Clinical Significance and Prognostic Value of Hemostasis Parameters in 337 Patients with Acute Infective Endocarditis.

(1) Background: The aim of this study was to assess the clinical significance and prognostic role of the main hemostasis parameters in infective endocarditis (IE): prothrombin time as international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT), fibrinogen, D-dimers, platelet count, homocysteine. (2) Methods: We studied 337 patients with IE. Clinical, hemato-chemical and echocardiography parameters were analyzed. Coagulation parameters were measured on admission. (3) Results: D-dimers levels (p = 0.012) and a prolonged PT-INR (p = 0.013) were associated with higher in-hospital mortality, while prolonged aPTT (p = 0.021) was associated with increased 1-year mortality. Staphylococcus aureus (S. aureus) infection (p = 0.003), prosthetic valve endocarditis (PVE) (p = 0.001), surgical indication (p = 0.002) and higher D-dimer levels (p = 0.005) were independent predictors of in-hospital mortality. PVE (p = 0.001), a higher Charlson Comorbidity Index (p = 0.049), surgical indication (p = 0.001) and prolonged aPTT (p = 0.012) were independent predictors of 1-year mortality. Higher levels of D-dimers (p < 0.001) and a shorter aPTT (p < 0.001) were associated with embolic complications of IE. S. aureus etiology was bound to higher D-dimers levels (p < 0.001) and a shorter aPTT (p = 0.006). (4) Conclusions: Elevated D-dimers are associated with a higher risk for in-hospital mortality in IE patients. High D-dimers and a short aPTT are associated with a higher risk for embolic events in IE. A longer aPTT is associated with 1-year mortality.

Prognostic value of pro-adrenomedullin and copeptin in acute infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is a life-threatening disease whose prognosis is often difficult to predict based on clinical data. Biomarkers have been shown to favorably affect disease management in a number of cardiac disorders. Aims of this retrospective study were to assess the prognostic role of procalcitonin (PCT), pro-adrenomedullin (pro-ADM) and copeptin in IE and their relation with disease characteristics and the traditional biomarker C-reactive protein (CRP). METHODS: We studied 196 patients with definite IE. Clinical, laboratory and echocardiography parameters were analyzed, with a focus on co-morbidities. PCT, pro-ADM and copeptin were measured on stored plasma samples obtained on admission during the acute phase of the disease. RESULTS: Pro-ADM and copeptin were significantly higher in older patients and associated with prior chronic kidney disease. Pro-ADM was an independent predictor of hospital mortality (OR 3.29 [95%C.I. 1.04-11.5]; p = 0.042) whilst copeptin independently predicted 1-year mortality (OR 2.55 [95%C.I. 1.18-5.54]; p = 0.017). A high PCT value was strictly tied with S. aureus etiology (p = 0.001). CRP was the only biomarker associated with embolic events (p = 0.003). CONCLUSIONS: Different biomarkers correlate with distinct IE outcomes. Pro-ADM and copeptin may signal a worse prognosis of IE on admission to the hospital and could be used to identify patients who need more aggressive treatment. CRP remains a low-cost marker of embolic risk. A high PCT value should suggest S. aureus etiology.

Hepatitis B virus reactivation after heart transplant: Incidence and clinical impact.

BACKGROUND: Occult hepatitis B infection consists of persistence of HBV genomes in hepatocytes,absence of serum HBsAg, low/undetectable serum HBVDNA. Reactivation of HBV infection may occur during immunosuppression, but few data are available in heart transplant. OBJECTIVES: We followed-up heart recipients with or without markers of previous HBV infection,evaluating prevalence of HBV markers, incidence of HBV reactivation and its virological and clinical features. STUDY DESIGN: Heart failure patients listed for heart transplant (2007-2013) were screened for current or past HBV infection. Transplanted patients with past HBV infection (anti-HBc+/±anti-HBs+/HBVDNA-) were followed up as cases, and an equal number of HBV negative patients as controls. Virological reactivation was detected by standard real-time and home-made highly sensitive PCR (surface/core HBVDNA regions). Clinical status and progression were assessed by liver histology, ultrasound or elastography. RESULTS: 67 patients underwent heart transplant, including 4 (5.9%) HBsAg+ subjects. Cases were 11/67 (16.4%). During a median follow-up of 30 months, only one of these 11 patients presented viral reactivation (HBVDNA 209IU/mL) at month 22, and started antiviral treatment. Four other recipients showed virological events of uncertain significance (sensitive PCR-only intermittently positive). Clinical signs of liver disease were observed in only one case at the last follow-up. A nonsignificant difference in survival was observed between cases and all other heart recipients without prior HBV contact (death rate 5/11 vs 15/52, respectively; p=0.097). CONCLUSIONS: HBV genotypic reactivation in HBsAg-/anti-HBc+/HBVDNA- heart recipients is uncommon. Virological events of uncertain significance occur more frequently; their clinical impact seems to be negligible.

