Impact of major bleeding and thrombosis on 180-day survival in patients with severe COVID-19 supported with veno-venous extracorporeal membrane oxygenation in the United Kingdom: a multicentre observational study.

Bleeding and thrombosis are major complications in patients supported with extracorporeal membrane oxygenation (ECMO). In this multicentre observational study of 152 consecutive patients (≥18 years) with severe COVID-19 supported by veno-venous (VV) ECMO in four UK commissioned centres during the first wave of the COVID-19 pandemic (1 March to 31 May 2020), we assessed the incidence of major bleeding and thrombosis and their association with 180-day mortality. Median age (range) was 47 years (23-65) and 75% were male. Overall, the 180-day survival was 70·4% (107/152). The rate of major bleeding was 30·9% (47/152), of which intracranial bleeding (ICH) was 34% (16/47). There were 96 thrombotic events (63·1%) consisting of venous 44·7% [68/152 of which 66·2% were pulmonary embolism (PE)], arterial 18·6% (13/152) and ECMO circuit thrombosis 9·9% (15/152). In multivariate analysis, only raised lactate dehydrogenase (LDH) at the initiation of VV ECMO was associated with an increased risk of thrombosis [hazard ratio (HR) 1·92, 95% CI 1·21-3·03]. Major bleeding and ICH were associated with 3·87-fold (95% CI 2·10-7·23) and 5·97-fold [95% confidence interval (CI) 2·36-15·04] increased risk of mortality and PE with a 2·00-fold (95% CI1·09-3·56) risk of mortality. This highlights the difficult balancing act often encountered when managing coagulopathy in COVID-19 patients supported with ECMO.

Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis.

BACKGROUND & AIMS: One-year survival in cirrhosis ranges from 1 to 57% depending on the clinical stage. Accurate sub-classification has important prognostic implications but there is no stage beyond cirrhosis using current qualitative histological systems. We compared the performance of all histological semi-quantitative and quantitative methods specifically developed for sub-classifying cirrhosis that have been described to date, with collagen proportionate area (CPA), to evaluate how well they distinguish patients with and without hepatic clinical decompensation at presentation, and in predicting future decompensating events. METHODS: We included consecutive patients with a histological diagnosis of cirrhosis that had a suitable liver biopsy between 2003 and 2007. We used semi-quantitative histological scoring systems proposed by Laennec, Kumar, and Nagula. We also measured quantitatively nodule size, septal width and fibrous tissue expressed in CPA. RESULTS: Sixty-nine patients, mean age 52.3±11years, mean MELD 11.8±5.8, median follow-up 56months. Main aetiologies were alcohol (38%) and hepatitis C (27.5%). Twenty-four patients (34.8%) had had a previous episode of clinical decompensation. Amongst the 45 patients who were compensated, 11 (24%) decompensated on follow-up. In Cox regression, amongst all histological parameters, CPA was the only variable independently associated with clinical decompensation up to the time of biopsy, with an odds ratio that ranged from 1.245 to 1.292. Furthermore, only CPA was significantly associated with future decompensation (OR: 1.117, 95% CI 1.020-1.223; p=0.017). CONCLUSIONS: Cirrhosis can be accurately sub-classified using quantification of fibrosis with CPA, and furthermore CPA is the only independent predictor of clinical decompensation amongst all other histological sub-classification systems described to date.

Thombosis, major bleeding, and survival in COVID-19 supported by veno-venous extracorporeal membrane oxygenation in the first vs second wave: a multicenter observational study in the United Kingdom.

