Clinical and microbiological characteristics of bacterial infections in patients with cirrhosis. A prospective cohort study from Argentina and Uruguay.

INTRODUCTION AND OBJECTIVES: there is insufficient data regarding bacterial infections in patients with cirrhosis to support recommendations for empiric antibiotic treatments, particularly in Latin America. This study aimed to evaluate bacterial infection's clinical impact and microbiological characteristics, intending to serve as a platform to revise current practices. MATERIALS AND METHODS: multicenter prospective cohort study of patients with cirrhosis and bacterial infections from Argentina and Uruguay. Patient and infection-related information were collected, focusing on microbiology, antibiotic susceptibility patterns, and outcomes. RESULTS: 472 patients were included. Spontaneous bacterial infections and urinary tract infections (UTIs) were registered in 187 (39.6%) and 116 (24.6%) patients, respectively, representing the most common infections. Of the 256 culture-positive infections, 103 (40.2%) were caused by multidrug-resistant organisms (reaching 50% for UTI), and 181 (70.7%) received adequate initial antibiotic treatment. The coverage of cefepime and ceftriaxone was over 70% for the empirical treatment of community-acquired spontaneous infections, but ceftazidime´s coverage was only 40%. For all UTI cases and for healthcare-associated or nosocomial spontaneous bacterial infections, the lower-spectrum antibiotics that covered at least 70% of the isolations were imipenem and meropenem. During hospitalization, a second bacterial infection was diagnosed in 9.8% of patients, 23.9% required at least one organ support, and 19.5% died. CONCLUSIONS: short-term mortality of bacterial infections in patients with cirrhosis is very high, and a high percentage were caused by multidrug-resistant organisms, particularly in UTIs. The information provided might serve to adapt recommendations, particularly related to empirical antibiotic treatment in Argentina and Uruguay. The study was registered in Clinical Trials (NCT03919032).

Liver decompensation is a frequent cause of treatment discontinuation and prognostic factor in intermediate-advanced HCC.

INTRODUCTION AND OBJECTIVES: With the advent of new therapeutic options for patients with hepatocellular carcinoma (HCC) for intermediate or advanced stages of the Barcelona Clinic Liver Cancer (BCLC), regional real-world data regarding prognostic survival factors are of significant importance. PATIENTS AND METHODS: A multicenter prospective cohort study was conducted in Latin America including BCLC B or C patients since 15th May 2018. We report here the second interim analysis focusing on prognostic variables and causes of treatment discontinuation. Cox proportional hazard survival analysis was performed, estimating hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: Overall, 390 patients were included, 55.1% and 44.9% were BCLC B and C at the time of study enrollment. Cirrhosis was present in 89.5% of the cohort. Among the BCLC-B group, 42.3% were treated with TACE with a median survival since the first session of 41.9 months. Liver decompensation before TACE was independently associated with increased mortality [HR 3.22 (CI 1.64;6.33); P<.001]. Systemic treatment was initiated in 48.2% of the cohort (n=188), with a median survival of 15.7 months. Of these, 48.9% presented first-line treatment discontinuation (44.4% tumor progression, 29.3% liver decompensation, 18.5% symptomatic deterioration, and 7.8% intolerance), and only 28.7% received second-line systemic treatments. Liver decompensation [HR 2.9 (1.64;5.29); P<.0001], and symptomatic progression [HR 3.9 (1.53;9.78); P=0.004] were independently associated with mortality after first-line systemic treatment discontinuation. CONCLUSIONS: The complexity of these patients, with one-third presenting liver decompensation after systemic therapies, underlines the need for multidisciplinary team management and the central role of hepatologists.

Norfloxacin prophylaxis effect on multidrug resistance in patients with cirrhosis and bacterial infections.

It is unclear whether norfloxacin predisposes to infections by multidrug-resistant organisms (MDROs). We aimed to evaluate if patients with cirrhosis receiving norfloxacin prophylaxis at the time of the diagnosis of bacterial infections were more likely to present a multidrug-resistant isolate than those without prophylaxis. This is a cross-sectional study of hospitalized patients with cirrhosis and bacterial infections from Argentina and Uruguay (NCT03919032) from September 2018 to December 2020. The outcome variable was a multidrug-resistant bacterial infection. We used inverse probability of treatment weighting to estimate the odds ratio (OR) of norfloxacin on infection caused by MDROs considering potential confounders. Among the 472 patients from 28 centers, 53 (11%) were receiving norfloxacin at the time of the bacterial infection. Patients receiving norfloxacin had higher MELD-sodium, were more likely to have ascites or encephalopathy, to receive rifaximin, beta-blockers, and proton-pump inhibitors, to have a nosocomial or health-care-associated infection, prior bacterial infections, admissions to critical care units or invasive procedures, and to be admitted in a liver transplant center. In addition, we found that 13 (24.5%) patients with norfloxacin and 90 (21.5%) of those not receiving it presented infections caused by MDROs (adjusted OR 1.55; 95% CI: 0.60-4.03; p = 0.360). The use of norfloxacin prophylaxis at the time of the diagnosis of bacterial infections was not associated with multidrug resistance. These results help empiric antibiotic selection and reassure the current indication of norfloxacin prophylaxis in well-selected patients.Study registration number: NCT03919032.

