Intravenous BCAA infusion does not lead to a sustained recovery from overt HE in ACLF – An open label randomized clinical trial

Background –Hepatic encephalopathy(HE) in acute-on-chronic liver failure(ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study efficacy of intravenous branched chain amino acids(IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24h, day 3 & day 7. Primary outcome was improvement in encephalopathy by ≥ 1 grade at 72 hours. Patients and Methods –EASL defined ACLF patients with overt HE were assessed and randomized into experimental arm (IV-BCAA - 500mL/day for 3 days + Lactulose;n=39) and comparator arm (Lactulose alone;n=37). Six patients developed COVID-19 after randomization & were excluded (4-experimental arm & 2-comparator arm). Results –Of 222 screened patients, 70 (35 in each arm) were included in analysis. Baseline characteristics including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7;P = 0.86) and CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7;P = 0.65) were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%;P=0.14). Improvement in HESA by ≥1 grade at 24h occurred in 14 patients (40%) in BCAA arm and 6 patients (17.1%) in control group (P=0.03) which translated to shorter ICU stay. Median change in HESA at 24h was more in BCAA arm than control arm(P=0.006) which was not sustained at day 3 or 7. Ammonia levels did not correlate with grade of HE (Spearman's correlation coefficient(ρ) = - 0.0843;P=0.29). Conclusion Intravenous BCAA does not lead to a sustained improvement in HE grade in ACLF. Trial registration no NCT04238416 (clinicaltrials.gov)

Primary Norfloxacin Prophylaxis for APASL-Defined Acute-on-Chronic Liver Failure: A Placebo-Controlled Double-Blind Randomized Trial.

INTRODUCTION: This study aimed to evaluate the role of prophylactic norfloxacin in preventing bacterial infections and its effect on transplant-free survival (TFS) in patients with acute-on-chronic liver failure (ACLF) identified by the Asian Pacific Association for the Study of the Liver criteria. METHODS: Patients with ACLF included in the study were randomly assigned to receive oral norfloxacin 400 mg or matched placebo once daily for 30 days. The incidence of bacterial infections at days 30 and 90 was the primary outcome, whereas TFS at days 30 and 90 was the secondary outcome. RESULTS: A total of 143 patients were included (72 in the norfloxacin and 71 in the placebo groups). Baseline demographics, biochemical variables, and severity scores were similar between the 2 groups. On Kaplan-Meier analysis, the incidence of bacterial infections at day 30 was 18.1% (95% confidence interval [CI], 10-28.9) and 33.8% (95% CI, 23-46) (P = 0.03); and the incidence of bacterial infections at day 90 was 46% (95% CI, 34-58) and 62% (95% CI, 49.67-73.23) in the norfloxacin and placebo groups, respectively (P = 0.02). On Kaplan-Meier analysis, TFS at day 30 was 77.8% (95% CI, 66.43-86.73) and 64.8% (95% CI, 52.54-75.75) in the norfloxacin and placebo groups, respectively (P = 0.084). Similarly, TFS at day 90 was 58.3% (95% CI, 46.11-69.84) and 43.7% (95% CI, 31.91-55.95), respectively (P = 0.058). Thirty percent of infections were caused by multidrug-resistant organisms. More patients developed concomitant candiduria in the norfloxacin group (25%) than in the placebo group (2.63%). DISCUSSION: Primary norfloxacin prophylaxis effectively prevents bacterial infections in patients with ACLF.

Antibody Response and Safety of ChAdOx1-nCOV (Covishield) in Patients with Cirrhosis: A Cross-Sectional, Observational Study.