BACKGROUND: Bleeding and thrombosis are major complications of veno-venous (VV) extracorporeal membrane oxygenation (ECMO). OBJECTIVES: To assess thrombosis, major bleeding (MB), and 180-day survival in patients supported by VV-ECMO between the first (March 1 to May 31, 2020) and second (June 1, 2020, to June 30, 2021) waves of the COVID-19 pandemic. METHODS: An observational study of 309 consecutive patients (aged ≥18years) with severe COVID-19 supported by VV-ECMO was performed in 4 nationally commissioned ECMO centers in the United Kingdom. RESULTS: Median age was 48 (19-75) years, and 70.6% were male. Probabilities of survival, thrombosis, and MB at 180 days in the overall cohort were 62.5% (193/309), 39.8% (123/309), and 30% (93/309), respectively. In multivariate analysis, an age of >55 years (hazard ratio [HR], 2.29; 95% CI, 1.33-3.93; P = .003) and an elevated creatinine level (HR, 1.91; 95% CI, 1.19-3.08; P = .008) were associated with increased mortality. Correction for duration of VV-ECMO support, arterial thrombosis alone (HR, 3.0; 95% CI, 1.5-5.9; P = .002) or circuit thrombosis alone (HR, 3.9; 95% CI, 2.4-6.3; P < .001) but not venous thrombosis increased mortality. MB during ECMO had a 3-fold risk (95% CI, 2.6-5.8, P < .001) of mortality. The first wave cohort had more males (76.7% vs 64%; P = .014), higher 180-day survival (71.1% vs 53.3%; P = .003), more venous thrombosis alone (46.4% vs 29.2%; P = .02), and lower circuit thrombosis (9.2% vs 28.1%; P < .001). The second wave cohort received more steroids (121/150 [80.6%] vs 86/159 [54.1%]; P < .0001) and tocilizumab (20/150 [13.3%] vs 4/159 [2.5%]; P = .005). CONCLUSION: MB and thrombosis are frequent complications in patients on VV-ECMO and significantly increase mortality. Arterial thrombosis alone or circuit thrombosis alone increased mortality, while venous thrombosis alone had no effect. MB during ECMO support increased mortality by 3.9-fold.

Fibrosis distribution in explanted cirrhotic livers.

AIMS: Little information is available regarding the distribution of fibrosis within cirrhotic livers. We measured collagen in cirrhotic explants to determine if fibrosis differs (i) between left (L) and right (R) lobes, and (ii) between different aetiologies. METHODS AND RESULTS: Ten cases each of common aetiologies of cirrhosis were studied: alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), hepatitis C virus (HCV) and hepatitis B virus (HBV). A total of 120 tissue blocks (one block each from L and R lobes) were studied. Collagen was measured as collagen proportionate area (CPA), i.e. the proportion of the tissue sections stained by picro-Sirius red. L and R lobes contained similar amounts of fibrosis (r = 0.788; P < 0.0001) with good agreement between L and R lobes (Bland-Altman analysis, R lobe bias = 1.35%). Median CPA across all aetiologies (R plus L lobes) was 21.5%, (L = 8-40%, R = 10-47%). There was more fibrosis in ALD (30%, 15-47%) than PBC (23.5%, 16-34%) and PSC (22.5%, 8-33%), which in turn showed more than AIH (18.5%, 10-40%), HCV (17%, 13-31%) and HBV (16.5%, 8-30%). CONCLUSIONS: At the time of transplantation cirrhotic livers have different ranges of collagen proportionate area, according to aetiology. R lobe fibrosis corresponds with L lobe fibrosis. The range of fibrosis within each aetiological group could be useful for prognostic subclassification.

Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is often the preferred local ablation therapy for hepatocellular carcinoma (HCC). Percutaneous ethanol injection (PEI) is less frequently used, and percutaneous acetic acid injection (PAI) has been mostly abandoned. Robust evidence showing benefit of one therapy versus another is lacking. Our aim was to evaluate the evidence comparing RFA, PEI and PAI using meta-analytical techniques. METHODS: Literature search was undertaken until December 2008 to identify comparative studies evaluating survival, recurrence, complete necrosis of tumour and complications. Only randomized clinical trials and quasi-randomized studies were included. Adjusted indirect comparisons were made when direct comparative studies were insufficient. RESULTS: Eight studies were identified: RFA vs. PEI (n=5), PAI vs. PEI (n=2) and RFA vs. PAI vs. PEI (n=1) including 1035 patients with nine comparisons. RFA was superior to PEI for survival (OR 0.52; 95% CI 0.35-0.78; p=0.001), complete necrosis of tumour and local recurrence. For tumours 2 cm RFA was not significantly better than PEI. PAI did not differ significantly from PEI for survival (OR 0.55; 95% CI 0.23-1.33; p=0.18), and local recurrence but required less sessions. PAI had similar outcomes, except local recurrence, to RFA in the direct and indirect comparison. CONCLUSIONS: RFA seems to be a superior ablative therapy than PEI for HCC, particularly for tumours >2 cm. PAI did not differ significantly from PEI for all the outcomes evaluated. RFA and PAI have similar survival rates. For tumours 2 cm outcome benefits comparing RFA and PEI are similar. PAI needs re-evaluation versus both PEI and RFA for tumours 2 cm.

Primary biliary cirrhosis after liver transplantation: influence of immunosuppression and human leukocyte antigen locus disparity.

Patients with primary biliary cirrhosis (PBC), despite excellent outcomes after liver transplantation (LT), may develop recurrent primary biliary cirrhosis (rPBC). The impact of immunosuppression and HLA mismatches on rPBC is unclear. We evaluated 103 consecutive PBC patients who underwent transplantation (follow-up > or = 10 months) with serial protocol biopsies. Cox regression was used to evaluate factors associated with rPBC: the Model for End-Stage Liver Disease score pre-LT, year of transplantation, age and gender of the recipient and donor, cold and warm ischemic times, HLA mismatches, rejection, infections, and immunosuppression (initial/maintenance). The mean follow-up was 108 months (10-239 months), rPBC occurred in 36, and the mean was 44 months (10-200 months). Immunosuppression was cyclosporine-based in 38 (10 initially on monotherapy) and tacrolimus-based in 62 (19 initially on monotherapy). Steroids were discontinued in all but 7. Azathioprine was part of the initial immunosuppression in 70, 26 discontinued it, and 33 were never exposed to it. rPBC was associated independently with nonuse/discontinuation of azathioprine (P = 0.015, hazard ratio = 0.046, 95% confidence interval = 0.008-0.261). The mean time to rPBC was 74 months with azathioprine, 43 months when AZA was discontinued, and 31 months if no azathioprine was used. Cyclosporine or tacrolimus alone had no impact on rPBC, but cyclosporine with azathioprine was protective for rPBC in comparison with tacrolimus/azathioprine (0/18 versus 7/25, respectively; P < 0.001). rPBC was not affected by HLA mismatches. Azathioprine use in PBC patients who underwent transplantation was associated with less disease recurrence and a longer time to rPBC. Tacrolimus or cyclosporine individually had no effect, but cyclosporine and azathioprine in combination resulted in the least rPBC.

Variability of reverse transcriptase and overlapping S gene in hepatitis B virus isolates from untreated and lamivudine-resistant chronic hepatitis B patients.

BACKGROUND: The high degree of diversity of the hepatitis B virus (HBV) quasispecies in chronically infected individuals raises the possibility that HBV genetic variants favouring resistance to nucleoside/nucleotide analogues (NAs) might pre-exist to treatment. The aim of this study was to investigate the genetic variability of the entire HBV reverse transcriptase (RT) domain and of the overlapping S gene in a large series of untreated hepatitis B surface antigen carriers and in lamivudine (3TC)-resistant patients. METHODS: Sequencing analysis of the entire HBV RT domain of isolates from 100 untreated (treatment-naive group) and 59 3TC-resistant (3TC-resistant group) consecutive patients with chronic hepatitis B was performed. RESULTS: In the treatment-naive group, primary mutations known to cause resistance to NAs were not detected, but variably combined secondary/compensatory mutations were found in 46 (46%) patients. Moreover, four patients carried mutations that modified the S protein antigenicity. In the 3TC-resistant group, besides the primary 3TC-resistant mutations, various combinations of primary and secondary mutations conferring resistance to other NAs were detected in 41/59 (69.5%) patients. Importantly, the RT mutations induced by 3TC provoked stop codons in the overlapping S gene in two patients and modified the S protein antigenicity in another nine. CONCLUSIONS: This study shows that HBV mutants associated with resistance to NAs might already be present as the major infecting population in untreated patients, and that variants emerging under 3TC might also carry mutations favouring resistance to other NAs and/or potentially altering the S protein immunoreactivity.

