

The authors present a case of a 22-year-old male with no previous medical history, apart from COVID-19 in January 2022, which had a mild course. He was referred to a medical appointment in our department after routine blood tests, from March 2022, that revealed abnormal liver biochemistry elevation (ALT 476U/L, AST 139U/L, GGT 135U/L, normal ALP and total bilirubin), which was normal in the previous year. He reported no symptoms and physical examination was unremarkable. There was no chronic medication, recent introduction of drugs, herbal products or epidemiology for zoonoses.
Abdominal ultrasound and CT scan with IV contrast showed discrete hepatomegaly with homogeneous steatosis, without focal lesions, and splenomegaly.
An extensive work-up excluded hepatotropic agents, metabolic causes, autoimmune aetiologies and haematological or lymphoproliferative disorders. The serum protein electrophoresis and immunofixation, immunoglobulins count, tumour markers and celiac disease serology were also normal. During this period, the patient maintained the same liver elevation pattern with stable values, without any alteration in total bilirubin, albumin, coagulation and hemogram, except for the appearance of discrete thrombocytopenia. We remained asymptomatic, with no signs of hepatic decompensation or haemorrhagic diathesis.
The percutaneous liver biopsy documented septal fibrosis and regenerative nodules, interface hepatitis, focal hepatocellular necrosis and, notably, the presence of numerous multinucleated giant hepatocytes, allowing the diagnosis of post-infantile giant cell hepatitis (PIGCH), in cirrhotic phase.
We present a case of PIGCH, with rapid progression to cirrhosis, whose aetiology remains unknow. Viral aetiologies account for 20% of the cases. Given the temporal association between SARS-CoV-2 infection and liver enzymes’ elevation, we cannot exclude this agent as a possible culprit. To our knowledge, this is the first case reporting this possible trigger.

References

Xiao, Y., Gao, Z. H., & Deschenes, M. (2021). Autoimmune post-infantile giant cell hepatitis: a case report and review of the literature. Canadian liver journal, 4(2), 104–109. https://doi.org/10.3138/canlivj-2020-0024;
Jiao, J., & Zhang, X. (2022). Post-infantile Giant Cell Hepatitis: A Literature Review and Meta-analysis. Journal of clinical and translational pathology, 2(3), 100–107. https://doi.org/10.14218/jctp.2022.00016.

Introduction

COVID-19, as a systemic disease, critically affects the liver and biliary system. Secondary sclerosing cholangitis (SSC) is an increasing complication in critically ill patients. After severe COVID-19 infection, the occurrence of bile duct changes resembling the picture of SSC has been increasingly observed. The early prognosis of COVID-19-associated SSC has not been adequately studied.

Aims & Methods

The aim of this study is to investigate the effects of COVID-19 on the liver in relation to previous hepatic disease, as well as to identify early prognostic markers for the course of disease in patients and the development of any complications. 261 patients treated in intensive care units of the University Hospital Regensburg and suffering from COVID-19 were analyzed in different groups. The classification was based on the presence and type of previous hepatic disease. Laboratory and clinical parameters collected during hospitalization included values at the time of admission and maximum values that developed during hospitalization. These were evaluated concerning mortality rates and the development of COVID-19-associated SSC in the different patient groups.

Results

Patients with pre-existing chronic liver disease had a hazard ratio for death of 2.045 (p=0.0446) compared to patients without chronic liver disease. The hazard ratio for death was higher for patients with pre-existing chronic liver disease than for patients with malignant disease (HR=1.986, p=0.0135) or dialysis requirement on ICU admission (HR=1.732, p=0.034). In all groups, mortality was also significantly correlated with an increase in liver enzymes during hospitalization. High bilirubin (p=0.002) or INR (p=0.018) levels on admission also correlated with increased mortality, independent of pre-existing hepatic disease. Among the entire cohort, the cause of death was associated with COVID-19 in 90.8%. In addition, the risk of developing COVID-19-associated SSC increased with the duration of ECMO therapy and correlated significantly (p=0.004) with high AP levels on admission.

Conclusion

This study demonstrates the potent effects of COVID-19 on the liver and biliary system and potential complications in patients with and without pre-existing chronic liver disease. Bilirubin and INR could serve as predictive factors for mortality. AP could be considered an early predictor for the development of COVID-19-associated SSC in patients with COVID-19. In the future, this will provide crucial clues for an optimized treatment strategy, including ventilation and sedation.