INTRODUCTION: Patients with cirrhosis have a higher risk of severe COVID-19 and mortality and are high-priority patients for vaccination. However, cirrhotics were excluded from the phase 2/3 vaccine trials. Hence, we aimed to assess the antibody response and safety of Covishield (ChAdOx1nCoV-19) among patients with cirrhosis. METHODS: Patients who attended the tele-hepatology services at our institute from March 2020 to June 2021 and diagnosed with cirrhosis as per their medical records were telephonically interviewed in July 2021 using a pre-specified questionnaire. Patients who had completed 2 doses of ChAdOx1-nCOV (with the 2nd dose administered at least 2 weeks back) and without history of documented COVID-19 infection (pre- or post-vaccination) were tested for antibodies against the spike protein. Seropositive patients were divided into high, moderate, and low antibody responses based on the signal/cut-off. RESULTS: We interviewed 784 patients with cirrhosis. At least 1 dose of ChAdOx1-nCOV was received by 231 patients among whom 134 (58%) had received 2 doses. Documented COVID-19 was reported in 3.9% patients who received at least 1 dose of ChAdOx1-nCOV including breakthrough infections in 3.7% patients vaccinated with 2 doses. Local and systemic adverse events were reported by 42% and 22.1% patients. None developed anaphylaxis, acute decompensation, acute-on-chronic liver failure, or other serious adverse events requiring hospitalization. Seroconversion was documented in 81 (92%) out of 88 patients. No difference was observed in level of antibody response between patients with compensated and decompensated cirrhosis (p = 0.12). CONCLUSION: Our preliminary data suggest that ChAdOx1-nCOV is safe with high seroconversion rates in patients with cirrhosis.

Factors Associated With Non-invasive Oxygen Therapy Failure in COVID-19 Pneumonia: A Single Center, Retrospective Study in a Tertiary Hospital in North India.

BACKGROUND: Non-invasive oxygen therapy (NIT) consists of high-flow nasal oxygen (HFNO) and continuous positive airway pressure (CPAP). NIT is routinely being used for the management of acute respiratory failure secondary to coronavirus disease-2019 (COVID-19) with variable outcomes. However, previously published studies show that NIT failure might delay endotracheal intubation and invasive mechanical ventilation and results in worse outcomes in patients with hypoxemic respiratory failure. Early prediction of failure of NIT, will help in early decision-making in initiating invasive mechanical ventilation. We retrospectively studied the predictors for NIT failure in patients with moderate to severe COVID-19. METHODS: Adult patients (>18 years) admitted to the intensive care unit (ICU) with moderate to severe COVID-19 ARDS and received NIT [HFNO and CPAP non-invasive ventilation (NIV)] were included in this study. Baseline clinical and laboratory data were collected retrospectively from the electronic hospital information system. NIT failure was defined as the need for invasive mechanical ventilation after the initiation of NIT in the ICU. Univariate and multivariate logistic regression analyses were used to find out the possible predictors of NIT failure. RESULTS: Out of 254 patients admitted to ICU, 127 patients were initiated NIT at admission to ICU. During the course of the ICU stay, 33 (26%) patients subsequently required invasive mechanical ventilation (NIT failure). Respiratory rate-oxygenation index (ROX index) of <2.97 at two hours and <3.63 at six hours of ICU admission predicted NIT failure in our cohort of patients with a high positive predictive value. CONCLUSION: Patient selection is crucial for successful NIT in COVID-19. Application of ROX index measured in the first six hours of ICU admission helps in the identification of patients at risk of NIT failure with moderate to severe COVID-19 ARDS.

Early Diagnosis and Prevention of Infections in Cirrhosis.

Strategies to prevent infection and improve outcomes in patients with cirrhosis. HAV, hepatitis A virus; HBV, hepatitis B virus; COVID-19, novel coronavirus disease 2019; NSBB, nonselective ß-blocker; PPI, proton pump inhibitors.Cirrhosis is a risk factor for infections. Majority of hospital admissions in patients with cirrhosis are due to infections. Sepsis is an immunological response to an infectious process that leads to end-organ dysfunction and death. Preventing infections may avoid the downstream complications, and early diagnosis of infections may improve the outcomes. In this review, we discuss the pathogenesis, diagnosis, and biomarkers of infection; the incremental preventive strategies for infections and sepsi; and the consequent organ failures in cirrhosis. Strategies for primary prevention include reducing gut translocation by selective intestinal decontamination, avoiding unnecessary proton pump inhibitors' use, appropriate use of ß-blockers, and vaccinations for viral diseases including novel coronavirus disease 2019. Secondary prevention includes early diagnosis and a timely and judicious use of antibiotics to prevent organ dysfunction. Organ failure support constitutes tertiary intervention in cirrhosis. In conclusion, infections in cirrhosis are potentially preventable with appropriate care strategies to then enable improved outcomes.

