Distinct histopathological features of post-COVID-19 cholangiopathy (preprint)

Background: Cholangiopathy has been described in survivors of severe COVID-19, presenting significant clinical parallels to the pre-pandemic condition of secondary sclerosing cholangitis in critically ill patients (SSC-CIP).  Aim: Herein, we examined the liver histopathology of individuals with persistent cholestasis following severe COVID-19.  Methods: Post-COVID-19 cholestasis liver samples were subjected to routine staining techniques and cytokeratin 7 immunostaining, and the portal and parenchymal changes were semi-quantitatively analyzed.  Results: All ten patients, five men, median age 56, interquartile range (IQR) 51–60, requiring mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP, 605 (390–1,105); GGT, 925 (776–2,169); ALT, 92 (86–110); AST, 90 (68–108); and bilirubin, 3 (1–6) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. Biopsies were performed at a median of 203 (150–249) days after molecular confirmation of infection. Portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy were found in all patients, while hepatocyte biliary metaplasia was observed in all tested cases. Mild-to-severe parenchymal cholestasis and bile plugs were observed in nine and six cases. Mild swelling of the arteriolar endothelial cells was observed in five patients. A thrombus in a small portal vein branch and mild periductal fibrosis were observed in one case each. One patient developed multiple small biliary infarctions. Ductopenia was not observed in any patient.  Conclusions: The alterations were similar to those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.

COVID-19 related biliary injury: A review of recent literature.

Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications.

COVID-19-associated secondary sclerosing cholangitis - A case series of 4 patients.

We report a case series of four patients diagnosed with COVID-19-associated secondary sclerosing cholangitis (SSC), a recently described rare late complication of severe COVID-19. Following prolonged stays in the intensive care unit, these patients developed marked sustained cholestasis and jaundice despite clinical improvement. Cholangiography showed beaded appearance of intra-hepatic bile ducts and bile casts were removed in one patient. None of the patients reached normalization of liver enzymes and at least one progressed to liver cirrhosis (follow-up time of 11 to 16 months). COVID-19-associated SSC has a dismal prognosis with rapid progression to advanced chronic liver disease.

Real-life patency of plastic biliary stents in the pandemic era: is stent removal after 6 months safe and effective?

BACKGROUND: The SARS-CoV-2 pandemic conditioned the optimal timing of some endoscopic procedures. ESGE guidelines recommend replacement or removal of the plastic biliary stents within 3-6 months to reduce the risk of complications. Our aim was to analyse the outcomes of patients who had delayed plastic biliary stent removal following endoscopic retrograde cholangiopancreatography (ERCP) in the pandemic era. METHODS: Retrospective study including consecutive ERCPs with plastic biliary stent placement between January 2019 and December 2021. Delayed removal was defined as presence of biliary stent >6 months after ERCP. The evaluated outcomes were stent migration, stent dysfunction, obstructive jaundice, cholangitis, acute pancreatitis, hospitalization, and biliary pathology-related mortality. RESULTS: One-hundred and twenty ERCPs were included, 56.7% male patients, with a mean age of 69.4 ± 15.7 years. Indications for plastic biliary stent insertion were choledocholithiasis (72.5%), benign biliary stricture (20.0%), and post-cholecystectomy fistula (7.5%). Delayed stent removal occurred in 32.5% of the cases. The median time to stent removal was 3.5 ± 1.3 months for early removal and 8.6 ± 3.1 months for delayed removal. Patients who had delayed stent removal did not have a significantly higher frequency of stent migration (20.5 vs 11.1%, p = 0.17), stent dysfunction (17.9 vs 13.6%, p = 0.53), hospitalization (17.9 vs 14.8%, p = 0.66), obstructive jaundice (2.6 vs 0.0%, p = 0.33), cholangitis (10.3 vs 13.6%, p = 0.77), acute pancreatitis (0.0 vs 1.2%, p = 1.0), or biliary pathology-related mortality (2.6 vs 1.2%, p = 0.55). CONCLUSIONS: Delayed plastic biliary stent removal does not seem to have a negative impact on patients' outcomes. In the current pandemic situation, while scheduled endoscopic procedures may have to be postponed, elective removal of plastic biliary stents can be safely deferred.

Biodegradable biliopancreatic stents could help conserve health care resources during the COVID-19 pandemic: An observational multicenter study.