Viability of pegIFNα-RBV for CHC in the direct acting antiviral era: a practical algorithm between efficacy and cost containment.

The classical pegylated interferon α (peg-IFNα) and ribavirin (RBV) treatment of chronic hepatitis C (CHC) is progressively being replaced by new direct acting antivirals, whose costs remain a major barrier to widespread use. Using baseline data and viral kinetics, we developed a predictive algorithm to allocate to DAA patients who are not going to respond to peg-IFNα/RBV. This prospective study evaluated 205 CHC patients treated with peg-IFNα/RBV. HCVRNA kinetics during the initial 3 days of therapy and baseline variables including age, genotype, fibrosis and ALTs were used to construct a prediction rule in terms of sustained virological response (SVR). One hundred and twenty-one patients achieved an SVR (59%). Variables independently associated with SVR were HCVRNA, ALT, glycaemia, viral genotype, and fibrosis. The decline of viremia from baseline to 48/72 h was significantly different in SVR compared to non-SVR patients (2.2 vs. 0.65 log10 IU/mL; p < 0.001), and was influenced by viral genotype, levels of ALT, stage of fibrosis and IL28B polymorphism. In genotype 1, HCVRNA decline <0.8 logs had a negative predictive value of 90%, and in genotype 2, HCVRNA decline >1.2 logs had a positive predictive value of 92%. A combination of HCVRNA kinetics and a score based on pre-treatment parameters was highly accurate in predicting SVR in most patients. Outcome of peg-IFNα/RBV treatment may be predicted combining evaluation of baseline variables and HCVRNA kinetics. This allows to individualize treatment, reserving newer and more expensive DAAs to CHC patients who are in most need of them.

Clinical significance of hyperhomocysteinemia in infective endocarditis: A case-control study.

Blood coagulation plays a key role in the pathogenesis of infective endocarditis (IE). Conditions associated with thrombophilia could enhance IE vegetation formation and promote embolic complications.In this study, we assessed prevalence, correlates, and clinical consequences of hyper-homocysteinemia (h-Hcy) in IE.Homocysteine (Hcy) plasma levels were studied in 246 IE patients and 258 valvular heart disease (VHD) patients, as well as in 106 healthy controls.IE patients showed Hcy levels comparable to VHD patients (14.9 [3-81] vs 16 [5-50] µmol/L, respectively; P = 0.08). H-Hcy was observed in 48.8% of IE patients and 55.8% of VHD (P = 0.13). Vegetation size and major embolic complications were not related to Hcy levels. IE patients with h-Hcy had a higher prevalence of chronic kidney disease and a higher 1-year mortality (19.6% vs 9.9% in those without h-Hcy; OR 2.21 [1.00-4.89], P = 0.05). However, at logistic regression analysis, h-Hcy was not an independent predictor of 1-year mortality (OR 1.87 [95% CI 0.8-4.2]; P = 0.13).Our data suggest h-Hcy in IE is common, is related to a worse renal function, and may be a marker of cardiac dysfunction rather than infection. H-Hcy does not appear to favor IE vegetation formation or its symptomatic embolic complications.