COVID-19-related dynamic coagulation disturbances and anticoagulation strategies using conventional D-dimer and point-of-care Sonoclot tests: a prospective cohort study.

OBJECTIVES: Coagulation changes associated with COVID-19 suggest the presence of a hypercoagulable state with pulmonary microthrombosis and thromboembolic complications. We assessed the dynamic association of COVID-19-related coagulation abnormalities with respiratory failure and mortality. DESIGN: Single-centre, prospective cohort study with descriptive analysis and logistic regression. SETTING: Tertiary care hospital, North India. PARTICIPANTS: Patients with COVID-19 pneumonia requiring intensive care unit (ICU) admission between August 2020 and November 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: We compared the coagulation abnormalities using standard coagulation tests like prothrombin time, D-dimer, platelet count, etc and point-of-care global coagulation test, Sonoclot (glass beaded(gb) and heparinase-treated(h)). Incidence of thromboembolic or bleeding events and presence of endogenous heparinoids were assessed. Cox proportional Hazards test was used to assess the predictors of 28-day mortality. MEASUREMENT: All patients underwent Sonoclot (glass beaded) test at admission apart from the routine investigations. In patients at risk of thromboembolic or bleeding phenomena, paired tests were performed at day 1 and 3 with Sonoclot. Activated clotting time (ACT) <110 s and peak amplitude >75 units were used as the cut-off for hypercoagulable state. Presence of heparin-like effect (HLE) was defined by a correction of ACT ≥40 s in h-Sonoclot. RESULTS: Of 215 patients admitted to ICU, we included 74 treatment naive subjects. A procoagulant profile was seen in 45.5% (n=5), 32.4% (n=11) and 20.7% (n=6) in low-flow, high-flow and invasive ventilation groups. Paired Sonoclot assays in a subgroup of 33 patients demonstrated the presence of HLE in 17 (51.5%) and 20 (62.5%) at day 1 and 3, respectively. HLE (day 1) was noted in 59% of those who bled during the disease course. Mortality was observed only in the invasive ventilation group (16, 55.2%) with overall mortality of 21.6%. HLE predicted the need for mechanical ventilation (HR 1.2 CI 1.04 to 1.4 p=0.00). On multivariate analysis, the presence of HLE (HR 1.01; CI 1.006 to 1.030; p=0.025), increased C reactive protein (HR 1.040; CI 1.020 to 1.090; p=0.014), decreased platelet function (HR 0.901; CI 0.702 to 1.100 p=0.045) predicted mortality at 28days. CONCLUSION: HLE contributed to hypocoagulable effect and associated with the need for invasive ventilation and mortality in patients with severe COVID-19 pneumonia. TRIAL REGISTRATION: NCT04668404; ClinicalTrials.gov.in. Available from https://clinicaltrials.gov/ct2/show/NCT04668404.

Invasive Pulmonary Aspergillosis and Tuberculosis Complicated by Hemophagocytic Lymphohistiocytosis - Sequelae of COVID-19 in a Liver Transplant Recipient.

Liver transplant recipients are at an increased risk of opportunistic infections due to the use of immunosuppression. Coronavirus disease of 2019 (COVID-19) increases the risk of these infections further due to associated immune dysfunction and the use of high-dose steroids. We present a case of a liver transplant recipient who developed disseminated tuberculosis and invasive pulmonary aspergillosis complicated by acquired hemophagocytic lymphohistiocytosis after recovering from severe COVID-19.

Impact of COVID-19 on liver transplant recipients-A systematic review and meta-analysis.

