Prevalence, incidence and residual risk of transfusion-transmitted hepatitis B virus infection in Italy from 2009 to 2018.

BACKGROUND: In Italy, the use of nucleic acid testing for hepatitis B virus (HBV) in donor screening has allowed the detection of infections in the window phase, as well as the presence of occult infections which could potentially be transmitted. The aim of this study was to analyse the trends of epidemiological data focused on HBV infection in blood donors and to estimate the residual risk of transmitting HBV from both the window phase and occult infection over a 10-year period in Italy. MATERIALS AND METHODS: Data were obtained from the Italian Haemovigilance System which includes the results of screening tests for transfusion transmissible infections. During the period of this survey (2009-2018), the molecular methods used for HBV screening were transcription-mediated amplification and polymerase chain reaction tests. Prevalence and incidence were calculated. The residual risk was estimated by applying the incidence-window period model for acute cases and a more recently reported model for estimating the risk due to occult infections. RESULTS: A total of 17,424,535 blood donors and 30,842,794 donations were tested for HBV. Altogether, 6,250 donors tested positive for HBV markers: 4,782 (175.6×105) were first time donors and 1,468 (10.0×105) were repeat donors. The prevalence of HBV markers in first time donors was 275.9×105 in 2009, declining to 143.6×105 in 2018. The incidence of new infections was 3.37×105 in 2009 and 2.17×105 in 2018. The overall residual risk for HBV amounted to 1 in 2,566,854 donations calculated as the sum of risks of both acute infections in the window period (1 in 5,835,306 donations) and occult infections (1 in 4,582,270 blood units). DISCUSSION: In Italy, the residual risk of transfusing a blood unit infected with HBV, both from window phase and occult infections, is currently very low, amounting to levels that can be considered tolerable.

The growing importance of achieving national self-sufficiency in immunoglobulin in Italy. The emergence of a national imperative.

Since the inception of industrial plasma fractionation during the Second World War, a succession of protein therapies isolated from plasma have determined the volume of plasma requiring collection, and have also shaped the economics of the industry. These so-called plasma drivers have successively included albumin, coagulation Factor VIII (FVIII) and, for the past thirty years, intravenously (IV) and subcutaneously (SC) administered immunoglobulin (IG) solutions. The sale of IG underpins the profitability of the industry and has experienced continuous growth over the past decades, as the result of growing clinical demand. Modelling this demand using decision analysis indicates that supplying the evidence-based indications for IG therapies will generate a need for IG which exceeds the current plasma collection capacity of most countries. A notable exception to this situation is the United States (US) of America, whose population of compensated plasma donors generates two thirds of the global supply of plasma for fractionation. The US is also the leading consumer of IG, and its health care providers pay the highest price for the product globally. Shortages of IG occur whenever the demand for the product outstrips the supply. Current shortages, following other historical periods of shortage, threaten the well-being of patients dependant on these products and incur heavy costs on health systems. In Italy, the national blood system, which is based on voluntary unpaid donors, reflects a policy of national self-sufficiency in blood-derived therapies (a strategic objective of the national blood system itself), based on solidarity as an ethical principle. This system has increased the collection of plasma for fractionation by 3.8% per annum over 2008-2017, in accordance to a plan for plasma procurement targeting a collection rate of 14.1 L of plasma per thousand (103) population by 2020. Over the same period, IG usage has increased by 8.5/per annum, to 89.2 g IG/103 population. In this paper, we review the factors which, increasingly, are causing an imbalance between the global supply and demand for IG, and we assess Italy's capacity to ensure that increasing this level of independence is no longer simply an ethical, but also an economic imperative, with implications for the security of Italy's health system.

Red blood cell alloimmunisation in transfusion-dependent thalassaemia: a systematic review.

