Monica Lanzoni

Hepatitis E: an old infection with new implications.

The availability of safe blood and blood products is an important public health issue. Improvements in donor screening and testing, pathogen inactivation1 and removal methods, the use of serological tests with greater diagnostic efficacy and the introduction of nucleic acid testing (NAT) have resulted in a substantial drop in transfusion-transmitted infections over the last two decades2. Nonetheless, blood supplies remain vulnerable to emerging and re-emerging infections. In recent years, numerous infectious agents found worldwide have been identified or reconsidered as potential threats to blood supplies3–5. Hepatitis E virus (HEV) has long been considered an enterically transmitted virus causing self-limiting acute viral hepatitis. The disease is endemic in many developing countries, but in recent years an increasing number of autochthonous and sporadic HEV infections have been described in developed countries6. This virus usually causes an acute self-limiting hepatitis, but in some cases fulminant hepatic failure resulting in morbidity and mortality may occur, especially in at-risk groups such as the elderly, pregnant women and patients with pre-existing liver disease or those who are immunocompromised. Furthermore, recent seroprevalence studies are questioning the concept of the low circulation of HEV in developed countries7. This narrative review aims at providing a comprehensive view of HEV and its possible “role” in transfusion medicine.

Plasma-derived medicinal products in Italy: information sources and flows.

For the purpose of a systematic analysis of the manufacturing, marketing and usage of plasma-derived medicinal products (PMPs), it is essential to define all stages of the medicinal product life-cycle and to properly identify all information sources suitable for detecting and quantifying the information related to the assessment of each stage. The PMPs present some peculiarities. Their biological active substances are obtained by an industrial extraction process of human plasma derived from voluntary donations, instead of chemical synthesis. As a raw material, plasma can be a vehicle of blood born infectious diseases. Therefore, the Italian and European legislations identified several measures aimed at reducing the risk of infection, such as: donor selection, biological validation tests, methods of pathogen removal and inactivation; moreover, the adoption of prescriptive measures is envisaged in order to guarantee both traceability and pharmacovigilance of all PMPs1–11. Another peculiar feature of PMPs is related to the ownership of the raw material and of the derived medicinal products. In Italy, as regards the national plasma collected by Regional Blood Transfusion Services, Regions and Autonomous Provinces (henceforth referred to as ‘Regions’) retain the ownership of both of them within the toll fractionation agreements with the authorised manufacturer. On the contrary, the commercial product ownership is assigned to pharmaceutical companies, which obtain the raw material from blood establishments in all other countries where plasma provision for commercial use is allowed. The aim of this manuscript is to provide an exhaustive critical description of all data sources available in Italy for the study and monitoring of the entire medicinal product life-cycle and then to highlight the degree of overlap of various information sources and to demonstrate the feasible analyses that might be developed using each of them.

The demand for human albumin in Italy.

Human albumin (HA) is a blood plasma protein produced in the liver. It constitutes about 60% of plasma proteins and is a physiological plasma-expander. However, its limited availability and high cost make it essential to define recommendations for its appropriate use, as an alternative to other therapeutic strategies including solutions of crystalloids and non-protein colloids. According to all official recommendations, the choice to use albumin rather than an artificial colloid strictly depends on the clinical situation of the patient1–6. HA is also used in all cases in which there is a contraindication to the use of non-protein colloids7. Based on clinical evidence, the 2009 guidance document of the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI)7 recommends the use of HA in acute conditions, which call for blood volume expansion and maintenance of adequate blood flow, as well as in some chronic conditions of low serum albumin levels. “There are some widely shared and fully agreed indications for the appropriate use of human albumin and indications that are occasionally appropriate, that is, when other criteria are fulfilled”7. In addition, in haemorrhagic shock HA should only be used as a second choice [i.e. when solutions of crystalloids or non-protein colloids (first choice treatment) have already been used at maximum doses without having produced a clinically adequate response] and in cases in which non-protein colloids are contraindicated7.