The relationship between transient elastography and histological collagen proportionate area for assessing fibrosis in chronic viral hepatitis.

BACKGROUND: Collagen proportionate area (CPA) has a better correlation with hepatic venous pressure gradient (HVPG) than with Ishak stage. Liver stiffness measurement (LSM) is proposed as non invasive marker of portal hypertension/disease progression. Our aim was to compare LSM and CPA with Ishak staging in chronic viral hepatitis, and HVPG in HCV hepatitis after transplantation. METHODS: One hundred and sixty-nine consecutive patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections pre/post liver transplantation (LT), had a liver biopsy combined with LSM (transient elastography), CPA (biopsies stained with Sirius Red and evaluated by digital image analysis and expressed as CPA) and HVPG (measured contemporaneously with transjugular biopsies in LT HCV patients). RESULTS: LSM was dependent on CPA in HBV (r (2) = 0.61, p < 0.0001), HCV (r (2) = 0.59, p < 0.0001) and LT groups (r (2) = 0.64, p < 0.0001). In all three groups, CPA and Ishak were predictors of LSM, but multivariately CPA was better related to LSM (HBV: r (2) = 0.61, p < 0.0001; HCV: r (2) = 0.59, p < 0.0001; post-LT: r (2) = 0.68, p < 0.0001) than Ishak stage. In the LT group, multiple regression analysis including HVPG, LSM, aspartate aminotransferase to platelet ratio index (APRI) and Ishak stage/grade, showed that only CPA was related to HVPG (r (2) = 0.41, p = 0.01), both for HVPG ≥6 mmHg (OR 1.34, 95 % CI 1.14-1.58; p < 0.0001) or ≥10 mmHg (OR 1.25, 95 % CI 1.06-1.47; p = 0.007). CONCLUSION: CPA was related to LSM in HBV or HCV hepatitis pre/post-LT. CPA was better related to LSM than Ishak stage. In the LT HCV group, CPA was better related to HVPG than Ishak stage/grade, LSM or APRI. CPA may represent a better comparative histological index for LSM, rather than histological stages.

Treatment of hepatocellular carcinoma (HCC) by intra-arterial infusion of radio-emitter compounds: trans-arterial radio-embolisation of HCC.

Traditional radiotherapy is only effective in treating hepatocellular cancer (HCC) in doses above 50 Gy, but this is above the recommended liver radiation exposure of about 35 Gy, which is an important limitation making this treatment unsuitable for routine clinical practice. Trans-arterial radio-embolisation (TARE), consists of delivery of compounds linked to radio-emitter particles which end up in hepatic end-arterioles or show affinity for the neoplasm itself, allowing localised delivery of doses beyond 120 Gy. These are well tolerated in patients treated with this type of internal radiation therapy. TARE for HCC is used for palliative treatment of advanced disease which cannot be treated in other ways, or for tumour down-staging before liver transplantation, or as adjuvant therapy for surgically resected HCC. Tumour response after TARE is between 25% and 60% if assessed by using RECIST criteria, and 80% by EASL criteria. In this review we outline the advantages and limitations of radio-emitter therapy including 131-I, 90-Y and 188-Re. We include several observational, and all comparative studies using these compounds. In particular we compare TARE to trans-arterial chemo-embolisation and other intra-arterial techniques.

Surveillance and diagnosis of hepatocellular carcinoma in patients with cirrhosis.

Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy.