Comorbidity in lipoprotein apheresis: Their role in the era of new lipid-lowering therapies.

BACKGROUND: Despite advance in pharmacotherapy of lipid disorders, lipoprotein apheresis (LA) plays a leading role in the management of severe hypercholesterolemia and in atherosclerosis prevention. METHODS: Aim of this study was to retrospectively evaluate Charlson Comorbidity Index (CCI), presence of major comorbidity, and/or concomitant polypharmacy (definite as 5+ drugs daily) in patients with inherited dyslipidemias on chronic LA. RESULTS: Since 1994, we performed more than 500 LA treatment/year and followed a total of 83 patients (age 56 [47-65] years, male 75%). In subjects with more than 5 years of LA treatment (38 patients, age 54 [45-62] years, male 66%), at the end of the observation time (9 [7-16] years), patients had higher CCI, polypharmacy, anemia, heart failure, peptic ulcer disease, and benign prostatic hyperplasia. DISCUSSION: Even in the era of new lipid-lowering therapies, the LA treatment established itself as a safe and lifesaving intervention. Patients on chronic LA require a multidisciplinary approach to address their comorbidity and the apheresis unit's medical staff (doctors and nurses) play a pivotal role creating a bridge toward the general practitioner and other specialists for overcoming clinical issues.

Alirocumab in lipoprotein apheresis: A synergy for patients with high-Lp(a).

Until today lipoprotein apheresis (LA) is considered the most effective treatment for patients with high-Lp(a) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are often combined with LA to dampen the rebound in lipoprotein concentrations. The aim of the present work is to evaluate the effect of dose-adjustment strategy for alirocumab in a small cohort of high-Lp(a) subjects with ischemic heart disease and in chronic LA treatment. Chronic LA effect on Lp(a) levels is a significant reduction in pre-LA Lp(a) concentrations compared to native Lp(a) value (118 [116-119] mg/dl vs 150 [137-155] mg/dl; p < 0.001). Furthermore, the administration of Arilocumab 75 mg after 7 days from LA shows a significant pre-LA reduction in the Lp(a) concentrations respect to those obtained with administration immediately after the LA treatment. In high-Lp(a) patients treated with chronic LA the deferred addition of alirocumab, resulted in lower LDL-cholesterol and Lp(a) values.

Consensus document on Lipoprotein(a) from the Italian Society for the Study of Atherosclerosis (SISA).

AIMS: In view of the consolidating evidence on the causal role of Lp(a) in cardiovascular disease, the Italian Society for the Study of Atherosclerosis (SISA) has assembled a consensus on Lp(a) genetics and epidemiology, together with recommendations for its measurement and current and emerging therapeutic approaches to reduce its plasma levels. Data on the Italian population are also provided. DATA SYNTHESIS: Lp(a) is constituted by one apo(a) molecule and a lipoprotein closely resembling to a low-density lipoprotein (LDL). Its similarity with an LDL, together with its ability to carry oxidized phospholipids are considered the two main features making Lp(a) harmful for cardiovascular health. Plasma Lp(a) concentrations vary over about 1000 folds in humans and are genetically determined, thus they are quite stable in any individual. Mendelian Randomization studies have suggested a causal role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis and observational studies indicate a linear direct correlation between cardiovascular disease and Lp(a) plasma levels. Lp(a) measurement is strongly recommended once in a patient's lifetime, particularly in FH subjects, but also as part of the initial lipid screening to assess cardiovascular risk. The apo(a) size polymorphism represents a challenge for Lp(a) measurement in plasma, but new strategies are overcoming these difficulties. A reduction of Lp(a) levels can be currently attained only by plasma apheresis and, moderately, with PCSK9 inhibitor treatment. CONCLUSIONS: Awaiting the approval of selective Lp(a)-lowering drugs, an intensive management of the other risk factors for individuals with elevated Lp(a) levels is strongly recommended.

Cefditoren: a clinical overview.