Performance of pre-transplant criteria in prediction of hepatocellular carcinoma progression and waitlist dropout.

BACKGROUND & AIM: Liver transplantation (LT) selection models for hepatocellular carcinoma (HCC) have not been proposed to predict waitlist dropout because of tumour progression. The aim of this study was to compare the alpha-foetoprotein (AFP) model and other pre-LT models in their prediction of HCC dropout. METHODS: A multicentre cohort study was conducted in 20 Latin American transplant centres, including 994 listed patients for LT with HCC from 2012 to 2018. Longitudinal tumour characteristics, and patterns of progression were recorded at time of listing, after treatments and at last follow-up over the waitlist period. Competing risk regression models were performed, and model's discrimination was compared estimating Harrell's adapted c-statistics. RESULTS: HCC dropout rate was significantly higher in patients beyond (24% [95% CI 16-28]) compared to those within Milan criteria (8% [95% IC 5%-12%]; p < .0001), with a SHR of 3.01 [95% CI 2.03-4.47]), adjusted for waiting list time and bridging therapies (c-index 0.63 [95% CI 0.57; 0.69). HCC dropout rates were higher in patients with AFP scores >2 (adjusted SHR of 3.17 [CI 2.13-4.71]), c-index of 0.71 (95% CI 0.65-0.77; p = .09 vs Milan). Similar discrimination power for HCC dropout was observed between the AFP score and the Metroticket 2.0 model. In patients within Milan, an AFP score >2 points discriminated two populations with a higher risk of HCC dropout (SHR 1.68 [95% CI 1.08-2.61]). CONCLUSIONS: Pre-transplant selection models similarly predicted HCC dropout. However, the AFP model can discriminate a higher risk of dropout among patients within Milan criteria.

Failure in all steps of hepatocellular carcinoma surveillance process is frequent in daily practice.

INTRODUCTION AND OBJECTIVES: Failures at any step in the hepatocellular carcinoma (HCC) surveillance process can result in HCC diagnostic delays and associated worse prognosis. We aimed to estimate the prevalence of surveillance failure and its associated risk factors in patients with HCC in Argentina, considering three steps: 1) recognition of at-risk patients, 2) implementation of HCC surveillance, 3) success of HCC surveillance. METHODS: We performed a multi-center cross-sectional study of patients at-risk for HCC in Argentina seen between10.01.2018 and 10.30.2019. Multivariable logistic regression analysis was used to identify correlates of surveillance failure. RESULTS: Of 301 included patients, the majority were male (74.8%) with a mean age of 64 years old. At the time of HCC diagnosis, 75 (25%) patients were unaware of their diagnosis of chronic liver disease, and only 130 (43%) patients were under HCC surveillance. Receipt of HCC surveillance was significantly associated with follow-up by a hepatologist. Of 119 patients with complete surveillance, surveillance failure occurred in 30 (25%) patients. Surveillance failure was significantly associated with alpha fetoprotein ≥20 ng/mL (OR 4.0, CI 95% 1.43-11.55). CONCLUSIONS: HCC surveillance failure was frequent in all the evaluated steps. These data should help guide strategies to improve the implementation and results of HCC surveillance in our country.

Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort.

BACKGROUND & AIM: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.

Liver transplantation for hepatocellular carcinoma: impact of expansion criteria in a multicenter cohort study from a high waitlist mortality region.

This study aimed to compare liver transplantation (LT) outcomes and evaluate the potential rise in numbers of LT candidates with hepatocellular carcinoma (HCC) of different allocation policies in a high waitlist mortality region. Three policies were applied in two Latin American cohorts (1085 HCC transplanted patients and 917 listed patients for HCC): (i) Milan criteria with expansion according to UCSF downstaging (UCSF-DS), (ii) the AFP score, and (iii) restrictive policy or Double Eligibility Criteria (DEC; within Milan + AFP score ≤2). Increase in HCC patient numbers was evaluated in an Argentinian prospective validation set (INCUCAI; NCT03775863). Expansion criteria in policy A showed that UCSF-DS [28.4% (CI 12.8-56.2)] or "all-comers" [32.9% (CI 11.9-71.3)] had higher 5-year recurrence rates compared to Milan, with 10.9% increase in HCC patients for LT. The policy B showed lower recurrence rates for AFP scores ≤2 points, even expanding beyond Milan criteria, with a 3.3% increase. Patients within DEC had lower 5-year recurrence rates compared with those beyond DEC [13.3% (CI 10.1-17.3) vs 24.2% (CI 17.4-33.1; P = 0.0006], without significant HCC expansion. In conclusion, although the application of a stricter policy may optimize the selection process, this restrictive policy may lead to ethical concerns in organ allocation (NCT03775863).