Effect of the immunosuppressive regimen on the incidence of cytomegalovirus infection in 378 heart transplant recipients: A single centre, prospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) infection is a major complication of immunosuppression after heart transplant. Recent studies suggest the actual immunosuppressive regimen may affect the risk of CMV infection. OBJECTIVES: To evaluate incidence, risk factors and clinical consequences of CMV infection and assess the possible differential effect of distinct immunosuppressive protocols. STUDY DESIGN: Single centre, prospective cohort study of 378 consecutive heart transplant recipients undergoing CMV monitoring. Preemptive treatment was the standard of care. Patients were grouped as follows: group A, without any CMV infection; group B, with CMV infection not requiring pre-emptive treatment; group C, treated for CMV infection or disease. RESULTS: Most recipients never required antiviral therapy because of no CMV infection/disease (group A, 31%) or CMV levels below the cut-off for pre-emptive treatment (group B, 28%). Group C recipients (41%) were significantly older than group A patients (49.1±13.2 vs. 44.8±15.1 years; p=0.028). Most cases occurred within the second month post-transplant. CMV viremia was detected in 77% and 62% of patients primed with thymoglobulin or ATG Fresenius, respectively, (OR 2.06, 95% C.I. 1.27-3.34; p=0.0034). Use of everolimus was associated with a significantly lower rate of CMV infection compared to azathioprine or mycophenolate (OR 0.19, 95% C.I. 0.09-0.39; p<0.0001). Major opportunistic infections were significantly more common in groups B and C. CONCLUSION: In a large and homogeneous cohort of heart transplant recipients, we observed a strong relationship between the immune suppressive regimen and CMV infection, as well as an increased incidence of other opportunistic infections in recipients with CMV infection/disease.

Prevalence and significance of two major inherited thrombophilias in infective endocarditis.

The pathogenesis of infective endocarditis (IE) involves activation of the haemostasis system at the site of endocardial defects. Whether prothrombotic conditions are associated with IE by enhancing early vegetation formation is unknown. In this study, we assess the prevalence and clinical significance of two major conditions associated with thrombophilia in patients with IE. Mutations G20210A of the prothrombin (PTH) gene and G1691A of factor V (FV Leiden) gene were studied by means of allele-specific polymerase chain reaction in 203 IE patients, 175 valvular heart disease (VHD) patients and 200 blood donors (BD). IE patients show higher cumulative frequencies of mutated alleles of PTH and FV Leiden [6.4 vs 3.25 %; OR 2.03 (95 % CI 0.97-3.66); p = 0.047] compared to BD, but not VHD. Device-related IE is enriched with FV Leiden, and prosthetic valve IE with PTH mutations (allele frequency 8.3 vs 2.2 % in native valve IE; p = 0.021). Vegetation size and embolic complications are not influenced by the examined thrombophilias. A trend for a higher mortality was observed in IE patients with any of the two thrombophilias studied. Our data do not support a role for factor V Leiden and G20210A prothrombin gene mutations in the susceptibility to IE. Whether any of these genetic polymorphisms play a role in a specific subtype of IE needs to be re-examined in larger studies.

Differential antiviral effects of pegylated interferon-α2a and pegylated interferon-α2b in chronic hepatitis C.

BACKGROUND AND OBJECTIVES: Pegylated interferon (peg-IFN)-α2a and -α2b show different pharmacokinetic properties but are used interchangeably for hepatitis C treatment in traditional dual combinations and with newer agents. We assessed whether peg-IFN antiviral effects vary with peg-IFN subtype, affecting viral response in a differential manner. METHODS: Chronic hepatitis C patients treated with ribavirin combined with peg-IFN-α2a (N = 109) or -α2b (N = 114) were studied. Hepatitis C virus RNA quantitation was performed by Cobas TaqMan 5 min before treatment start and subsequently after 48/72 h and 7, 14, 28 and 90 days. Antiviral effect was assessed in terms of viraemia changes over treatment. Histology grading and staging, interleukin-28B (IL28B) status and baseline viral genotype, alanine aminotransferase, gamma glutamyltransferase and glucose were analysed. RESULTS: Viraemia decline after 48/72 h and 7 days was significantly greater with peg-IFN-α2b (1.96 and 2.12 vs 1.49 and 1.20 log10 IU/mL with peg-IFN-α2a; p < 0.001). Differences were of larger extent in patients with advanced fibrosis (p = 0.002), genotype 1 infection (p = 0.002) and CT/TT genotypes of IL28B (p = 0.001). A rebound in viral load was observed significantly more often after the first dose in patients treated with peg-IFN-α2b (78 vs 28 % in those with peg-IFN-α2a; p = 0.0001). Differences between peg-IFNs disappeared by day 28 of treatment. CONCLUSION: There are significant pharmacodynamic differences between peg-IFN-α2a and -α2b in the early phase of chronic hepatitis C treatment. The greater early viral decline observed with peg-IFN-α2b was essentially confined to 'difficult to treat' patients. Whether this could affect response-guided treatment decision making, as well as triple drug regimens, needs to be assessed.