BACKGROUND: Immunosuppression and comorbidities increase the risk of severe coronavirus disease-2019 (COVID-19) in solid organ transplant (SOT) recipients. The outcomes of COVID-19 in liver transplant (LT) recipients remain unclear. We aimed to analyse the outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients. METHODS: The electronic databases were searched for articles published from 1 December 2019 to 20 May 2021 with MeSH terms COVID-19, SARS-CoV-2, and liver transplantation. Studies reporting outcomes in more than 10 LT recipients were included for analysis. LT vs non-LT patients with COVID-19 infection were compared for all-cause mortality, which was the primary outcome studied. We also evaluated the relation between the timing of COVID-19 infection post-LT (< one year vs > one year) and mortality. FINDINGS: Eighteen articles reporting 1,522 COVID-19 infected LT recipients were included for the systematic review. The mean age (standard deviation [SD]) was 60·38 (5·24) years, and 68·5% were men. The mean time (SD) to COVID-19 infection was 5·72 (1·75) years. Based on 17 studies (I2 = 7·34) among 1,481 LT recipients, the cumulative incidence of mortality was 17·4% (95% confidence interval [CI], 15·4-19·6). Mortality was comparable between LT (n = 610) and non-LT (n = 239,704) patients, based on four studies (odds ratio [OR], 0·8 [0·6-1·08]; P = 0·14). Additionally, there was no significant difference in mortality between those infected within one year vs after one year of LT (OR, 1·5 [0·63-3·56]; P = 0·35). The cumulative incidence of graft dysfunction was 2·3% (1·3-4·1). Nearly 23% (20·71-25) of the LT patients developed severe COVID-19 infection. Before infection, 71% and 49% of patients were on tacrolimus and mycophenolate mofetil, respectively. Immunosuppression was modified in 55·9% (38·1-72·2) patients after COVID-19 infection. INTERPRETATION: LT and non-LT patients with COVID-19 have a similar risk of adverse outcomes.

Feasibility, Outcomes, and Safety of Telehepatology Services During the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has hampered health care delivery globally. We evaluated the feasibility, outcomes, and safety of telehepatology in delivering quality care amid the pandemic. A telemedicine setup using smartphones by hepatologists was organized at our tertiary-care center after pilot testing. Consecutive patients availing telehepatology services were recruited between March and July 2020. An adapted model for assessment of telemedicine was used after validity and reliability testing, to evaluate services 7-21 days after index teleconsultation. Of the 1,419 registrations, 1,281 (90.3%) consultations were completed. From 245 randomly surveyed patients, 210 (85.7%) responded (age [years, interquartile range]: 46 [35-56]; 32.3% females). Seventy percent of patients belonged to the middle or lower socio-economic class, whereas 61% were from rural areas. Modes of teleconsultation were audio (54.3%) or hybrid video call (45.7%). Teleconsultation alone was deemed suitable in 88.6% of patients. Diagnosis and compliance rates were 94% and 82.4%, respectively. Patients' convenience rate, satisfaction rate, improvement rate, success rate, and net promoter scores were 99.0%, 85.2%, 49.5%, 46.2% and 70, respectively. Physical and mental quality of life improved in 67.1% and 82.8% of patients, respectively, following index teleconsultation. Person-hours and money spent by patients were significantly lower with teleconsultation (P < 0.001); however, person-hours spent by hospital per teleconsultation were higher than in physical outpatient services (P < 0.001). Dissatisfied patients were more likely to have lower diagnosis rate, unsuitability for teleconsultation, noncompliance, poorer understanding, and uncomfortable conversation during teleconsultation. Connectivity issues (22.9%) were the most common barrier. Three patients, all of whom were advised emergency care during teleconsultation, succumbed to their illness. Conclusion: Telehepatology is a feasible and reasonably effective tool for rendering health care services using smartphones during the COVID-19 pandemic. Systematic implementation, possible integration into routine health care delivery, and formal cost-effectiveness of telehepatology services need further exploration.

Point-of-Care Thoracic Ultrasonography in Patients With Cirrhosis and Liver Failure.

