Nosocomial Infections Are Frequent and Negatively Impact Outcomes in Hospitalized Patients With Cirrhosis.

OBJECTIVES: Nosocomial infections (NIs) can be a major cause of morbidity and mortality in cirrhosis. This study aims to define the determinants of NI development and its impact on 30-day outcomes among hospitalized patients with cirrhosis. METHODS: North American Consortium for the Study of End-Stage Liver Disease enrolled patients with cirrhosis who were admitted nonelectively. Admission variables and 30-day outcomes were compared between patients with and without NI. These were also compared based on whether there was an isolated admission infection, NI, or both. Models were created for NI development using admission variables and for 30-day mortality. RESULTS: The study included 2,864 patients; of which, 15% (n = 436) developed NI. When comparing NI vs no NI, 1,866 patients were found to be infection free, whereas 562 had admission infections only, 228 had only NI, and 208 had both infections. At admission, patients with NI were more likely to be infected and have advanced cirrhosis. NIs were associated with higher rates of acute-on-chronic liver failure, death, and transplant regardless of admission infections. Patients with NI had higher respiratory infection, urinary tract infection, Clostridium difficile infection, fungal infections, and infection with vancomycin-resistant enterococci compared with patients without NI. Risk factors for NIs were admission infections, model for end-stage liver disease (MELD) > 20, systemic inflammatory response syndrome criteria, proton pump inhibitor, rifaximin, and lactulose use, but the regression model (sensitivity, 0.67; specificity, 0.63) was not robust. Age, alcohol etiology, admission MELD score, lactulose use, acute-on-chronic liver failure, acute kidney injury, intensive care unit, and NI increased the risk of death, whereas rifaximin decreased the risk of death. DISCUSSION: NIs are prevalent in hospitalized patients with cirrhosis and are associated with poor outcomes. Although higher MELD scores and systemic inflammatory response syndrome are associated with NI, all hospitalized patients with cirrhosis require vigilance and preventive strategies.

Outcomes in Patients With Cirrhosis on Primary Compared to Secondary Prophylaxis for Spontaneous Bacterial Peritonitis.

OBJECTIVES: Antibiotic prophylaxis is recommended for prevention of the first episode of spontaneous bacterial peritonitis (SBP; primary prophylaxis 1°) and subsequent episodes (secondary prophylaxis 2°). We aimed to compare outcomes in cirrhotic inpatients on 1° vs 2° SBP prophylaxis. METHODS: Data from North American Consortium for the Study of End-Stage Liver Disease were evaluated for cirrhosis details, reasons for admission/medications, inpatient course recorded, and outcomes over 90 days. Outcomes (intensive care units, acute kidney injury, inpatient/90-day mortality) were compared between the 2 groups after propensity-matching on admission model for end-stage liver disease (MELD) score and serum albumin. RESULTS: Among the 2,731 patients enrolled, 305 were on 1° and 187 on 2° SBP prophylaxis. After propensity-matching, 154 patients remained in each group. Patients on 1° prophylaxis were more likely to have admission systemic inflammatory response syndrome (P = 0.02), with higher intensive care unit admissions (31% vs 21%; P = 0.05) and inpatient mortality (19% vs 9%; P = 0.01) than the 2° prophylaxis group. Patients on 2° prophylaxis had higher total (22% vs 10%; P = 0004), readmission (16% vs 9%; P = 0.03), and nosocomial (6% vs 0.5%; P = 0.01) SBP rates with predominant Gram-negative organisms compared to 1° prophylaxis patients. At 90 days, 1° prophylaxis patients had a higher mortality (35% vs 22%; P = 0.02) and acute kidney injury incidence (48% vs 30%; P = 0.04) compared to 2° prophylaxis patients. DISCUSSION: In this inpatient cirrhosis study, despite prophylaxis, a high proportion of patients developed SBP, which was associated with mortality. Cirrhotic inpatients on 1° prophylaxis had worse outcomes than those on 2° prophylaxis when propensity-matched for the MELD score and serum albumin during the index admission and 90-day follow-up.

The Impact of Albumin Use on Resolution of Hyponatremia in Hospitalized Patients With Cirrhosis.