Outbreak of hepatitis A in a post-vaccination era: High rate of co-infection with sexually transmitted diseases.

INTRODUCTION AND OBJECTIVES: After hepatitis A (HAV) mandatory immunization in 2005 in Argentina, the incidence of HAV declined drastically. However, several new autochthonous cases of HAV have been reported since 2017. We aimed to evaluate the clinical and epidemiological characteristics and possible transmission routes of affected patients. PATIENTS OR MATERIALS AND METHODS: We performed a cross-sectional study of patients residing in Argentina with acute hepatitis A between 30.06.2017 and 31.12.2018. RESULTS: 66 cases of HAV were registered. Fifty-six patients (86%) were males, with a mean age of 34 ±â€¯12 years old. The most likely routes of transmission were sexual intercourse of men with men, reported by 31 patients. Additionally, 23% and 26% of patients tested positive for HIV and syphilis, respectively. In total, 35% of patients required hospitalization. When assessing outcomes, 79% had a mild presentation and 21% had a severe/fulminant presentation: one patient underwent liver transplantation, and one patient died. CONCLUSIONS: Our study describes that during the study period, HAV infection affected predominantly young adults, particularly men who have sex with men. An elevated proportion of them was diagnosed with a concomitant sexually transmitted disease, and several patients had a severe presentation of the disease.

Grasa epicárdica y esteatosis hepática como marcadores de riesgo cardiovascular / Epicardial Fat and Hepatic Steatosis as Cardiovascular Risk Markers

RESUMEN El tejido adiposo epicardico (TAE) es un tejido metabólicamente activo que ha cobrado gran interés en la última década como marcador de riesgo cardiovascular. El TAE se relaciona con la producción de citoquinas proinflamatorias y de ácidos grasos libres, con la promoción de un estado de hipercoagulabilidad, y con numerosos factores de riesgo cardiometabólico. Existe una íntima relación entre las arterias coronarias y el TAE, no solo anatómica, sino en cuanto a aspectos fisiológicos bidireccionales de regulación paracrina. Además, numerosos estudios han encontrado una relación entre el TAE y la presencia de disfunción endotelial, ateromatosis no obstructiva, estrés oxidativo, fibrilación auricular, y disfunción diastólica. En paralelo, existe una estrecha relación entre la esteatosis hepática (la enfermedad hepática crónica más frecuente), la ateromatosis coronaria, y el riesgo cardiovascular. Una de las características interesantes de la esteatosis hepática y diferenciales con respecto a la enfermedad coronaria es su carácter dinámico y, en cierta medida, reversible. A pesar de las asociaciones descriptas con la ateromatosis y con el riesgo cardiovascular, y de su evaluación sencilla a partir de métodos de imagen no invasivos, la grasa epicárdica y el hígado graso no alcohólico son raramente considerados como marcadores de riesgo en la práctica clínica.

ABSTRACT Epicardial adipose tissue (EAT) is a metabolically active tissue which has raised great interest in the last decade as a cardiovascular risk marker. It is related with the production of proinflammatory cytokines and free fatty acids, the promotion of a state of hypercoagulability and with numerous cardiometabolic risk factors. Between EAT and coronary arteries, there is not only an intimate anatomical association, but also bidirectional physiological aspects of paracrine regulation. In addition, several studies have found a relationship between EAT and endothelial dysfunction, non-obstructive atheromatosis, oxidative stress, atrial fibrillation and diastolic dysfunction. Parallel to these findings, there is a tight association between hepatic steatosis (the most prevalent chronic hepatic disease), coronary atheromatosis and cardiovascular risk. One of the interesting and differential characteristics of hepatic steatosis with respect to coronary artery disease is its dynamic, and to a certain point reversible, character. Despite their association with atheromatosis and cardiovascular risk and simple assessment from non-invasive imaging methods, epicardial fat and non-alcoholic fatty liver are seldom considered as risk markers in clinical practice.

Direct-Acting Antivirals and Hepatocellular Carcinoma: No Evidence of Higher Wait-List Progression or Posttransplant Recurrence.

