Valerie Durkalski

Background: Activated T-cell pediatric acute liver failure (TC-PALF) is the most common cause of non-acetaminophen PALF, with poor transplant-free survival. Livers in TC-PALF are infiltrated by effector cytotoxic T lymphocytes with markers of tissue-resident memory function (CD8 Trm) and an interferon gamma (IFNγ) transcriptional signature. The PALF-Immune Response Network (PALF-IRN) and the prospective TReatment for ImmUne-Mediated PathopHysiology (TRIUMPH) clinical trial (NCT04862221) aim to characterize the TC-PALF immune pathology and utility of T-cell directed therapy to improve transplant-free survival. Methods: TRIUMPH patients with TC-PALF were compared with healthy children and disease controls utilizing multiparameter flow cytometry and 3′ single-cell RNA sequencing from peripheral blood mononuclear cells. TC-PALF patient serum was compared with healthy children and those with PALF from other causes, utilizing the Olink Inflammation I 384 protein assay. Results: Two distinct endotypes of TC-PALF were identified, which differed in flow cytometry CD8+ Perforin1 (Prf) expression and liver biopsy staining of Prf. TC-PALF patients with high CD8+ Prf (TC-PALF High Prf) had monocytosis, with a unique circulating CD8 IFNγ+ Trm-like population and IFNγ-responsive CD14/CD16 monocyte ligand–receptor interaction. TC-PALF patients with normal CD8+ Prf expression had hypergammaglobulinemia, an increase in class-switched B-cells, and a decrease in serum inflammatory proteins associated with myeloid activation. Conclusions: TC-PALF high Prf patients have a unique circulating CD8+ IFNγ+ Trm-like population accompanied by monocyte proliferation and activation. Further understanding of the role of IFNγ in TC-PALF High Prf may provide a therapeutic target for this endotype to improve transplant-free survival. Export

INTRODUCTION: Prior small studies have suggested that patients with prior metabolic and bariatric surgery (MBS) may have increased susceptibility to acetaminophen (APAP)-related acute liver failure/acute liver injury (ALF/ALI). The aim of this study was to compare the presentation, etiology, and outcome of adult ALI/ALF patients who were enrolled in a prospective registry study with prior bariatric surgery to those without. METHODS: Among 3,364 ALF/ALI patients in the Acute Liver Failure Study Group registry enrolled between January 1998 and August 2019, 85 (2.3%) reported prior MBS. On review, 6 cases were deemed not ALF and excluded from the analysis. RESULTS: Among the 79 MBS ALF/ALI patients, 95% were female and 86% were White. Etiology included APAP-related ALF/ALI in 78.5% of the MBS group vs 49.3% in the non-MBS group (P < 0.001). The proportion of patients with MBS increased from 1.6% (1998–2008) to 3.4% in the later years (2009–2019) (P < 0.001). There were proportionately more unintentional overdoses in the MBS cohort (71% vs 52%, P < 0.001) with smaller median total APAP dose ingestion (6,500 mg vs 12,000 mg, P = 0.009). Although MBS patients had more severe encephalopathy at presentation, overall, 21-day and transplant-free survival between the groups were similar. DISCUSSION: ALF/ALI is more frequent in MBS patients than in the general population. APAP toxicity is the most common cause in MBS patients but not the only diagnosis observed. MBS may predispose to severe unintentional APAP liver injury at lower doses. Both MBS patients and providers should be aware regarding this potential risk of increased susceptibility to APAP hepatotoxicity.

Background: Acute liver failure (ALF) is a rare condition leading to morbidity and mortality. Liver transplantation (LT) is often required, but patients are not always listed for LT. There is a lack of data regarding outcomes in these patients. Our aim is to describe outcomes of patients with ALF not listed for LT and to compare this with those listed for LT. Methods: Retrospective analysis of all nonlisted patients with ALF enrolled in the Acute Liver Failure Study Group (ALFSG) registry between 1998 and 2018. The primary outcome was 21-day mortality. Multivariable logistic regression was done to identify factors associated with 21-day mortality. The comparison was then made with patients with ALF listed for LT. Results: A total of 1672 patients with ALF were not listed for LT. The median age was 41 (IQR: 30–54). Three hundred seventy-one (28.9%) patients were too sick to list. The most common etiology was acetaminophen toxicity (54.8%). Five hundred fifty-eight (35.7%) patients died at 21 days. After adjusting for relevant covariates, King’s College Criteria (adjusted odds ratio: 3.17, CI 2.23–4.51), mechanical ventilation (adjusted odds ratio: 1.53, CI: 1.01–2.33), and vasopressors (adjusted odds ratio: 2.10, CI: 1.43–3.08) (p < 0.05 for all) were independently associated with 21-day mortality. Compared to listed patients, nonlisted patients had higher mortality (35.7% vs. 24.3%). Patients deemed not sick enough had greater than 95% survival, while those deemed too sick still had >30% survival. Conclusions: Despite no LT, the majority of patients were alive at 21 days. Survival was lower in nonlisted patients. Clinicians are more accurate in deeming patients not sick enough to require LT as opposed to deeming patients too sick to survive.

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury—international normalized ratio 2.0 but no encephalopathy—ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional (N-acetylcysteine and ornithine phenylacetate), 1 prognostic [¹³C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG’s accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled “Acute Liver Failure: Science and Practice,” in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.

Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximately 2-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) of a single unit of COVID-19 convalescent plasma (CCP) versus saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30. Binding and neutralizing antibody responses were approximately 2-fold higher 1 hour after infusion in recipients of CCP compared with saline plus multivitamin, but levels achieved by the native immune system by day 15 were almost 10-fold higher than those seen immediately after CCP administration. Infusion of CCP did not block generation of the host antibody response or skew B or T cell phenotype or maturation. Activated CD4 ⁺ and CD8 ⁺ T cells were associated with more severe disease outcome. These data show that CCP leads to a measurable boost in anti–SARS-CoV-2 antibodies but that the boost is modest and may not be sufficient to alter disease course.

Goals and Background: Using natural language processing to create a nonalcoholic fatty liver disease (NAFLD) cohort in primary care, we assessed advanced fibrosis risk with the Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS) and evaluated risk score agreement. Materials and Methods: In this retrospective study of adults with radiographic evidence of hepatic steatosis, we calculated patient-level FIB-4 and NFS scores and categorized them by fibrosis risk. Risk category and risk score agreement was analyzed using weighted κ, Pearson correlation, and Bland-Altman analysis. A multinomial logistic regression model evaluated associations between clinical variables and discrepant FIB-4 and NFS results. Results: Of the 767 patient cohorts, 71% had a FIB-4 or NFS score in the indeterminate-risk or high-risk category for fibrosis. Risk categories disagreed in 43%, and scores would have resulted in different clinical decisions in 30% of the sample. The weighted κ statistic for risk category agreement was 0.41 [95% confidence interval (CI): 0.36-0.46] and the Pearson correlation coefficient for log FIB-4 and NFS was 0.66 (95% CI: 0.62-0.70). The multinomial logistic regression analysis identified black race (odds ratio=2.64, 95% CI: 1.84-3.78) and hemoglobin A1c (odds ratio=1.37, 95% CI: 1.23-1.52) with higher odds of having an NFS risk category exceeding FIB-4. Conclusions: In a primary care NAFLD cohort, many patients had elevated FIB-4 and NFS risk scores and these risk categories were often in disagreement. The choice between FIB-4 and NFS for fibrosis risk assessment can impact clinical decision-making and may contribute to disparities of care.

Background: The prevalence and significance of digestive manifestations in COVID-19 remain uncertain. Methods: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were manually abstracted from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. Results: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least one gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were elevated to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio 0.93, 95% confidence interval 0.76-1.15) or liver test abnormalities on admission (odds ratio 1.31, 95% confidence interval 0.80-2.12) were not independently associated with mechanical ventilation or death. Conclusions: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common but the majority were mild and their presence was not associated with a more severe clinical course

Background: The optimal approach to the drainage of malignant obstruction at the liver hilum remains uncertain. We aim to compare percutaneous transhepatic biliary drainage (PTBD) to endoscopic retrograde cholangiography (ERC) as the first intervention in patients with cholestasis due to suspected malignant hilar obstruction (MHO). Methods: The INTERCPT trial is a multi-center, comparative effectiveness, randomized, superiority trial of PTBD vs. ERC for decompression of suspected MHO. One hundred and eighty-four eligible patients across medical centers in the United States, who provide informed consent, will be randomly assigned in 1: 1 fashion via a web-based electronic randomization system to either ERC or PTBD as the initial drainage and, if indicated, diagnostic procedure. All subsequent clinical interventions, including crossover to the alternative procedure, will be dictated by treating physicians per usual clinical care. Enrolled subjects will be assessed for successful biliary drainage (primary outcome measure), adequate tissue diagnosis, adverse events, the need for additional procedures, hospitalizations, and oncological outcomes over a 6-month follow-up period. Subjects, treating clinicians and outcome assessors will not be blinded. Discussion: The INTERCPT trial is designed to determine whether PTBD or ERC is the better initial approach when managing a patient with suspected MHO, a common clinical dilemma that has never been investigated in a randomized trial.

The combination of prophylactic pancreatic stent placement (PSP) – a temporary plastic stent placed in the pancreatic duct – and rectal non-steroidal anti-inflammatory drugs (NSAIDs) is recommended for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. Preliminary data, however, suggest that PSP may be unnecessary if rectal NSAIDs are administered. Given the costs and potential risks of PSP, we aim to determine whether rectal indomethacin obviates the need for pancreatic stent placement in patients undergoing high-risk ERCP. The SVI (Stent vs. Indomethacin) trial is a comparative effectiveness, multicenter, randomized, double-blind, non-inferiority study of rectal indomethacin alone versus the combination of rectal indomethacin and PSP for preventing PEP in high-risk cases. One thousand four hundred and thirty subjects undergoing high-risk ERCP, in whom PSP is planned solely for PEP prevention, will be randomized to indomethacin alone or combination therapy. Those who are aware of study group assignment, including the endoscopist, will not be involved in the post-procedure care of the patient for at least 48 hours. Subjects will be assessed for PEP and its severity by a panel of independent and blinded adjudicators. Indomethacin alone will be declared non-inferior to combination therapy if the two-sided 95 % upper confidence bound of the treatment difference is less than 5 % between the two groups. Biological specimens will be obtained from trial participants and centrally banked. The SVI trial is designed to determine whether PSP remains necessary in the era of NSAIDs pharmacoprevention. The associated bio-repository will establish the groundwork for important scientific breakthrough. NCT02476279, registered June 2015.