Introduction

It is well established that the gut microbiota plays an important role in host health and is perturbed by several factors including antibiotics and diseases like coronavirus disease 2019 (COVID-19). The microbiome contributes to the pathogenesis of ulcerative colitis (UC). Some vitamins have been shown to beneficially modulate the gut microbiome by increasing the abundance of presumed commensals. Also, probiotics could shape the intestinal microbiota leading to potential control of multiple bowel diseases and promotion of overall wellness.

Aims & Methods

In 6-month time (June 2021 to December 2021) 49 ulcerative colitis (UC) outpatients from Riga East Clinical University Hospital were included in a Cross-sectional study. All patients were divided into groups according to medically proven data about COVID-19 status (COVID-19pos vs. COVID-19neg) within the last 6 months. Information about vitamin, probiotic, and antibiotic intake, as well as fecal samples was collected. For taxonomical classifying of the gut microbiome metagenome data, MetaPhlAn v.2.6.0 tool was used. In further analysis gut microbiome (mostly bacteria phyla) and related data were analyzed with SPSS 20.0.

Results

Out of 49 patients, 31(63%) were male and 18(37%) were female, mean age was Md=38[IQR:34-51]. Fourteen patients (28.6%) have been COVID-19pos, 35(71.4%) COVID-19neg. Patients who were not using antibiotics in the last month had more Firmicutes Md= 64 [IQR:52.3-69.4] than users Md=31 [IQR:25.5-39.8], p=0.008. Only 9 patients (18.4%) consumed probiotics within the last month and 40 (81.6%) did not. Evaluating differences in bacteria composition in phylum level in-between probiotic users and non-users there were found no statistically significant difference. Most common used vitamins were vitamin D 18(64.3%), from those 15(42.9%) were COVID-19neg, 3(21.4%) COVID-19pos; vitamin C 7(32.8%), from those 4(11.4%) were COVID-19neg, 3(21.4%) COVID-19pos, p>0.5. Evaluating vitamin D and C users and non-users and bacteria type there were found no statistically significant differences.

Conclusion

Patients who were not using antibiotics in the last month had more Firmicutes than users. There were no statistically significant differences between probiotic users and non-users, nor between vitamin users and non-users.

Introduction

Patients with the coronavirus disease 2019 (COVID-19) develop venous thromboembolism, resulting in a poor prognosis. Therefore, thromboprophylaxis is important for treatment, but anticoagulation is a risk for gastrointestinal bleeding. Gastrointestinal bleeding has been reported to occur in 2% to 13% of COVID-19 hospitalized patients¹, but few reports have examined the association between COVID-19 and gastrointestinal bleeding.

Aims & Methods

This study aimed to identify gastrointestinal bleeding risk factors in COVID-19 patients. A multicenter, retrospective cohort study was conducted in patients admitted with a diagnosis of COVID-19 between January 2020 and December 2021 in Japan. Thirteen hospitals around Tokyo area participated in this study. The severity of COVID-19 was classified in this study according to the NIH severity classification, Cases below moderate were classified as not severe in this study. We collected information on the background factors (gender, age, severity of COVID-19, medical history, medication at admission, treatment details）and presence of gastrointestinal bleeding during hospitalization. A multivariable logistic regression analysis model was adjusted to evaluate the association between background confounding factors and presence of gastrointestinal bleeding. Multivariate analysis was also performed separately for upper and lower gastrointestinal bleeding. Additionally, we evaluated the association between post-hospitalization treatment and gastrointestinal bleeding using descriptive statistics.​

Results

12,044 patients were included in the analysis. 4165 (34.6 %) were severe COVID-19 patients, and 1257 (10.4%) were critical COVID-19 patients. 103 (0.9 %) had gastrointestinal bleeding, of which 60 (0.5 %) were diagnosed with upper gastrointestinal bleeding and 45 (0.4%) with lower gastrointestinal bleeding. Two patients had both upper and lower gastrointestinal bleeding. Multivariate analysis showed that COVID-19 severe group had a significantly higher risk of gastrointestinal bleeding than COVID-19 not severe group (odds ratio (OR) 2.8, 95% confidence interval (CI): 1.3-5.7), and COVID-19 critical group also had a significantly higher risk of gastrointestinal bleeding (OR 22.0, 95% CI: 11.2-43.0). The risk of upper gastrointestinal bleeding was significantly higher in the critical group (OR 16.9, 95% CI: 7.5-37.8), but the severe group did not have a significantly increased risk (OR 1.6 , 95% CI: 0.6-4.1). On the other hand, the risk of lower gastrointestinal bleeding was significantly higher in the severe group (OR 6.0, 95% CI: 1.7-21.3) and in the critical group (OR 35.5, 95% CI: 10.5-120.4) compared to the not severe group, suggesting that COVID-19 severe group was associated with lower gastrointestinal bleeding risk but not associated with upper gastrointestinal bleeding. No significant association was found between gastrointestinal bleeding and post-hospitalization anticoagulation in the COVID-19 severe group.