Cefditoren is an oral third-generation cephalosporin with a large spectrum activity against Gram-negative and Gram-positive bacteria which are reported to be responsible for respiratory tract and skin and skin structure infections. In this work we reviewed the pharmacodynamics, pharmacokinetics, and the main clinical indications of cefditoren. Similarly to other beta-lactams, cefditoren is a time-dependent antibiotic, and its "best" PK/PD target is probably 40% dosing interval time > 4- 5-fold MIC and 40-70% dosing interval time > 4- 5-fold MIC for bacteriostatic and bactericidal effect, respectively. In fasting patients oral bioavailability is low and increases when the drug is taken with food. This cephalosporin has significant bactericidal activity against S. pneumoniae (both penicillin-susceptible and penicillin-resistant strains), S. pyogenes, H. Influenzae and M. catarrhalis, as well as methicillin-susceptible S. aureus (MSSA). Regarding Enterobacterales, cefditoren has very low MICs90 against K. pneumoniae andE. coli but is not active against AmpC-, ESBL- and carbapenemase-producer' strains. Licensed indications are treatment of exacerbations of chronic bronchitis,acute rhinosinusitis, otitis media, upper respiratory tract infections (pharyngitis/tonsillitis), lower community-acquired respiratory tract infections (LRTIs), and skin and skin-structure infections (SSTI). Cefditoren might have a role in switching from parenteral to oral therapy in acute pyelonephritis and LRTIs. with a reduction of adverse effects and hospital costs. Eventually, due to its supposed binding to enterococcal penicillin binding proteins (PBPs) cefditoren, in combination with other beta-lactams, might have a role in partial oral enterococcal endocarditis treatment..

Monkeypox virus transmission in tattoo parlor.

In monkeypox virus (MPXV) transmission caused by contaminated material, we have to consider that recently the outbreak of several MPXV cases was linked to tattoo parlors in Cadiz, Spain. These tattoo parlors did not cause a single outbreak, but instead are an established transmission route for MPXV, underscoring the need for increased awareness. We recommend increasing awareness among tattooists and piercers not only to protect their own safety and health, but also to prevent spreading the virus to their customers. Personal protective equipment such as gloves should be utilized and vaccination can be considered for those at risk of occupational exposure.

Lactococcus lactis blood products contamination resulting in fatal human case: insights from a forensic case.

Lactococcus species are micro-aerophilic Gram positive bacteria characterized by low virulence features and other biotechnological properties of industrial interest. They are thus widely employed in food fermentation processes. Despite its low pathogenic potential and food grade safety, L. lactis may, however, rarely cause infections, especially among immunocompromised hosts. Moreover, the growing complexity of patients implies increased detections of such infections. This said, there is a paucity of data concerning L. lactis infections from infusion of blood transfusion products. To our knowledge, this is the first case of L. lactis infection from transfusion of blood products, as observed in an 82-year-old Caucasian male undergoing weekly platelet and blood transfusion due to sustained severe thrombocytopenia. Albeit minimally pathogenic, L. lactis should be considered for thorough testing, especially in the case of human-derived infusion products such as platelets due to their storage requirements for extended times at room temperature and their use in immunocompromised and critically ill subjects.

Pragmatic overview on acute bacterial and fungal infections of the central nervous system: a holistic update from diagnosis to treatment.

Although progress has led to a drop in infections, meningitis still represents a threat worldwide, affecting some areas more than others. As a medical emergency, it requires prompt recognition and treatment. Moreover, diagnosis relies on invasive methods, while representing a tug-of-war with timely therapeutic interventions, since delays are burdened by mortality and life-long sequalae. While counterbalancing the overuse of antimicrobials, it is imperative to assess correct interventions in order to optimize treatments and reduce negative outcomes. Because the drop in mortality and consequences has been consistent, although not as impactful as with other vaccine-preventable diseases, the WHO has traced a roadmap detailing actions to reduce the meningitis burden by 2030. There are currently no updated guidelines, whereas novel diagnostic methods as well as pharmacological interventions are increasing, along with the shifting epidemiology. In light of the above, this paper wishes to summarize existing data and evidences and suggest potential novel solutions to a complex problem.

Identification of COVID-19 patients at risk of hospital admission and mortality: a European multicentre retrospective analysis of mid-regional pro-adrenomedullin.