BACKGROUND: Considering limited resources for follow-up due to COVID-19, we used biodegradable stents (BPBS) for a range of biliopancreatic diseases. AIMS: This observational multicenter study aimed to evaluate technical safety and give first insights into clinical utility. METHODS: Technical success, clinical success, and necessity of follow-up visits for BPBS placed at three Austrian tertiary care hospitals between April 2020 and January 2021 were retrospectively analyzed. RESULTS: 63 stents were deployed in 60 patients. Main indications were prophylaxis of post-ERCP pancreatitis (PEP; n = 30/63; 48%) and bridging of prolonged waiting times to cholecystectomy (n = 21/63; 33%). Median time to surgery was 47 days (range: 136 days). The technical success rate was 94% (n = 59/63; 95% CI [0.84, 0.98]). Technical difficulties primarily arose with dislocations. Clinical success was achieved in 90% (n = 57/63; 95% CI [0.80, 0.96]). Clinical failure despite successful deployment was caused by papillary bleeding (1 patient) and cholestasis (1 patient). Both required reinterventions. No follow-up visits were needed in 97% of cases (n = 57/59; 95% CI [0.88, 1.00]). CONCLUSION: Biodegradable stents could help conserve health care resources without compromising treatment standards for PEP prophylaxis, which is particularly valuable in times of restricted resources. First insights into feasibility as bridging to cholecystectomy indicate a favorable safety profile.

Secondary sclerosing cholangitis after COVID-19 pneumonia: a report of two cases and review of the literature.

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) is a rare disease characterized by chronic cholestasis. The underlying pathophysiology of SC-CIP is not fully understood, and prognosis in severe cases remains poor with liver transplantation remaining the only curative treatment option. There is a growing amount of literature describing patients with chronic cholangiopathy after COVID-19 infection. The vast majority of the patients described in these reports were male and had a poor outcome. While the exact percentage of patients with COVID-19-related SC-CIP cannot be estimated accurately due to a lack of larger studies, an increase in patients with long-term complications of chronic cholestatic liver disease after severe COVID19-pneumonia can be expected in the upcoming years. Treatment options remain limited and further research is needed to improve the dismal prognosis of SC-CIP. Here, we present the cases of two patients who developed SC-CIP after prolonged intensive care unit stay due to severe COVID-19 pneumonia. Both patients required invasive ventilation for 31 and 141 days, respectively, as well as extra-corporal membrane oxygenation for 23 and 87 days. The patients suffered from jaundice and severe pruritus, and typical features of SC-CIP were present by MRCP and ERC. Repeated removal of biliary casts resulted in some alleviation of their clinical symptoms, but cholestasis parameters remain elevated. Furthermore, an increased liver stiffness was indicative of advanced fibrosis in both patients. In addition to these two case reports, we provide a concise review of the literature of SC-CIP after COVID-19 infection and discuss risk factors, treatment options and prognosis.

First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection.

Post-coronavirus disease 2019 (COVID-19) cholangiopathy (PCC) is a new entity observed in patients recovering from severe COVID-19 pneumonia. Most patients recover with cholestasis improving over a period of time. In some patients, cholestasis is severe and persists or progresses to liver failure necessitating liver transplant. We present a previously healthy 50-year-old man who developed PCC with peak total bilirubin of 42.4 mg/dl and did not improve with medical management. He underwent living donor auxiliary right lobe liver transplantation. He recovered well after transplant and remains asymptomatic at 6 months follow-up with good graft function and recovering function in native liver remnant.

The effects of neonatal resuscitation gamification program using immersive virtual reality: A quasi-experimental study.