Conclusion

COVID-19 severity was considered a significant risk for gastrointestinal bleeding in hospitalized patients. The COVID-19 severe group is at risk for lower gastrointestinal bleeding even without the use of anticoagulants after hospitalization. Patients with severe or critical COVID-19 should be treated with caution, as they are at higher risk for complications of gastrointestinal bleeding, especially lower gastrointestinal bleeding.

References

1. Martin TA, Wan DW, Hajifathalian K, et al. Gastrointestinal Bleeding in Patients With Coronavirus Disease 2019: A Matched Case-Control Study. Am J Gastroenterol. 2020;115(10):1609-1616.

Introduction

Non-alcoholic Fatty Liver Disease (NAFLD), is a state of hyperinflammation which is associated with release of pro-inflammatory cytokines. Obesity, diabetes and metabolic syndrome, which are usually accompanied by hepatosteatosis, are risk factors for severe Covid-19 infection.

Aims & Methods

We aimed to investigate the association of hepatosteatosis and liver fibrosis by non-invasive markers (FIB-4 and APRI) with the prognosis of Covid-19 disease among hospitalized patients. In this retrospective and observational study, 500 patients with the diagnosis of Covid-19 between March 2020 and March 2022 and underwent Thorax Computed Tomography (CT) were included. Demographics, clinical characteristics and laboratory data at admission were recorded. Liver-spleen attenuation value difference (CT _L-S) was obtained from CT images and non-invasive fibrosis markers as APRI and FIB-4 scores were calculated (1). Advanced fibrosis was defined as FIB-4>2.67, APRI≥1. Severe outcomes were defined as either intensive care unit (ICU) admission or mortality.

Results

Among the patients, 129 (25.8%) were admitted to the ICU, and mortality occurred in 53 (10.3%) cases. According to CT _L-S value, hepatosteatosis was in 32.6% of the cases. 82.8% of cases with hepatosteatosis were male, mean age was 52.6±13.5, 82% were overweight or obese. Hypertension and diabetes were the most common comorbidities. Among ICU patients, hepatosteatosis was found in 41.8% and ICU admission was associated with hepatosteatosis (p=0.002). Of the patients with hepatosteatosis, 58% of patients have FIB-4>1.3 and of these, FIB-4 and APRI score were significantly high in patients with ICU admission and mortality (p=0,001). Of the patients both with hepatosteatosis and advanced fibrosis, 71% were admitted to the ICU, mortality was seen in 32.5%. Mortality was significantly higher in patients with hepatosteatosis and advanced fibrosis according to the FIB-4 score (p=0.001). In the ROC analysis, combination of FIB-4 score and attenuation had highest sensitivity (sensitivity: 88.37%; Negative Predictive Value 90.85%; p=0.001) in determining the need for ICU need. The need for ICU follow-up was found to be 5 times higher in patients with a high FIB-4 score and low attenuation value [(Odds ratio (OR) 5.101; 95% Confidence Interval (CI): 2.865-9.083)]. The risk factors for the need for intensive care in patients with hepatosteatosis were advanced age, presence of fibrosis, high ferritin and IL-6 level in univariate analysis, whilst only high ferritin level was defined as a risk factor in multivariate analysis. Inflammation markers such as IL-6 and ferritin were significantly higher in patients with hepatosteatosis and fibrosis.

Conclusion

Hepatosteatosis and fibrosis determined by non-invasive tests were found to be associated with severe Covid-19 infection. Hepatosteatosis and fibrosis may increase inflammation-related markers such as ferritin and IL-6 and may create a synergistic effect with infectious conditions. Likewise high ferritin level in Covid-19 patients with hepatosteatosis is a risk factor for severe disease. CT_L-S and fibrosis scores have strong negative predictive value in the diagnostic evaluation for severity of Covid-19 disease.

References

1. Byun J, Lee SS, Sung YS, Shin Y, Yun J, Kim HS, et al. CT indices for the diagnosis of hepatic steatosis using non-enhanced CT images: development and validation of diagnostic cut-off values in a large cohort with pathological reference standard. European Radiology. 2019 Aug 1; 29(8):4427–35.