BACKGROUND: Chronic red blood cell transfusion is the first-line treatment for severe forms of thalassaemia. This therapy is, however, hampered by a number of adverse effects, including red blood cell alloimmunisation. The aim of this systematic review was to collect the current literature data on erythrocyte alloimmunisation. MATERIALS AND METHODS: We performed a systematic search of the literature which identified 41 cohort studies involving 9,256 patients. RESULTS: The prevalence of erythrocyte alloimmunisation was 11.4% (95% CI: 9.3-13.9%) with a higher rate of alloimmunisation against antigens of the Rh (52.4%) and Kell (25.6%) systems. Overall, alloantibodies against antigens belonging to the Rh and Kell systems accounted for 78% of the cases. A higher prevalence of red blood cell alloimmunisation was found in patients with thalassaemia intermedia compared to that among patients with thalassaemia major (15.5 vs 12.8%). DISCUSSION: Matching transfusion-dependent thalassaemia patients and red blood cell units for Rh and Kell antigens should be able to reduce the risk of red blood cell alloimmunisation by about 80%.

Prevalence, incidence and residual risk of transfusion-transmitted hepatitis C virus and human immunodeficiency virus after the implementation of nucleic acid testing in Italy: a 7-year (2009-2015) survey.

BACKGROUND: In Italy nucleic acid testing (NAT) became mandatory for hepatitis C virus (HCV) in 2002 and for human immunodeficiency virus (HIV) and hepatitis B virus in 2008. The aim of this study was to monitor the incidence and prevalence of HIV and HCV infections in Italian blood donors and the current residual risk of these infections after the introduction of NAT. MATERIALS AND METHODS: The Italian national blood surveillance system includes data from tests used to screen for transfusion-transmissible infections. During the period of this survey (2009-2015), the NAT methods used were the transcription-mediated amplification test, for individual donor testing, and polymerase chain reaction analysis, mainly for pools of six donors. Prevalence and incidence were calculated. Three published formulae were applied to estimate the residual risk (the window period ratio model and the formulae recommended by the European Medicines Agency and the World Health Organization). RESULTS: Overall, 12,258,587 blood donors and 21,808,352 donations were tested for HCV and HIV. The prevalence of HCV decreased from 110.3×105 to 58.9×105 in years 2009 and 2015, respectively, while that of HIV remained stable over time (15.5×105 vs 15.4×105). The incidence of HCV decreased from 3.19×105 in 2009 to 1.58×105 in 2015, while the incidence of HIV did not show any significant fluctuations (average incidence 4.39×105). The residual risk of a viraemic unit entering the blood supply was estimated to be 0.077×106 or 1 in 12,979,949 donations for HCV and 0.521×106 or 1 in 1,917,250 for HIV, according to the window period ratio model, and lower with the other two formulae. DISCUSSION: HCV infection has declined over time in both first-time and repeat donors, while the data for HIV infection are stable. All three methods employed in this study showed that the residual risk of transmitting HCV or HIV through an infected blood unit is currently very low in Italy, but there are considerable differences in estimates between methods. Thus, harmonisation of these methods is advisable.

A cost analysis of public cord blood banks belonging to the Italian Cord Blood Network.

BACKGROUND: Public cord blood banking is currently managed in Italy by a network of 19 regional cord blood banks coordinated by the National Blood Centre and the National Transplant Centre. A cost analysis was carried out within the Italian network to determine the relationship between cost of cord blood collection and banking and size of the bank inventory, which ranged from 106 to 9,341 units on December 31st, 2012. MATERIALS AND METHODS: The 19 banks were invited to report costs incurred in 2012 related to cord blood unit collection, transportation, biological validation, characterisation, manipulation, cryopreservation, storage, data management, and general costs. Missing information on selected items was replaced with standardised costs represented by average data obtained from the reporting banks. Eight banks (52%) participated in the study. Average costs were determined in the three banks with inventories of >3,000 units vs the three banks with inventories of <1,000 units. RESULTS: Both cord blood collection and cord blood banking costs per unit were lower in the larger banks than in the smaller banks (average collection costs: € 119.25 and € 151.31, respectively; average banking costs: € 3,614.15 and € 8,158.37, respectively). DISCUSSION: The study outlined an inverse relationship between the costs of cord blood collection and banking and the size of the bank inventory, suggesting that scale economies could be obtained through centralisation of banking activities.

Comparing regional models of congenital bleeding disorders: preliminary steps in the Italian context.