BACKGROUND: Clinical practice in neonatal intensive care units for nursing college students has been restricted due to the COVID-19 pandemic outbreak; thus, the gamification program has emerged as an alternative learning method. Consequently, there is a need to examine the effectiveness of such alternative learning methods to enhance the response to high-risk newborn emergencies. OBJECTIVES: To examine the effects (neonatal resuscitation nursing knowledge, problem-solving and clinical reasoning ability, self-confidence in practical performance, degree of anxiety, and learning motivation) of a neonatal resuscitation gamification program using immersive virtual reality based on Keller's ARCS model. DESIGN: A non-randomized controlled simulation study with a pretest-posttest design. SETTING: Lab and lecture rooms of two universities in South Korea, from June to November 2021. PARTICIPANTS: Prelicensure nursing students. METHODS: The virtual reality group (n = 29) underwent a neonatal resuscitation gamification program using virtual reality based on Keller's ARCS model. The simulation group (n = 28) received high-fidelity neonatal resuscitation simulations and online neonatal resuscitation program lectures. The control group (n = 26) only received online neonatal resuscitation program lectures. Changes in scores among these groups were compared using analysis of variance and analysis of covariance with SPSS for Windows version 27.0. RESULTS: Post intervention, neonatal resuscitation knowledge [F(2) = 3.83, p = .004] and learning motivation [F(2) = 1.79, p = .025] were significantly higher in the virtual reality and simulation groups than in the control group, whereas problem-solving ability [F(2) = 2.07, p = .038] and self-confidence [F(2) = 6.53, p < .001] were significantly higher in the virtual reality group than in the simulation and control groups. Anxiety [F(2) = 16.14, p < .001] was significantly lower in the simulation group than in the virtual reality and control groups. CONCLUSIONS: The neonatal resuscitation gamification program using immersive virtual reality was found to be effective in increasing neonatal resuscitation knowledge, problem-solving ability, self-confidence, and learning motivation of the nursing students who participated in the trial application process.

Persistent Cholestatic Injury and Secondary Sclerosing Cholangitis in COVID-19 Patients.

CONTEXT.­: COVID-19 has been associated with liver injury, and a small subset of patients recovering from severe disease have shown persistent markedly elevated liver biochemistries for months after infection. OBJECTIVE.­: To characterize persistent biliary injury after COVID-19. DESIGN.­: A search of the pathology archives identified 7 post-COVID-19 patients with persistent biliary injury, and the clinical, radiologic, and pathologic features were assessed. RESULTS.­: All patients in this cohort presented with respiratory symptoms and had a complicated clinical course with acute elevation of liver biochemistries. Alkaline phosphatase (ALP) was markedly and persistently elevated after discharge (median peak ALP, 1498 IU/L, at a median of 84 days from diagnosis). Magnetic resonance cholangiopancreatography showed 3 patients with irregularity, stricturing, and dilatation of intrahepatic ducts; no radiographic abnormalities were identified in the remaining 4 patients. Liver biopsies showed mild portal changes with features of cholestatic injury in 4 patients (bile duct injury and canalicular cholestasis) and marked biliary obstruction in 2 patients (profound cholestasis, ductular reaction, and bile infarcts), but no SARS-CoV-2 RNA was identified on in situ hybridization. On follow-up, most patients had minimal intervention and showed marked improvement of liver biochemistries but with mild persistent elevation of ALP. CONCLUSIONS.­: A subset of critically ill COVID-19 patients demonstrates marked and persistent cholestatic injury, with radiographic and histologic evidence of secondary sclerosing cholangitis, suggesting that cholestatic liver disease and secondary sclerosing cholangitis may be long-term sequelae of COVID-19 acute illness as a longstanding manifestation of critical illness.

Progressive cholestasis and associated sclerosing cholangitis are frequent complications of COVID-19 in patients with chronic liver disease.

BACKGROUND AND AIMS: Cholestasis is associated with disease severity and worse outcome in COVID-19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described. APPROACH AND RESULTS: Hospitalized patients with COVID-19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non-advanced CLD (non-ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non-COVID-19 pneumonia were matched to patients with CLD and COVID-19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS-CoV-2 infection (T1-T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% (n = 65) had CLD (non-ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID-19-related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS-CoV-2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma-glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD (n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID-19, and 15.4% of patients (n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID-19 than in patients with CLD and non-COVID-19 pneumonia (p = 0.040). COVID-19-associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% (n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS-CoV-2 infection. CONCLUSIONS: About 20% of patients with CLD develop progressive cholestasis after SARS-CoV-2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID-19.

Age-adjusted mortality and predictive value of liver chemistries in a Viennese cohort of COVID-19 patients.