BACKGROUND: Mid-Regional pro-Adrenomedullin (MR-proADM) is an inflammatory biomarker that improves the prognostic assessment of patients with sepsis, septic shock and organ failure. Previous studies of MR-proADM have primarily focussed on bacterial infections. A limited number of small and monocentric studies have examined MR-proADM as a prognostic factor in patients infected with SARS-CoV-2, however there is need for multicenter validation. An evaluation of its utility in predicting need for hospitalisation in viral infections was also performed. METHODS: An observational retrospective analysis of 1861 patients, with SARS-CoV-2 confirmed by RT-qPCR, from 10 hospitals across Europe was performed. Biomarkers, taken upon presentation to Emergency Departments (ED), clinical scores, patient demographics and outcomes were collected. Multiclass random forest classifier models were generated as well as calculation of area under the curve analysis. The primary endpoint was hospital admission with and without death. RESULTS: Patients suitable for safe discharge from Emergency Departments could be identified through an MR-proADM value of ≤ 1.02 nmol/L in combination with a CRP (C-Reactive Protein) of ≤ 20.2 mg/L and age ≤ 64, or in combination with a SOFA (Sequential Organ Failure Assessment) score < 2 if MR-proADM was ≤ 0.83 nmol/L regardless of age. Those at an increased risk of mortality could be identified upon presentation to secondary care with an MR-proADM value of > 0.85 nmol/L, in combination with a SOFA score ≥ 2 and LDH > 720 U/L, or in combination with a CRP > 29.26 mg/L and age ≤ 64, when MR-proADM was > 1.02 nmol/L. CONCLUSIONS: This international study suggests that for patients presenting to the ED with confirmed SARS-CoV-2 infection, MR-proADM in combination with age and CRP or with the patient's SOFA score could identify patients at low risk where outpatient treatment may be safe.

Evaluation of qualitative and semi-quantitative cut offs for rapid diagnostic lateral flow test in relation to serology for the detection of SARS-CoV-2 antibodies: findings of a prospective study.

BACKGROUND: There is limited information to compare the qualitative and semi-quantitative performance of rapid diagnostic tests (RDT) and serology for the assessment of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, the objective of the study was (a) to compare the efficacy of SARS-CoV-2 antibody detection between RDT and laboratory serology, trying to identify appropriate semi-quantitative cut-offs for RDT in relation with quantitative serology values and to (b) evaluate diagnostic accuracy of RDT compared to the NAAT gold standard in an unselected adult population. METHODS: SARS-CoV-2 antibodies were simultaneously measured with lateral flow immunochromatographic assays (LFA), the Cellex qSARS-CoV-2 IgG/IgM Rapid Test (by capillary blood), the iFlash-SARS-CoV-2 IgG/IgM chemiluminescent immunoassay (CLIA) (by venous blood) and the nucleic acid amplification test (NAAT) in samples from in- and out-patients with confirmed, suspected and negative diagnosis of coronavirus disease 2019 (COVID-19) attending Udine Hospital (Italy) (March-May 2020). Interpretation of RDT was qualitative (positive/negative) and semi-quantitative based on a chromatographic intensity scale (negative, weak positive, positive). RESULTS: Overall, 720 paired antibody measures were performed on 858 patients. The qualitative and semiquantitative agreement analysis performed in the whole sample between LFA and CLIA provided a Kendall's tau of 0.578 (p < 0.001) and of 0.623 (p < 0.001), respectively, for IgM and IgG. In patients with a diagnosis of COVID-19, accordance between LFA and CLIA was maintained as a function of time from the onset of COVID-19 disease and the severity of disease both for qualitative and semi-quantitative assessments. RDT compared to the NAAT gold standard in 858 patients showed 78.5% sensitivity (95% CI 75.1%-81.7%) and 94.1% specificity (95% CI 90.4%-96.8%), with variable accordance depending on the timing from symptom onset. CONCLUSION: The RDT used in our study can be a non-invasive and reliable alternative to serological tests and facilitate both qualitative and a semi-quantitative antibody detection in COVID-19.

Is treating severe He FH so easy? A combined treatment between lipoprotein apheresis and PCSK9 inhibitors.