BACKGROUND: Among these diseases, congenital bleeding disorders (CBD) represent a significant societal burden in terms of high morbidity costs and health outcomes. In Italy, the organization and provision of health care is a regional responsibility and regions must assure equity and quality to all their residents. This is also true for CBD care which is provided by 54 multidisciplinary Hemophilia Treatment Centers (HTCs) distributed among the regions. With the present study, we intend to stimulate a debate on the effect that the decentralization process have in the delivery of services to CBD patients across Italy. METHODS: The available comparable measures of caseloads per center and interregional patient mobility, as proxies of quality and responsiveness of the regional network of HTCs, were first analyzed for the using data from the Italian Hemophilia Centers Association for the year 2012. RESULTS: Nine thousand one hundred and thirty four Italian residents with CBD received care in at least one of the Italian HTC in 2012. Preliminary findings suggested room for improvement in health care delivery for CBD patients. In 2012, 16 HTCs out of 51 (31.4%) treated a number of patients under the minimum requirement for treatment center accreditation (10 severe patients). Moreover, data on interregional patient mobility highlighted differences in the ability of each region to retain its own residents or to attract residents from other regions. CONCLUSIONS: Preliminary study results showed significant disparities among regions in terms of volumes and mobility of residents with CBDs that cannot be completely explained by the different geographical characteristics. Therefore, the central government should consider taking concrete measures to bridge the gap between regions to assure access to quality care for all individuals with CBD independently from where they live and therefore to move toward a more integrated and homogeneous national network of care centers. Typology of disease, patients' needs, and cost for outcomes, should have high priority on the political agenda. For CBD patients, even in a federal healthcare system, the national government should have the global responsibility to guaranteeing uniform levels of quality care over the country and overcome local institutions when necessary.

Clinical effectiveness of platelets in additive solution treated with two commercial pathogen-reduction technologies.

BACKGROUND: Two noninferiority, randomized, controlled trials were conducted in parallel comparing the safety and efficacy of platelets treated with Intercept or Mirasol pathogen-reduction technologies versus standard platelets. STUDY DESIGN AND METHODS: The primary endpoint was the percentage of hematology patients who developed World Health Organization Grade 2 or greater bleeding. A noninferiority margin of 11% was chosen based on expected Grade 2 or greater bleeding in 20% of controls. The study was closed for financial restrictions before reaching the planned sample size of 828 patients, and an intention-to-treat analysis was conducted on 424 evaluable patients. RESULTS: In the Intercept trial (113 treated vs. 115 control patients), the absolute risk difference in Grade 2 or greater bleeding was 6.1%, with an upper one-sided 97.5% confidence limit of 19.2%. The absolute risk difference in the Mirasol trial (99 treated vs. 97 control patients) was 4.1%, and the upper one-sided 97.5% confidence limit was 18.4%. Neither absolute risk difference was statistically significant. In both trials, posttransfusion platelet count increments were significantly lower in treated versus control patients. Mean blood component use in treated patients versus controls was 54% higher (95% confidence interval, 36%-74%; Intercept) and 34% higher (95% confidence interval, 16%-54%; Mirasol) for platelets and 23% higher (95% confidence interval, 8%-39%; Intercept) and 32% higher (95% confidence interval, 10%-57%; Mirasol) for red blood cells. Unexpected reactions and adverse events were not reported. Mortality did not differ significantly between treated and control patients. CONCLUSION: Although conclusions on noninferiority could not be drawn due to low statistical power, the study provides additional information on the safety and efficacy of pathogen-reduced platelets treated with two commercial pathogen-reduction technologies.

Health Technology Assessment of pathogen reduction technologies applied to plasma for clinical use.

Although existing clinical evidence shows that the transfusion of blood components is becoming increasingly safe, the risk of transmission of known and unknown pathogens, new pathogens or re-emerging pathogens still persists. Pathogen reduction technologies may offer a new approach to increase blood safety. The study is the output of collaboration between the Italian National Blood Centre and the Post-Graduate School of Health Economics and Management, Catholic University of the Sacred Heart, Rome, Italy. A large, multidisciplinary team was created and divided into six groups, each of which addressed one or more HTA domains.Plasma treated with amotosalen + UV light, riboflavin + UV light, methylene blue or a solvent/detergent process was compared to fresh-frozen plasma with regards to current use, technical features, effectiveness, safety, economic and organisational impact, and ethical, social and legal implications. The available evidence is not sufficient to state which of the techniques compared is superior in terms of efficacy, safety and cost-effectiveness. Evidence on efficacy is only available for the solvent/detergent method, which proved to be non-inferior to untreated fresh-frozen plasma in the treatment of a wide range of congenital and acquired bleeding disorders. With regards to safety, the solvent/detergent technique apparently has the most favourable risk-benefit profile. Further research is needed to provide a comprehensive overview of the cost-effectiveness profile of the different pathogen-reduction techniques. The wide heterogeneity of results and the lack of comparative evidence are reasons why more comparative studies need to be performed.

