Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. MATERIAL AND METHODS: We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. RESULTS: Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycemia were independently associated with a higher mortality. DISCUSSION: We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.

Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. MATERIAL AND METHODS: We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. RESULTS: Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycaemia were independently associated with a higher mortality. DISCUSSION: We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.

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.

Anthropometric parameters and liver histology influence lipid metabolic changes in HCV chronic hepatitis on direct-acting antiviral treatment.

BACKGROUND: Hepatitis C virus (HCV) infection affects lipid metabolism. We investigated the impact of direct-acting antiviral (DAA) treatment on lipid metabolism in chronic hepatitis C (CHC), with a focus on the effects of anthropometric parameters and liver histology. We also analyzed the dynamics of metabolic indexes used to estimate cardiovascular risk. METHODS: In 49 patients with CHC treated with DAAs, lipid metabolic changes, anthropometric parameters, liver histology and cardiovascular risk indexes, including triglyceride to HDL ratio (Tr/HDL), fatty liver index (FLI) and visceral adiposity index (VAI) were evaluated at baseline (BL), end of treatment (EOT) and 12 [sustained virological response (SVR) 12] and 24 (SVR24) weeks after EOT. RESULTS: SVR occurred in 96% of cases. Total and LDL cholesterol and ApoB levels increased significantly between BL and EOT (P<0.001, <0.001 and 0.05, respectively) and remained stable thereafter. Total and LDL cholesterol significantly increased only in patients with higher BL waist circumference (P<0.01 and 0.009), fibrosis (P=0.002 and 0.005) and steatosis (P=0.043 and 0.033, respectively). HDL cholesterol significantly rose at SVR24. However, cardiovascular risk indexes (Tr/HDL ratio, FLI and VAI) did not significantly change during DAA treatment and follow up. CONCLUSIONS: Patients with HCV eradication after DAA treatment develop a pro-atherogenic lipid pattern, which varies according to anthropometric parameters and liver histology. However, no increase of cardiovascular risk indexes occurs in the short-term. Total and LDL cholesterol should be monitored long-term in CHC patients cured from infection.

Effects of Direct-Acting Antiviral Agents on the Mental Health of Patients with Chronic Hepatitis C: A Prospective Observational Study.

In chronic hepatitis C (CHC) patients, interferon-based treatments showed toxicity, limited efficacy, and psychiatric manifestations. Direct-acting antiviral (DAA) agents appeared safer, though it remains unclear if they may exacerbate or foster mood symptoms in drug-naïve CHC patients. We evaluated 62 CHC patients' mental status, before and 12 weeks after DAA therapy, by assessment scales and psychometric instruments. We subdivided patients into two groups, CHC patients with (Group A) or without (Group B) a current and/or past psychiatric history. After DAA treatment, Group A patients showed low anxiety and improved depression, no variation in self-report distress, but worse general health perceptions. No significant difference emerged from coping strategies. Depression and anxiety improved in Group B, and no change emerged from total self-reported distress, except for somatization. Moreover, Group B increased problem-focused strategies for suppression of competing activities, and decreased strategies of instrumental social support. Contrarily, Group B reduced significantly emotion-focused strategies, such as acceptance and mental disengagement, and improved vitality, physical and social role functioning. DAA therapy is safe and free of hepatological and psychiatric side effects in CHC patients, regardless of current and/or past psychiatric history. In particular, patients without a psychiatric history also remarkably improved their quality of life.

Does this patient have COVID-19? A practical guide for the internist.

Coronavirus disease 2019 (COVID-19) is currently causing a pandemic and will likely persist in endemic form in the foreseeable future. Physicians need to correctly approach this new disease, often representing a challenge in terms of differential diagnosis. Although COVID-19 lacks specific signs and symptoms, we believe internists should develop specific skills to recognize the disease, learning its 'semeiotic'. In this review article, we summarize the key clinical features that may guide in differentiating a COVID-19 case, requiring specific testing, from upper respiratory and/or influenza-like illnesses of other aetiology. We consider two different clinical settings, where availability of the different diagnostic strategies differs widely: outpatient and inpatient. Our reasoning highlights how challenging a balanced approach to a patient with fever and flu-like symptoms can be. At present, clinical workup of COVID-19 remains a hard task to accomplish. However, knowledge of the natural history of the disease may aid the internist in putting common and unspecific symptoms into the correct clinical context.