Feasibility study for the introduction of a new treatment Method for benign thyroid nodules in a teaching and research hospital

RATIONALE, AIMS AND OBJECTIVES Numerous scientific publications have confirmed that percutaneous laser thermal ablation (LTA) represents a possible therapeutic option in selected patients with benign thyroid nodules. A study was carried out to evaluate the feasibility of adopting the LTA technique to treat benign thyroid nodules in a teaching and research hospital in northern Italy. METHODS A cost analysis from a companys perspective determined the impact of adoption of the new technique on the overall Hospital budget, considering currently available equipment, infrastructure and personnel, equipment costs and treatment tariffs. RESULTS The cost analysis shows that, strictly from an economic point of view, any provision of the LTA technique will result as a loss on the Hospitals balance sheet. However, it does not estimate the extent of the impact on the overall budget because it did not evaluate the savings that such a technique would make with respect to alternative therapeutic treatments. Therefore, the Hospital policy management decided to extend the current agreement with a private authorized health care structure that already carries out LTA. Also, although difficult to express in economic terms, this new technique would undoubtedly raise the profile and enhance the reputation of the Hospital. CONCLUSIONS Using the new technique in these patients could cut costs for the entire regional health care system, widen the experience of the Hospitals endocrinology team and offer the potential for the procedure also to be provided by operators on a freelance basis within the Hospital.

Clinical use and the Italian demand for prothrombin complex concentrates

Prothrombin complex concentrates (PCCs) are an important plasma-derived therapeutic option for the rapid correction of deficiency of vitamin-K dependent clotting factors1. PCCs are produced by ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools after removal of antithrombin and factor (F) XI2. Different processing techniques involving ion exchangers permit the production of either three- (i.e., FII, FIX and FX) or four-factor (i.e., FII, FVII, FIX and FX) concentrates with a final overall clotting factor concentration approximately 25 times higher than in normal plasma (Tables I and ​andIIII)3. To prevent activation of these factors, most PCCs contain heparin. In addition, they may also contain the physiological inhibitors of coagulation protein C and protein S. PCCs are standardised according to their FIX content and are subjected to viral inactivation processes, both by physical (vapour, heating) and chemical (solvent detergent treatment) methods. Table I Three-factors prothrombin complex concentrates brief fact sheet. Table II Four-factors prothrombin complex concentrates brief fact sheet. Various preparations are commercially available in Italy, as reported in Tables III4 and ​andIVIV4. Table III Products containing three-factors prothrombin complex concentrates currently available on the Italian market. Table IV Products containing four-factors prothrombin complex concentrates currently available on the Italian market. Clinical indications of prothrombin complex concentrates PCCs were originally developed for the treatment of haemophilia B patients; however, due to the availability in recent years of plasma-derived high purity FIX concentrates and, more recently, of a recombinant FIX product, they have progressively shifted from this clinical indication towards the replacement of vitamin K-dependent clotting factors. The current indications for the clinical use of PCCs are mostly based on retrospective or observational studies, as very few controlled randomised clinical trials have been conducted so far in this setting3. Therefore, PCCs are used for prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX; if PCCs are not available, fresh frozen plasma (FFP) can be used as an alternative. However, solvent/detergent plasma should be preferred in patients with inherited coagulation disorders who need replacement therapy when virus-inactivated single-factor concentrates are not available5. Similarly, in patients with congenital deficiency of FVII or FIX, PCCs can be used only when the specific clotting factor concentrate is not available. In patients with acquired deficiencies of factors of the prothrombin complex (due to severe liver disease, blood loss or dilution), PCCs could be administered, as a second choice alternative to FFP, taking into account that the potential utility of PCCs in (bleeding) patients not being treated with vitamin K antagonist (VKA) is only based on limited evidence from retrospective studies involving few patients6 and that the risk of thrombosis is higher with PCC than with plasma7–10. Thus, the current clinical indications for PCC use include: - patients on VKA therapy requiring emergency reversal in case of bleeding or need for urgent surgery (grade of recommendation: 1B)7,9,11–19. PCCs are able to completely reverse the warfarin-induced anticoagulation within 10 minutes but the infused clotting factors have a finite half-life. Therefore, intravenous vitamin K (10 mg) should be given with the PCC. The recently published ACCP (American College of Chest Physicians) guidelines suggest, for patients with VKA-associated major bleeding, rapid reversal of anticoagulation with four-factor PCCs, due to the presence of FVII (Grade of recommendation: 2C)19; - prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX (grade of recommendation: 2C)7,9,20,21; - prophylaxis or treatment of bleeding in patients with congenital deficiency of FVII or FIX if the specific clotting factor concentrate is not available (grade of recommendation: 2C)7,9,20,21; - patients with acquired deficiencies of factors of the PCCs and limitations to the use of FFP, such as those at a risk of circulatory overload or with the need for urgent restoration of normal haemostasis (grade of recommendation: 2C)6,7,9,22. Quantification and characterisation of the three-factors prothrombin complex concentrates demand Tables V and ​andVIVI show both the absolute and standardised demand (expressed in I.U. and per capita I.U., respectively) for three-factors PCCs in the period 2007–2011, at the national and regional level, according to medicinal products traceability data23. Table V Quantification of total (public and private) demand for three-factors prothrombin complex concentrates (expressed in international units) in Italy and Italian regions, from 2007 to 2011. Table VI Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (expressed in per capita international units) in Italy and Italian regions, from 2007 to 2011. The three-factors PCCs national demand showed an increase of about 65%, from 15,645,100 I.U. in 2007 to 25,782,200 I.U. in 2011 (Table V), with a per capita consumption of 0.4 I.U. in 2011 (Table VI). Regions with the highest per capita demand are Aosta Valley and Emilia-Romagna, as well as the Autonomous Province (AP) of Bolzano with about 2 and 1 I.U., respectively (Figure 1), with a percentage change from the national mean demand of +313%, +84%, and +156%, respectively (Figure 2). Figure 1 Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (in per capita international units), in Italy and Italian regions, year 2011. Figure 2 Percentage change from the national mean value of standardised regional demand of prothrombin complex concentrates (per capita international units) in 2011. Regions with the lowest observed demand are Calabria, Latium and Abruzzo with 0.1, 0.2, and 0.3 per capita I.U., with a percentage departure of −71%, −46%, and −42% from the national mean value (Figure 2). The distribution of PCCs takes place almost exclusively through the public health facilities distribution channel23. Aosta Valley, the AP of Bolzano and Emilia-Romagna have the largest demand through this channel, i.e. about 2 per capita I.U. for the first Region and about 1 I.U. for the latter two, respectively (Figure 3). Figure 3 Demand for three-factors prothrombin complex concentrates (per capita international units), in Italy and Italian regions, by public health facilities channel, year 2011. It is also necessary to underline the use of the pharmacies open to the public channel in Latium and Campania, which represents on average of about 6% of the total demand of both Regions (data reported elsewhere)24.

The demand for polyvalent immunoglobulins in Italy.

Polyvalent immunoglobulins (IG) for subcutaneous administration (SCIG) and for intravascular administration (IVIG) are used in the replacement therapy of the immunodeficiencies and in the treatment of autoimmune pathologies or systemic inflammatory processes (Tables I and ​andIIII)1,2. However, in the clinical practice IGs are often used more extensively than what the authorised indications allow (“off-label” use) even if, in this case, the use is not always supported by available scientific evidence1–4. Table I Polyvalent immunoglobulins, for subcutaneous administration, brief fact sheet. Table II Polyvalent immunoglobulins, for intravascular administration, brief fact sheet IGs are isolated from pooled plasma that has been donated by 1,000–100,000 people. With such large pools of donors, the entire spectrum of antibodies produced by the population is represented in the final product. IVIG contains 8–15 g/dL of protein, of which >90% is IgG. IVIG is further purified to remove or inactivate infectious agents and prevent aggregates1,3–5.

Public expenditure for plasma-derived and recombinant medicinal products in Italy.

BACKGROUND In Italy, the supply of plasma-derived medicinal products funded by the National Health Service can be through public healthcare facilities, accredited pharmacies or toll fractionation agreements between Regions and the manufacturer. Pharmaceutical public expenditure includes the supply related to the first two channels and costs can significantly vary because of channel-specific price reductions. This paper describes 2011 public expenditure for plasma-derived medicinal products purchased on the market, as well as the cost analysis per active substance. MATERIALS AND METHODS Analysis of the usage of plasma-derived medicinal products and of the related expenditure in public facilities has been carried out using medicinal product traceability data. The analysis related to the accredited pharmacies channel has been carried out using quantities for every medicinal package recorded by Pharmacy Associations and applying reference prices in force on March 1(st), 2012 as well as discounts for the accredited pharmaceutical expenditure imposed by law. RESULTS At national and regional level, total and total per capita expenditures on plasma-derived medicinal products by market channel and funded by the National Health Service are shown. Analysis was conducted considering the active substances in three groups: substances included in toll fractionation agreements, recombinant coagulation factors, and other substances not included in toll fractionation agreements. In 2011, the national expenditure estimate for plasma-derived and recombinant medicinal product acquisition on the market was about € 535 million. DISCUSSION The purchased volumes and mean purchased prices per unit of each substance have a significant influence on the observed regional variability of the pharmaceutical public expenditure. A strategy of regional comparison aimed at both sharing a national range of reference for purchase prices and evaluating modalities for centralised purchasing is desirable.

Clinical use and the Italian demand for antithrombin

Antithrombin (AT) is a single-stranded glycoprotein synthesised in the liver with a plasma concentration of approximately 150 μg/mL and a molecular weight of approximately 59,000 Da1. It is a complex molecule with multiple biologically important properties. It is a serine protease inhibitor (serpin) that inactivates many enzymes in the coagulation cascade2,3. Indeed, it is the key inhibitor of the coagulation system and is estimated to provide 80% of the inhibitory activity against thrombin but it also inhibits activated factors X, IX, VII, XI, and XII. AT has a great affinity for thrombin and is also known as heparin cofactor as it is responsible for the anticoagulant effect of heparin. Heparins markedly accelerate the rate of complex formation between AT and the serine proteases thus increasing AT inhibitory activity 5,000–40,000-fold4. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Other anti-inflammatory properties of AT involve direct interactions with endothelial cells, leading to the release of prostacyclin, which also mediates its anti-platelet effect3. In addition, recent evidence of interactions of the endothelial cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with a heparin-like molecule in matrix provide the rationale for further investigation into the possible role of AT as a potent anti-angiogenic factor5. Normal values of AT activity in the plasma range from 80% to 120%. In normal conditions, its biological half-life is 1.5–2.5 days. In conditions of acquired deficiency and in the presence of heparin, the half-life of AT can be notably shorter, being reduced to only a few hours6.

Trauma e discontinuità temporale nei minori vittime di disastri naturali. Il Test de trois dessins: Avant, pendant et avenir

Le catastrofi naturali sono eventi traumatici in quanto possono generare fratture esistenziali nella vita dell’individuo. Il disegno e stato impiegato per rilevare la presenza del trauma psichico nel bambino in quanto puo svelare contenuti traumatici. Lo studio e finalizzato a esplorare la capacita dello strumento grafico del Test de trois dessins: avant, pendant et avenir di mettere in scena il trauma psichico nei bambini vittime di terremoto. Il campione e composto da 248 bambini, dai 5 ai 15 anni, vittime dei sismi in Abruzzo, Cile e Haiti. Lo studio presenta una metodologia mista, in cui al test grafico si accompagnano delle scale di misura delle sintomatologie post-traumatiche. I risultati mostrano l’efficacia dello strumento nel mettere in scena aspetti peculiari dell’esperienza traumatica relativi alla discontinuita temporale e alla frattura esistenziale generata.

Definition of an organisational model for the prevention and reduction of health and social impacts of inherited bleeding disorders.

INTRODUCTION Due to the increase in life expectancy, patients with haemophilia and other inherited bleeding disorders are experiencing age-related comorbidities that present new challenges. In order to meet current and emerging needs, a model for healthcare pathways was developed through a project funded by the Italian Ministry of Health. The project aimed to prevent or reduce the social-health burden of the disease and its complications. MATERIAL AND METHODS The National Blood Centre appointed a panel of experts comprising clinicians, patients, National and Regional Health Authority representatives. Following an analysis of the scientific and regulatory references, the panel drafted a technical proposal containing recommendations for Regional Health Authorities, which has been formally submitted to the Ministry of Health. Finally, a set of indicators to monitor haemophilia care provision has been defined. RESULTS In the technical document, the panel of experts proposed the adoption of health policy recommendations summarised in areas, such as: multidisciplinary integrated approach for optimal healthcare provision; networking and protocols for emergency care; home therapy; registries/databases; replacement therapy supply and distribution; recruitment and training of experts in bleeding disorders. The recommendations became the content of proposal of agreement between the Government and the Regions. Monitoring and evaluation of haemophilia care through the set of established indicators was partially performed due to limited available data. CONCLUSIONS The project provided recommendations for the clinical and organisational management of patient with haemophilia. A particular concern was given to those areas that play a critical role in the comorbidities and complications prevention. Recommendations are expected to harmonise healthcare care delivery across regional networks and building the foundation for the national haemophilia network.