BACKGROUND AND AIMS: The coronavirus disease of 2019 (COVID-19) causes considerable mortality worldwide. We aimed to investigate the frequency and predictive role of abnormal liver chemistries in different age groups. METHODS: Patients with positive severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) test between 03/2020-07/2021 at the Vienna General Hospital were included. Patients were stratified for age: 18-39 vs. 40-69 vs. ≥70 years (y). Aspartate aminotransferase (AST), alanine-aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) were recorded. RESULTS: 900 patients (18-39 years: 32.2%, 40-69 years: 39.7%, ≥70 years: 28.1%) were included. Number of comorbidities, median D-dimer and C-reactive protein increased with age. During COVID-19, AST/ALT and ALP/GGT levels significantly increased. Elevated hepatocellular transaminases (AST/ALT) and cholestasis parameters (ALP/GGT/BIL) were observed in 40.3% (n  = 262/650) and 45.0% (n  = 287/638) of patients respectively. Liver-related mortality was highest among patients with pre-existing decompensated liver disease (28.6%, p < .001). 1.7% of patients without pre-existing liver disease died of liver-related causes, that is consequences of hepatic dysfunction or acute liver failure. Importantly, COVID-19-associated liver injury (16.0%, p < .001), abnormal liver chemistries and liver-related mortality (6.5%, p < .001) were most frequent among 40-69 years old patients. Elevated AST and BIL after the first positive SARS-CoV-2 PCR independently predicted mortality in the overall cohort and in 40-69 years old patients. CONCLUSIONS: Almost half of the COVID-19 patients exhibit abnormal hepatocellular and cholestasis-related liver chemistries with 40-69 years old patients being at particularly high risk for COVID-19-related liver injury and liver-related mortality. Elevated AST and BIL after SARS-CoV-2 infection are independent predictors of mortality, especially in patients aged 40-69 years.

SARS-CoV-2 vaccination response in patients with autoimmune hepatitis and autoimmune cholestatic liver disease.

BACKGROUND/AIMS: In this observational study, we explored the humoral and cellular immune response to SARS-CoV-2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). METHODS: Anti-SARS-CoV-2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID-19 vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of individuals. RESULTS: Previous SARS-CoV-2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p = 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n = 85) and without immunosuppression (n = 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike-specific T-cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike-specific T-cell response. CONCLUSION: Patients with AIH show an increased SARS-CoV-2 infection rate as well as an impaired B- and T-cell response to SARS-CoV-2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.

Severe acute respiratory syndrome coronavirus-2-associated cholangiopathies.

PURPOSE OF REVIEW: SARS-CoV2 is a ß-coronavirus, isolated for the first time in Wuhan in December 2019. Bilateral interstitial pneumonia is the hallmark of this disease. Liver is the second viral target for frequency and AST and ALT elevation is a common finding. From February 2020, two different cholangiopathies have been reported in COVID-19 patients. The aim of this article is to review the cases so far described in order to share information and awareness about these new clinical entities. RECENT FINDINGS: SARS-CoV2 seems to trigger autoimmunity and two cases of primary biliary cholangitis (PBC) have been developed after viral infection while more than 30 patients have showed a rapidly progressing cholangiopathy with features of secondary sclerosing cholangitis (SSC). For what concerns SSC pathogenesis, a theory combining multiple hits is the most recognized. SUMMARY: Two different cholangiopathies have been reported in patients after severe-COVID-19. Attention should be paid to the development of cholestasis in ICU setting but above all after discharge and liver function tests should be, therefore, periodically performed. No treatment strategies are available and liver transplantation remains the last option in individuals with liver failure because of SSC. Other efforts are necessary to better understand the pathogenesis and to expand therapeutic options.

Differential expression in humans of the viral entry receptor ACE2 compared with the short deltaACE2 isoform lacking SARS-CoV-2 binding sites (preprint)

ACE2 is a membrane protein that regulates the cardiovascular system. Additionally, ACE2 acts as a receptor for host cell infection by human coronaviruses, including SARS-CoV-2 that emerged as the cause of the on-going COVID-19 pandemic and has brought unprecedented burden to economy and health. ACE2 binds the spike protein of SARS-CoV-2 with high affinity and shows little variation in amino acid sequence meaning natural resistance is rare. The discovery of a novel short ACE2 isoform (deltaACE2) provides evidence for inter-individual differences in SARS-CoV-2 susceptibility and severity, and likelihood of developing subsequent ‘Long COVID’. Critically, deltaACE2 loses SARS-CoV-2 spike protein binding sites in the extracellular domain, and is predicted to confer reduced susceptibility to viral infection. We aimed to assess the differential expression of full-length ACE2 versus deltaACE2 in a panel of human tissues (kidney, heart, lung, and liver) that are implicated in COVID-19, and confirm ACE2 protein in these tissues. Using dual antibody staining, we show that deltaACE2 localises, and is enriched, in lung airway epithelia and bile duct epithelia in the liver. Finally, we also confirm that a fluorescently tagged SARS-CoV-2 spike protein monomer shows low binding at lung and bile duct epithelia where dACE2 is enriched.