Hepatitis B core-related antigen to detect hepatitis B virus (HBV) reactivation in heart transplant recipients with past HBV infection: A pilot study.

Hepatitis B core-related antigen (HBcrAg) has been proposed as a new marker of hepatitis B virus (HBV) replication. We analyzed HBcrAg dynamics in 15 heart transplant recipients with active or prior HBV infection and correlated it with quantitative (QT)-HBsAg and HBV-DNA pre- and post-transplant. Serum HBcrAg was detected in HBsAg/HBV-DNA-positive subjects but not in recipients with past HBV infection. HBcrAg levels correlated with QT-HBsAg in pre- and post-transplant samples. In prior HBV infection, HBcrAg levels were unrelated to HBV-DNA positivity. In heart transplant recipients with prior HBV infection, HBcrAg does not correlate with viral replication and cannot be applied to detect HBV reactivation during follow-up.

Dynamics and management of oral anticoagulant treatment in chronic hepatitis C patients undergoing therapy with direct antiviral agents.

Current regimens of direct-acting antiviral agents (DAA) are effective and safe for chronic hepatitis C (CHC). However, DAA often interfere with concomitant medications. We treated seven CHC patients with DAA who were on chronic anticoagulant treatment with warfarin, and describe the dynamics of prothrombin time, providing novel data, useful for the clinician.

Liver histopathological findings in advanced heart failure: a reappraisal of cardiac cirrhosis concept.

Cardiogenic liver disease is a common yet poorly characterized complication of advanced heart failure (HF), and may impact clinical management in the setting of heart transplant evaluation. In this retrospective study, we describe clinical and histopathological features of liver injury in advanced HF, with a focus on the role of liver biopsy. Included were 45 HF patients, assessed for possible heart transplant, who underwent liver biopsy for suspected liver disease. Median duration of HF symptoms was 5 years. Most patients had stiff hepatomegaly and elevated bilirubin. Viral hepatitis (19 patients, 42.2%) was the most common cause of prior known liver disease. Sinusoidal dilatation was detected in the majority of patients (64.4%). Median necroinflammatory index was 3 and median fibrosis was 1, consistent with a small burden of histologically proven liver disease. Viral hepatitis was the only variable associated with a higher grade of necroinflammation and fibrosis. Nine of the 14 (64.3%) advanced fibrosis/cirrhosis patients had a viral hepatitis infection. Fibrosis was significantly associated with splenomegaly. The MELD score was not correlated with cardiac index. A coarse liver echo-pattern had a 29% positive and 63% negative predictive value for advanced fibrosis/cirrhosis. Severe liver disease is uncommon in patients with advanced HF in the absence of splenomegaly or primary causes of liver disease. Ultrasound data need to be carefully evaluated, as it may overstate the severity of liver disease. Liver biopsy may be needed to accurately stage liver disease before excluding patients from advanced treatment strategies.

Effect of a Cooperation Strategy between Primary Care Physicians and Hospital Liver Units on HBV Care in Campania, Italy.

Aims: This study is aimed at assessing the efficacy of an active search and treat strategy for HBV-infected subjects in an endemic area (Campania, Italy). To do this, we created a cooperation bundle between 24 General Practitioners (GPs) and 3 Hospital Liver Units (HLU). We assessed whether this strategy improved the detection of HBV infection in patients at risk and the overall quality of care, with the aim of reducing liver disease progression. Methods: We estimated that, among about 20,000 patients cared for by the 24 GPs, approximately 280 patients unaware of or underestimating HBV infection would be found. Identified patients were to be referred to the HLU for clinical evaluation and treatment from February 2016 for 12 months. Results: Unexpectedly, screening and enrolment were poor (48 patients only). GP workloads, patient financial difficulties, and patients' refusal were the major causes of enrolment failure according to GPs. All patients referred to HLU completed the program; most of them were HBV inactive carriers. Conclusions: This program failed to scavenge chronic HBV-infected patients in an endemic area and establish a successful clinical collaboration between GPs and HLU. Underlying reasons are diverse and call for new strategies to implement cooperation between primary care providers and hospital specialists.

HCV genotype-3h, a difficult-to-diagnose sub-genotype in the DAA era.