Point-of-care ultrasonography (POCUS) helps determine liver-related pathologies like an abscess, portal vein or hepatic vein thromboses, presence of ascites, site for pleural or ascitic paracentesis, and guiding biopsies. POCUS is revolutionizing the management of critically ill patients presenting with pneumonia, acute respiratory distress syndrome, acute-on-chronic liver failure, and in the emergency. The objectives of thoracic ultrasonography (TUS) are to aid the clinician in differentiating between pneumonia, effusions, interstitial edema and collections, and in estimating the volume status of patients with liver disease using inferior vena cava dynamic indices. The use of POCUS in patients with cirrhosis has since evolved. It is now widely used to help diagnose volume status, left ventricular diastolic dysfunction, myocardial infarction, and right ventricular dilation due to pulmonary embolism and to determine the causes for weaning failures such as effusions, lung collapse, and pneumothorax. During the Coronavirus Disease 2019 (COVID-19) pandemic, moving patients for computed tomography can be difficult. Therefore, TUS is now essential in liver transplantation and intensive care practice to assess ventilatory pressures, cardiac function, and fluid management. This review indicates the current and optimized use of TUS, offers a practical guide on TUS in the liver intensive care unit (ICU), and presents a diagnostic pathway for determining lung and pleural pathology, resolution of respiratory failure, and aid weaning from mechanical ventilation.

Cytokine Storm of COVID-19 and Its Impact on Patients with and without Chronic Liver Disease.

The coronavirus pandemic has resulted in increased rates of hepatic decompensation, morbidity and mortality in patients suffering from existing liver disease, and deranged liver biochemistries in those without liver disease. In patients with cirrhosis with coronavirus disease 2019 (COVID-19), new onset organ failures manifesting as acute-on-chronic liver failure have also been reported. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) also directly binds to enterocytes and cholangiocytes via the angiotensin converting enzyme receptor 2, although the lung remains the portal of entry. Superadded with the COVID-19 related bystander hepatitis, a systemic inflammatory response is noted due to unregulated macrophage activation syndrome and cytokine storm. However, the exact definition and diagnostic criteria of the 'cytokine storm' in COVID-19 are yet unclear. In addition, inflammatory markers like C-reactive protein, ferritin, D-dimer and procalcitonin are frequently elevated. This in turn leads to disease progression, activation of the coagulation cascade, vascular microthrombi and immune-mediated injury in different organ systems. Deranged liver chemistries are also noted due to the cytokine storm, and synergistic hypoxic or ischemic liver injury, drug-induced liver injury, and use of hepatotoxic antiviral agents all contribute to deranged liver chemistry. Control of an unregulated cytokine storm at an early stage may avert disease morbidity and mortality. Several immunomodulator drugs and repurposed immunosuppressive agents have been used in COVID-19 with varying degrees of success.

Multidimensional dynamic healthcare personnel (HCP)-centric model from a low-income and middle-income country to support and protect COVID-19 warriors: a large prospective cohort study.

OBJECTIVES: Healthcare personnel (HCP) are at an increased risk of acquiring COVID-19 infection especially in resource-restricted healthcare settings, and return to homes unfit for self-isolation, making them apprehensive about COVID-19 duty and transmission risk to their families. We aimed at implementing a novel multidimensional HCP-centric evidence-based, dynamic policy with the objectives to reduce risk of HCP infection, ensure welfare and safety of the HCP and to improve willingness to accept and return to duty. SETTING: Our tertiary care university hospital, with 12 600 HCP, was divided into high-risk, medium-risk and low-risk zones. In the high-risk and medium-risk zones, we organised training, logistic support, postduty HCP welfare and collected feedback, and sent them home after they tested negative for COVID-19. We supervised use of appropriate personal protective equipment (PPE) and kept communication paperless. PARTICIPANTS: We recruited willing low-risk HCP, aged <50 years, with no comorbidities to work in COVID-19 zones. Social distancing, hand hygiene and universal masking were advocated in the low-risk zone. RESULTS: Between 31 March and 20 July 2020, we clinically screened 5553 outpatients, of whom 3012 (54.2%) were COVID-19 suspects managed in the medium-risk zone. Among them, 346 (11.4%) tested COVID-19 positive (57.2% male) and were managed in the high-risk zone with 19 (5.4%) deaths. One (0.08%) of the 1224 HCP in high-risk zone, 6 (0.62%) of 960 HCP in medium-risk zone and 23 (0.18%) of the 12 600 HCP in the low-risk zone tested positive at the end of shift. All the 30 COVID-19-positive HCP have since recovered. This HCP-centric policy resulted in low transmission rates (<1%), ensured satisfaction with training (92%), PPE (90.8%), medical and psychosocial support (79%) and improved acceptance of COVID-19 duty with 54.7% volunteering for re-deployment. CONCLUSION: A multidimensional HCP-centric policy was effective in ensuring safety, satisfaction and welfare of HCP in a resource-poor setting and resulted in a willing workforce to fight the pandemic.