The role of hemostasis in infective endocarditis.

Infective endocarditis (IE) is a thromboinflammatory disease of the endocardium, with pathophysiology mostly the result of the interplay between microorganisms and modifiers of the hemostasis system. In this setting, the evidence gathered so far warrants a more systematic appraisal. In this review article, experimental and clinical data on the role of hemostasis in IE are summarized. Starting from the current pathogenetic model of IE, we discuss the dual role of platelets in this condition, the microbial interaction with the hemostasis system, also describing nonspecific hemostasis changes during sepsis. We finally propose our hypothesis of thrombophilia as a possible trigger of IE, highlighting the challenges that the study of hemostasis in IE presents. The role of hemostasis in IE appears to be an exciting field of research. The activity of the hemostasis system is highly relevant in terms of susceptibility, progression, and treatment of IE. Pharmacologic modulation of hemostasis before and after IE onset is possible and represents still a largely unexplored area of study.

Clinico-pathological significance of hepatitis C virus core antigen levels in chronic infection.

Hepatitis C virus core antigen (HCVcoreAg) may be measured in serum with a sensitive, recently validated assay. Beyond its value as a marker of viral infection, there are little data on its relation with clinical, histological, and virological parameters. In this study, the significance of HCVcoreAg levels was studied in a prospective cohort of 114 patients with chronic hepatitis C. HCVcoreAg was measured by a commercial chemiluminescent microparticle immunoassay. Clinical and virological data included quantitative HCV-RNA, HCV genotype, ALT, GGT, IL28B rs12979860 polymorphism as well as liver histology parameters. HCVcoreAg levels were correlated significantly with HCV-RNA (r=0.56; P<0.0001) but also with ALT levels (r=0.258; P<0.01) and liver necroinflammatory activity (r=0.205; P<0.04). Patients harbouring HCV genotype 3 showed lower levels of HCVcoreAg than both genotype 1 and two patients. In genotype 3, a direct correlation between steatosis and HCVcoreAg was found. Levels of HCVcoreAg also varied according to the IL28B genotype. These data suggest that the evaluation of HCVcoreAg serum levels may provide relevant data for the baseline clinical evaluation of chronic hepatitis C patients. HCVcoreAg serum levels may be a useful tool to further the understanding of chronic hepatitis C pathobiology.

Adefovir treatment for chronic hepatitis B in heart transplant recipients.

Chronic hepatitis B is prevalent in the transplant setting and may cause significant complications. Effective control of viral replication is needed. Besides lamivudine, very little data are available on safety and efficacy of other drugs. We describe our experience with adefovir dipivoxil (ADV) in eight heart transplant recipients. Studies included a baseline liver biopsy, thrice-monthly clinical, biochemical, and virological evaluations, including genotyping and viral load, polymerase gene sequencing for resistance mutations, liver and kidney function tests, and liver ultrasound. Of eight patients, six had fibrosis score ≤2 and negative HBeAg and seven had hepatitis B virus (HBV) genotype D. Upon ADV start, median HBV-DNA was 5.8 logs IU/mL and alanine aminotransferase (ALT) levels were mostly normal. All patients had prior mild-to-moderate renal functional impairment. Seven of eight patients started ADV after a previous course of lamivudine. Five of these seven patients became HBV-DNA undetectable within eight months. One patient with low baseline viremia started ADV de novo and suppressed HBV-DNA. Median treatment duration was 66 months. ADV daily dose was halved in one patient due to renal function worsening. No ALT flares, hypophosphatemia, liver decompensation, liver cancer, or emergence of resistance was observed. Our data suggest that ADV may be a safe and effective rescue treatment for heart transplant recipients with lamivudine-resistant chronic hepatitis B.