OBJECTIVES: Hyponatremia is associated with poor outcomes in cirrhosis independent of MELD. While intravenous albumin has been used in small series, its role in hyponatremia is unclear. The aim of this study is to determine the effect of albumin therapy on hyponatremia. METHODS: Hospitalized cirrhotic patients included in the NACSELD (North American Consortium for End-Stage Liver Disease) cohort with hyponatremia (Na <130mmol/L) were divided into those receiving intravenous albumin or not. Determinants of hyponatremia resolution (Na ≥135 meq/L) and 30-day survival were analyzed using regression and ANCOVA models. RESULTS: Overall, 2435 patients, of whom 1126 had admission hyponatremia, were included. Of these, 777 received 225 (IQR 100,400) g of albumin, while 349 did not. Patients given albumin had a higher admission MELD score, and serum creatinine and lower admission Na and mean arterial pressure (MAP). However they experienced a higher maximum Na and hyponatremia resolution (69% vs 61%, p = 0.008) compared to those who did not. On regression, delta Na was independently associated with admission creatinine, MAP and albumin use. On ANCOVA with logistic regression, there was a significant difference in hyponatremia resolution between those who did or did not receive albumin, even after adjustment for admission Na and GFR (85.41% vs 44.78%, p = 0.0057, OR: 1.50 95% CI: 1.13-2.00). Independent predictors of 30-day survival were hyponatremia resolution, age, ACLF, and admission GFR. CONCLUSION: Hospitalized patients with cirrhosis and hyponatremia who received intravenous albumin had a higher rate of hyponatremia resolution independent of renal function and baseline sodium levels, which was in turn associated with a better 30-day survival.

Prediction of Fungal Infection Development and Their Impact on Survival Using the NACSELD Cohort.

OBJECTIVES: Bacterial infections are associated with negative outcomes in cirrhosis but fungal infections are being increasingly recognized. The objective of this study is to define risk factors for fungal infection development and impact on 30-day survival. METHODS: In a large, multi-center cirrhotic inpatient cohort, demographics, cirrhosis details, intensive care unit (ICU), organ failures/acute-on-chronic liver failure (ACLF), and 30-day survival were compared between patients without infections and with bacterial infections alone, with those with fungal infections. Variables associated with fungal infection development were determined using multi-variable regression. Ordinal variables (0=no infection, 1=community-acquired bacterial infection, 2=nosocomial bacterial, and 3=fungal infection) were input into a 30-day survival model. RESULTS: A total of 2,743 patients (1,691 no infection, 918 bacterial, and 134 fungal infections) were included. Patients with fungal infection, all of which were nosocomial, were more likely to be admitted with bacterial infections, on spontaneous bacterial peritonitis prophylaxis, and have diabetes and advanced cirrhosis. Bacterial infection types did not predict risk for fungal infections. Multi-variable analysis showed male gender to be protective, whereas diabetes, longer stay, ICU admission, acute kidney injury (AKI), and admission bacterial infection were associated with fungal infection development (area under the curve (AUC)=0.82). Fungal infections were associated with significantly higher ACLF, inpatient stay, ICU admission, and worse 30-day survival. The case fatality rate was 30% with most fungal infections but >50% for fungemia and fungal peritonitis. On a multi-variable analysis, age, AKI, model for end-stage liver disease, ICU admission, and ordinal infection variables impaired survival (P<0.0001, AUC=0.83). CONCLUSIONS: Fungal infections are associated with a poor 30-day survival in hospitalized cirrhotic patients compared with uninfected patients, and those with bacterial infections. Patients with diabetes, AKI, and those with an admission bacterial infection form a high-risk subgroup.

Non-HLA Antibodies Impact on C4d Staining, Stellate Cell Activation and Fibrosis in Liver Allografts.

BACKGROUND: Recent data have shown an increased risk for rejection, fibrosis progression, and death in liver transplantation (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1 of 2000 to 4 of 2009 with known HLA DSA status for angiotensin II type-1 receptor and endothelin-1 type A receptor autoantibodies pre-LT, and year 1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death (hazard ratio [HR], 1.66; P = 0.02) especially if the HLA DSA was of the IgG3 subclass (HR, 2.28; P = 0.01). A single de novo non-HLA autoantibody was associated with an increased risk for T cell-mediated rejection or antibody-mediated rejection (68% vs 41%, P = 0.01) and fibrosis progression (HR, 1.84; P = 0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared with HLA DSA (71% vs 3%; P < 0.001). Liver sinusoidal endothelial cell activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-angiotensin II type-1 receptor and anti-endothelin-1 type A receptor autoantibodies are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to liver sinusoidal endothelial cell capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients.

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.