Impact of cord blood banking technologies on clinical outcome: a Eurocord/Cord Blood Committee (CTIWP), European Society for Blood and Marrow Transplantation and NetCord retrospective analysis.

BACKGROUND: Techniques for banking cord blood units (CBUs) as source for hematopoietic stem cell transplantation have been developed over the past 20 years, aimed to improve laboratory efficiency without altering the biologic properties of the graft. A large-scale, registry-based assessment of the impact of the banking variables on the clinical outcome is currently missing. STUDY DESIGN AND METHODS: A total of 677 single cord blood transplants (CBTs) carried out for acute leukemia in complete remission in centers affiliated with the European Society for Blood and Marrow Transplantation were selected. An extensive set of data concerning CBU banking were collected and correlations with clinical outcome were assessed. Clinical endpoints were transplant-related mortality, engraftment, and graft-versus-host disease (GVHD). RESULTS: The median time between collection and CBT was 4.1 years (range, 0.2-16.3 years). Volume reduction (VR) of CBUs before freezing was performed in 59.2% of available reports; in half of these the frozen volume was less than 30 mL. Cumulative incidences of neutrophil engraftment on Day 60, 100-day acute GVHD (II-IV), and 4-year chronic GVHD were 87, 29, and 21 ± 2%. The cumulative incidence of nonrelapse mortality (NRM) at 100 days and 4-year NRM were, respectively, 16 ± 2 and 30 ± 2%. Neither the variables related to banking procedures nor the interval between collection and CBT influenced the clinical outcome. CONCLUSION: These findings indicate a satisfactory validation of the techniques associated with CBU VR across the banks. Cell viability assessment varied among the banks, suggesting that efforts to improve the standardization of CBU quality controls are needed.

Multicentre standardisation of a clinical grade procedure for the preparation of allogeneic platelet concentrates from umbilical cord blood.

BACKGROUND: In addition to a largely prevalent use for bleeding prophylaxis, platelet concentrates from adult blood have also been used for many years to prepare platelet gels for the repair of topical skin ulcers. Platelet gel can be obtained by activation of fresh, cryopreserved, autologous or allogeneic platelet concentrates with calcium gluconate, thrombin and/or batroxobin. The high content of tissue regenerative factors in cord blood platelets and the widespread availability of allogeneic cord blood units generously donated for haematopoietic transplant but unsuitable for this use solely because of low haematopoietic stem cell content prompted us to develop a national programme to standardise the production of allogeneic cryopreserved cord blood platelet concentrates (CBPC) suitable for later preparation of clinical-grade cord blood platelet gel. MATERIALS AND METHODS: Cord blood units collected at public banks with total nucleated cell counts <1.5×10(9), platelet count >150×10(9)/L and volume >50 mL, underwent soft centrifugation within 48 hours of collection. Platelet-rich plasma was centrifuged at high speed to obtain a CBPC with target platelet concentration of 800-1,200×10(9)/L, which was cryopreserved, without cryoprotectant, below -40 °C. RESULTS: During 14 months, 13 banks produced 1,080 CBPC with mean (± standard deviation) volume of 11.4±4.4 mL and platelet concentration of 1,003±229×10(9)/L. Total platelet count per CBPC was 11.3±4.9×10(9). Platelet recovery from cord blood was 47.7±17.8%. About one-third of cord blood units donated for haematopoietic transplant could meet the requirements for preparation of CBPC. The cost of preparation was € 160.92/CBPC. About 2 hours were needed for one technician to prepare four CBPC. DISCUSSION: This study yielded valuable scientific and operational information regarding the development of clinical trials using allogeneic CBPC.