Despite advance in pharmacotherapy of lipid disorders, many heterozygous Familial Hypercholesterolemia patients do not achieve a desirable lipid target to significantly reduce the risk of atherosclerotic cardiovascular disease. The aim of the present work is to evaluate the interaction between Lipoprotein apheresis (LA) and PCSK9i in a small FH cohort in which the guidelines therapeutic target is not achieved. During one year, together with a complete adherence to PCSK9i therapy, we recorded a 3 to 5 LA sessions less per year in each patient. This therapeutic approach suggests: i) the possibility of increasing the number of patients treated with LA, ii) the improvement of their quality of life, and iii) the costs reduction for the single patient-treatment.

Approach to patients with COVID-19 disease: the procedure in Udine.

Coronavirus disease 2019 poses a serious threat to public health. The protocol developed at the Azienda Sanitaria Universitaria Friuli Centrale (Italy) is based on clinical data, laboratory tests, chest echography and HRCT. Several therapeutic options are considered, since patients vary in disease severity, evolution and co-morbidities and because so far there are no clear indications about therapeutic strategy based on randomized clinical trial. In this protocol chest echography has a central role in categorizing patient status, follow-up and decision-making.

Recognition in Emergency Department of Septic Patients at Higher Risk of Death: Beware of Patients without Fever.

Background and Objectives: Chances of surviving sepsis increase markedly upon prompt diagnosis and treatment. As most sepsis cases initially show-up in the Emergency Department (ED), early recognition of a septic patient has a pivotal role in sepsis management, despite the lack of precise guidelines. The aim of this study was to identify the most accurate predictors of in-hospital mortality outcome in septic patients admitted to the ED. Materials and Methods: We compared 651 patients admitted to ED for sepsis (cases) with 363 controls (non-septic patients). A Bayesian mean multivariate logistic regression model was performed in order to identify the most accurate predictors of in-hospital mortality outcomes in septic patients. Results: Septic shock and positive qSOFA were identified as risk factors for in-hospital mortality among septic patients admitted to the ED. Hyperthermia was a protective factor for in-hospital mortality. Conclusions: Physicians should bear in mind that fever is not a criterium for defining sepsis; according to our results, absence of fever upon presentation might be indicative of greater severity and diagnosis of sepsis should not be delayed.

Personalized machine learning approach to predict candidemia in medical wards.

PURPOSE: Candidemia is a highly lethal infection; several scores have been developed to assist the diagnosis process and recently different models have been proposed. Aim of this work was to assess predictive performance of a Random Forest (RF) algorithm for early detection of candidemia in the internal medical wards (IMWs). METHODS: A set of 42 potential predictors was acquired in a sample of 295 patients (male: 142, age: 72 ± 15 years; candidemia: 157/295; bacteremia: 138/295). Using tenfold cross-validation, a RF algorithm was compared with a classic stepwise multivariable logistic regression model; discriminative performance was assessed by C-statistics, sensitivity and specificity, while calibration was evaluated by Hosmer-Lemeshow test. RESULTS: The best tuned RF algorithm demonstrated excellent discrimination (C-statistics = 0.874 ± 0.003, sensitivity = 84.24% ± 0.67%, specificity = 91% ± 2.63%) and calibration (Hosmer-Lemeshow statistics = 12.779 ± 1.369, p = 0.120), markedly greater than the ones guaranteed by the classic stepwise logistic regression (C-statistics = 0.829 ± 0.011, sensitivity = 80.21% ± 1.67%, specificity = 84.81% ± 2.68%; Hosmer-Lemeshow statistics = 38.182 ± 15.983, p < 0.001). In addition, RF suggests a major role of in-hospital antibiotic treatment with microbioma highly impacting antimicrobials (MHIA) that are found as a fundamental risk of candidemia, further enhanced by TPN. When in-hospital MHIA therapy is not performed, PICC is the dominant risk factor for candidemia, again enhanced by TPN. When PICC is not used and MHIA therapy is not performed, the risk of candidemia is minimum, slightly increased by in-hospital antibiotic therapy. CONCLUSION: RF accurately estimates the risk of candidemia in patients admitted to IMWs. Machine learning technique might help to identify patients at high risk of candidemia, reduce the delay in empirical treatment and improve appropriateness in antifungal prescription.

Neonatal pertussis diagnosis: low procalcitonin level and high lymphocyte count are able to discriminate pertussis from bacterial and viral infections.

Pertussis is quite frequent and severe among infants; therefore, rapid diagnosis and timely targeted therapy are essential. Although a molecular test for etiological diagnosis is now available, it may not be available everywhere, and therefore adjunctive diagnostic tests are still useful for presumptive diagnosis. We describe the use of procalcitonin (PCT) and lymphocyte count to discriminate among pertussis, bacterial and viral infections. Fourteen infants per group were studied. The decision tree, built considering all available variables, showed a major role of PCT in predicting the different groups. A PCT value equal to or greater than 0.75 ng/ml selected for bacterial infections. A PCT value lower than 0.75 ng/ml and a lymphocyte count equal to or greater than 10,400/mm3 selected the subjects with pertussis, while a lymphocyte count lower than 10,400/mm3 selected for viral etiology. PCT should be used in the diagnosis of infants suspected of having pertussis.

A prediction rule for early recognition of patients with candidemia in Internal Medicine: results from an Italian, multicentric, case-control study.

PURPOSE: Increasing prevalence of candidemia in Internal Medicine wards (IMWs) has been reported in recent years, but risk factors for candida bloodstream infection in patients admitted to IMW may differ from those known in other settings. The aim of this study was to identify risk factors and define a prediction rule for the early recognition of the risk of candidemia in IMW inpatients. METHODS: This was a multicentric, retrospective, observational case-control study on non-neutropenic patients with candidemia admitted to IMWs of four large Italian Hospitals. Each eligible patient with candidemia (case) was matched to a control with bacteremia. Stepwise logistic regression analyses were performed. RESULTS: Overall, 300 patients (150 cases and 150 controls) were enrolled. The following factors were associated with an increased risk of candidemia and weighted to build a score: total parenteral nutrition (OR 2.45, p = 0.008; 1 point); central venous catheter (OR 2.19, p = 0.031; 1 point); peripherally inserted central catheter (OR 5.63, p < 0.0001; 3 points), antibiotic treatment prior (OR 2.06; p = 0.059; 1 point) and during hospitalization (OR2.38, p = 0.033; 1 point); neurological disability (OR 2.25, p = 0.01; 1 point); and previous hospitalization within 3 months (OR 1.56, p = 0.163; 1 point). At ROC curve analysis, a final score ≥ 4 showed 84% sensitivity, 76% specificity, and 80% accuracy in predicting the risk of candidemia. CONCLUSIONS: The proposed scoring system showed to be a simple and highly performing tool in distinguishing bloodstream infections due to Candida and bacteria in patients admitted to IMW. The proposed rule might help to reduce delay in empirical treatment and improve appropriateness in antifungal prescription in septic patients.

Reduced incidence of cardiovascular events in hyper-Lp(a) patients on lipoprotein apheresis. The G.I.L.A. (Gruppo Interdisciplinare Aferesi Lipoproteica) pilot study.

BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease. METHODS: We collected data of 23 patients (mean age 63 ± 9 years, male 77%; from hospital of Pisa 11/23, Pistoia 7/23, Verona 2/23, Padova 2/23 and Ferrara 1/23), with hyper-Lp(a), pre-apheresis LDL-cholesterol <100 mg/dL, cardiovascular disease, on maximally tolerated lipid lowering therapy and LA treatment (median 7 years, interquartile range 3-9 years). The LA treatment was performed by heparin-induced LDL precipitation apheresis (16/23), dextran-sulphate (4/23), cascade filtration (2/23) and immunoadsorption (1/23). The time lapse between first cardiovascular event and beginning of apheresis was 6 years (interquartile range 1-12 years). RESULTS: The recorded ACVE, before and after the LA treatment inception, were 40 and 10 respectively (p < 0.05), notably, the AVCE rates/year were 0.43 and 0.11 respectively (p < 0.05) with a 74% reduction of event occurrence. CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with hyper-Lp(a) and chronic ischemic heart disease on maximally tolerated lipid lowering therapy.