BACKGROUND: No data are available on the clinical presentation and virological pattern in the case of failure of interferon (IFN)-free regimens in patients with genotype-3h. In this paper authors identified the virological and clinical characteristics of patients with genotype-3h treated with suboptimal or not indicated IFN-free regimens for the misclassification of HCV genotype. METHODS: A total of 87 consecutive patients with failure to an IFN-free regimen were re-tested for HCV genotype by HCV NS5B sequencing; the 26 patients identified as harbouring HCV-3 were enrolled. RESULTS: Of the 26 patients enrolled, 4 (15.4%) harboured sub-genotype-3h and 22 (84.6%) 3a. All patients were Italian. Patients with genotype-3a infection were younger (median age 56 years, range 47-78) compared to those with genotype-3h infection (median 74 years, range 65-79; P<0.006). With regard to the failed direct-acting antiviral (DAA)-regimens, three of the four patients with genotype-3h (75%) had been treated with an ineffective​ DAA regimen (paritaprevir, ombitasvir, dasabuvir ± ribavirin for 3 months) more frequently than those with genotype-3a (13.6%; P=0.02), because of previous erroneous identification of HCV-1 genotype. NS5A resistance-associated substitutions (RASs) were observed in 10 (45.4%) genotype-3a-infected patients and in 2 (50%) with genotype-3h. NS5B RASs were observed in only two genotype-3a-infected patients and in none of the 3h-infected patients. CONCLUSIONS: This is the first time genotype-3h has been identified in Italian patients failing an IFN-free regimen, in the majority of cases because of a misclassification of the HCV genotype.

Can we go for a shorter treatment course in chronic hepatitis C? More inspiring cases.

Current interest in HCV therapy with direct acting antivirals is focused on shortening treatment length. We managed two cirrhotics who achieved virological cure after 4 weeks of ombitasvir/paritaprevir/ritonavir, dasabuvir, ribavirin treatment. Analysis to identify potential predictive factors for a successful outcome with a shorter treatment course was conducted.

Direct antiviral treatment of chronic hepatitis C in heart transplant recipients.

Direct-acting antiviral agents (DAAs) are a safe and effective treatment for chronic hepatitis C (CHC). This may be particularly valuable for patients with severe comorbidities or baseline conditions, including non-liver solid organ transplant. We report cases of two heart transplant recipients with CHC treated with DAAs (sofosbuvir and daclatasvir) achieving sustained virological response. Treatment was well tolerated and no relevant side effects were observed. The drug-drug interactions and graft function were carefully monitored.

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.

Infection of Retained Defibrillator Lead Fragment after Heart Transplant.

A 59-year old heart transplant recipient was admitted due to continuous pain in her left axilla. A purulent collection was found at the site of prior defibrillator placement, where a remnant proximal segment of an electric lead was found. Two years before, the patient had had pocket infection treated with revision, but without device extraction. The remnant lead was eventually removed transvenously without complications. This is the first description of infection complicating retention of lead fragments after heart transplant. The role of biofilm and net immune state on the persistence and late recurrence of infection is discussed.

Electrophysiological Adverse Effects of Direct Acting Antivirals in Patients With Chronic Hepatitis C.

Recently, several cases of symptomatic, sometimes fatal bradycardia during the first days of direct-acting antiviral (DAA) (eg, sofosbuvir [SOF]) administration have been reported. We analyzed in detail electrocardiographic (ECG) changes during SOF- or non-SOF-based chronic hepatitis C (CHC) treatment, specifically focusing on bradyarrhythmias. All 39 consecutive patients treated at our center with any interferon-free regimen between June and December 2015 were included in this study (26 SOF-based therapy vs 13 no-SOF interferon-free regimens). ECG tracings were obtained from all patients the first day of treatment and after 7, 14, and 28 days. ECG parameters (P-wave, QRS, QT interval, JT interval, Tapex -Tend interval duration) were compared between the 2 groups at baseline and at the 3 different time points during antiviral therapy. There were no cases of symptomatic bradycardia/syncope. In the SOF group, QTc duration rose after 1 week (from 424.3 to 431.2 milliseconds; P = .013) and returned to baseline during therapy. QT dispersion dropped since week 1 (from 85.6 to 67.2 milliseconds) and remained significantly reduced until the end of the observation period (72.9 msec) (P = .003). JT dispersion reduced up to week 2 (P = .010) and returned to baseline at week 4; in the no-SOF group, QRS dispersion transiently reduced (from 41 to 34.5 milliseconds, day 7). No other significant changes were observed in the remaining parameters. In CHC patients treated with SOF and other DAAs, ECG parameter changes were mild and/or transient and did not translate into clinically significant electrophysiological effects in the absence of amiodarone coadministration.