Blood donor selection in European Union directives: room for improvement.

BACKGROUND: Transfusion-transmissible infections have made both blood bankers and health authorities overly cautious. The general public expects and hence reinforces this policy. To obtain a high level of blood product safety, blood and plasma donors have to meet increasingly stringent eligibility criteria; however, it is not known whether this policy translates into improved outcomes for patients. There is a risk that the management of donors does not match the ambition of greater safety for patients. European directives related to the collection process and donor selection will probably be reconsidered in the next few years. MATERIAL AND METHODS: The development of European directives on donor selection and their basis in the literature were reviewed with an emphasis on the background and considerations for eligibility criteria to be included in the directives. RESULTS: The precautionary principle appears to be the predominant reason behind the set of eligibility criteria. However, the formal eligibility criteria, put into force in 2004, do not balance with the developments of the past decade in laboratory tests and measures that have substantially reduced actual infection risks. In no cases were the effects of eligibility criteria on the donor pool and donor well-being quantified. Regional differences in the epidemiology of transfusion-transmissible infections were not taken into consideration either. DISCUSSION: First, the Authors promote the collection of epidemiological data on the incidence and prevalence of conditions in the general population and in blood and plasma donors which could pose a risk for transfused patients, in order to use these data as a basis for decision-making in donor-selection policies. Second, the Authors suggest including allowance for differential deferral criteria throughout Europe, based on factual risk levels. There should be an accepted balance between donor and patient welfare, and also between risk to transfusion safety and risk of compromising the blood supply.

Human T-lymphotropic virus and transfusion safety: does one size fit all?

Human T-cell leukemia viruses (HTLV-1 and HTLV-2) are associated with a variety of human diseases, including some severe ones. Transfusion transmission of HTLV through cellular blood components is undeniable. HTLV screening of blood donations became mandatory in different countries to improve the safety of blood supplies. In Japan and Europe, most HTLV-infected donors are HTLV-1 positive, whereas in the United States a higher prevalence of HTLV-2 is reported. Many industrialized countries have also introduced universal leukoreduction of blood components, and pathogen inactivation technologies might be another effective preventive strategy, especially if and when generalized to all blood cellular products. Considering all measures available to minimize HTLV blood transmission, the question is what would be the most suitable and cost-effective strategy to ensure a high level of blood safety regarding these viruses, considering that there is no solution that can be deemed optimal for all countries.

Convalescent plasma: new evidence for an old therapeutic tool?

Passive immunisation for the prevention and treatment of human infectious diseases can be traced back to the 20(th) century. The recent Ebola virus outbreak in West Africa has turned the spotlight onto the possible use of convalescent whole blood and convalescent plasma in the treatment of infectious diseases because they are the only therapeutic strategy available in some cases, given the unavailability of vaccines, drugs or other specific treatments. Convalescent blood products could be a valid option in the treatment/prophylaxis of several infectious diseases both in association with other drugs/preventive measures and as the only therapy when a specific treatment is not available. However, there are still some issues to consider in determining the advisability of implementing a large-scale convalescent plasma transfusion programme.

Zika virus and the never-ending story of emerging pathogens and transfusion medicine.

In the last few years, the transfusion medicine community has been paying special attention to emerging vector-borne diseases transmitted by arboviruses. Zika virus is the latest of these pathogens and is responsible for major outbreaks in Africa, Asia and, more recently, in previously infection-naïve territories of the Pacific area. Many issues regarding this emerging pathogen remain unclear and require further investigation. National health authorities have adopted different prevention strategies. The aim of this review article is to discuss the currently available, though limited, information and the potential impact of this virus on transfusion medicine.

Leucoreduction of blood components: an effective way to increase blood safety?

Over the past 30 years, it has been demonstrated that removal of white blood cells from blood components is effective in preventing some adverse reactions such as febrile non-haemolytic transfusion reactions, immunisation against human leucocyte antigens and human platelet antigens, and transmission of cytomegalovirus. In this review we discuss indications for leucoreduction and classify them into three categories: evidence-based indications for which the clinical efficacy is proven, indications based on the analysis of observational clinical studies with very consistent results and indications for which the clinical efficacy is partial or unproven.