Point-of-Care Echocardiography and Hemodynamic Monitoring in Cirrhosis and Acute-on-Chronic Liver Failure in the COVID-19 Era.

Point-of-Care (POC) transthoracic echocardiography (TTE) is transforming the management of patients with cirrhosis presenting with septic shock, acute kidney injury, hepatorenal syndrome and acute-on-chronic liver failure (ACLF) by correctly assessing the hemodynamic and volume status at the bedside using combined echocardiography and POC ultrasound (POCUS). When POC TTE is performed by the hepatologist or intensivist in the intensive care unit (ICU), and interpreted remotely by a cardiologist, it can rule out cardiovascular conditions that may be contributing to undifferentiated shock, such as diastolic dysfunction, myocardial infarction, myocarditis, regional wall motion abnormalities and pulmonary embolism. The COVID-19 pandemic has led to a delay in seeking medical treatment, reduced invasive interventions and deferment in referrals leading to "collateral damage" in critically ill patients with liver disease. Thus, the use of telemedicine in the ICU (Tele-ICU) has integrated cardiology, intensive care, and hepatology practices across the spectrum of ICU, operating room, and transplant healthcare. Telecardiology tools have improved bedside diagnosis when introduced as part of COVID-19 care by remote supervision and interpretation of POCUS and echocardiographic data. In this review, we present the contemporary approach of using POC echocardiography and offer a practical guide for primary care hepatologists and gastroenterologists for cardiac assessment in critically ill patients with cirrhosis and ACLF. Evidenced based use of Tele-ICU can prevent delay in cardiac diagnosis, optimize safe use of expert resources and ensure timely care in the setting of critically ill cirrhosis, ACLF and liver transplantation in the COVID-19 era.

Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19.

BACKGROUND: The incidence of elevated liver chemistries and the presence of pre-existing chronic liver disease (CLD) have been variably reported in COVID-19. AIMS: To assess the prevalence of CLD, the incidence of elevated liver chemistries and the outcomes of patients with and without underlying CLD/elevated liver chemistries in COVID-19. METHODS: A comprehensive search of electronic databases from 1 December 2019 to 24 April 2020 was done. We included studies reporting underlying CLD or elevated liver chemistries and patient outcomes in COVID-19. RESULTS: 107 articles (n = 20 874 patients) were included for the systematic review. The pooled prevalence of underlying CLD was 3.6% (95% CI, 2.5-5.1) among the 15 407 COVID-19 patients. The pooled incidence of elevated liver chemistries in COVID-19 was 23.1% (19.3-27.3) at initial presentation. Additionally, 24.4% (13.5-40) developed elevated liver chemistries during the illness. The pooled incidence of drug-induced liver injury was 25.4% (14.2-41.4). The pooled prevalence of CLD among 1587 severely infected patients was 3.9% (3%-5.2%). The odds of developing severe COVID-19 in CLD patients was 0.81 (0.31-2.09; P = 0.67) compared to non-CLD patients. COVID-19 patients with elevated liver chemistries had increased risk of mortality (OR-3.46 [2.42-4.95, P < 0.001]) and severe disease (OR-2.87 [95% CI, 2.29-3.6, P < 0.001]) compared to patients without elevated liver chemistries. CONCLUSIONS: Elevated liver chemistries are common at presentation and during COVID-19. The severity of elevated liver chemistries correlates with the outcome of COVID-19. The presence of CLD does not alter the outcome of COVID-19. Further studies are needed to analyse the outcomes of compensated and decompensated liver disease.