The association between direct-acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait-list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait-list progression and post-LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait-list progression adjusted by a propensity score matching (pre-LT DAA effect) and for post-LT HCC recurrence (pre- or post-LT DAA effect). From 994 included patients, 50.6% were HCV-, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n = 66) or after LT (n = 98). Patients treated with DAAs before LT presented similar cumulative incidence of wait-list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P = 0.47) and a similar HCC-related dropout rate (12.1% [95% CI, 0.4%-8.1%] versus 12.9% [95% CI, 3.8%-27.2%]), adjusted for baseline tumor burden, alpha-fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6-1.6; P = 0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre- or post-LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%-4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait-list tumor progression and HCC recurrence after LT.

Isolated Intrapulmonary Vascular Dilatations and the Risk of Developing Hepatopulmonary Syndrome in Liver Transplant Candidates.

BACKGROUND: The natural history of intrapulmonary vascular dilations (IPVD) and their impact on patient outcomes in the setting of portal hypertension has only been described in small series. AIMS: To assess the development of hepatopulmonary síndrome (HPS) in patients with isolated IPVD and to evaluate outcomes of IPVD and HPS among patients evaluated for liver transplantation (LT). MATERIAL AND METHODS: Data from a prospective cohort of patients evaluated for LT with standardized screening for HPS were analyzed. IPVDs were defined as the presence of microbubbles in the left atrium > 3 cycles following right atrial opacification. HPS was defined as the presence of IPVD and hypoxemia (Alveolar-arterial gradient ≥ 15 mmHg) in the absence of concomitant cardiopulmonary disease. RESULTS: A total of 104 patients with negative contrast-enhanced echocardiogram (CE) were compared to 63 patients with IPVD and 63 patients with HPS. Only four patients were categorized as 'severe' HPS based on degree of hipoxemia (defined as PaO2 < 60 mmHg). Twenty IPVD patients were followed with ABG over a mean duration of 21 months (range 9-43), of whom 7 (35%) subsequently met HPS criteria. Overall unadjusted survival from the time of LT evaluation using multi-state survival models that accounted for pre- and post-LT time was not statistically different among the three groups (negative CE, IPVD, and HPS; p > 0.5). CONCLUSIONS: Patients with IPVD appear to have a substantial risk of developing oxygenation impairment over time and progress to HPS. In our cohort, survival in patients with HPS and isolated IPVD is not different when compared to those without IPVDs.

Neurological events after liver transplantation: a single-center experience.

The aim of this study was to identify potential risk factors linked to neurologic events (NE) occurring after liver transplantation (LT) and use them to construct a model to predict such events. From odds ratios (OR) of risk factors, a scoring system was assessed using multivariate regression analysis. Forty-one of 307 LT patients presented NE (13.3%), with prolonged hospital stay and decreased post-LT survival. On multivariate analysis, factors associated with NE included: severe pre-LT ascites OR 3.9 (1.80-8.41; P = 0.001), delta sodium ≥12 mEq/l OR 3.5 (1.36-8.67; P = 0.01), and post-LT hypomagnesemia OR 2.9 (1.37-5.98; P = 0.005). Points were assigned depending on ORs as follows: ascites 4 points, and hypomagnesemia and delta sodium ≥12 mEq/l, 3 points each (score range = 0-10 points). ROC curve analysis suggested good discriminative power for the model, with a c-statistic of 0.72 (CI 0.62-0.81; P < 0.0001), best performance for a cutoff value >3 points (71% sensitivity, 60% specificity). NE risk increased progressively from 6.4%, to 10.3%, 12.8%, 31.5% and 71.0% as scores rose from 0 to 3, 4, 6-7 and 10 cumulative points, respectively. The score described helps to identify patients potentially at risk for neurologic events, and its prevention would decrease morbidity and mortality after LT.

Successful orthotopic liver transplantation and delayed delivery of a healthy newborn in a woman with fulminant hepatic failure during the second trimester of pregnancy.

Severe liver dysfunction during pregnancy implies a serious risk for both mother and fetus, and represents a technical and ethical challenge for treating physicians. We report a case of a previously healthy 32-year old woman who was admitted to our hospital with idiopathic fulminant hepatic failure and underwent successful orthotopic liver transplantation (OLT) at gestation week 21. Patient's and fetus' immediate postoperative course were relatively uneventful until week six after OLT, when the mother developed oligohydramnios and preeclampsia. At pregnancy week 27, after inducing baby's lung maturation, a cesarean section was performed with the delivery of an otherwise healthy girl. After 3 years of follow-up, mother and child are leading normal lives with no complications related either to pregnancy or to OLT. We describe the case of a successful emergency liver transplant in a woman during the second trimester of pregnancy, demonstrating that OLT can be a viable option to preserve the life of the mother and an otherwise unviable fetus. Intrauterine baby's growths until the attainment of a viable gestational age was feasible despite the mother's fulminant hepatic failure and liver transplant surgery.