A forecasting model to estimate the drop in blood supplies during the SARS-CoV-2 pandemic in Italy.

OBJECTIVES: To estimate the number of actually Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infected blood donors applying a statistical forecasting model. BACKGROUND: Following the outbreak of the SARS-CoV-2 epidemic, a drop in blood donation has been observed. It is crucial to determine the actual number of potential SARS-CoV-2-positive donors to define the measures and ensure adequate blood supply. METHODS: The cumulative incidence of SARS-CoV-2 positivity, calculated on the general population, was applied to the donor population by estimating the number of positive subjects. The calculation model was validated by the linear interpolation method. The number of blood units actually discarded based on post-donation information was also taken into account. RESULTS: Three months after the outbreak, 5322 donors were estimated to be positive for SARS-CoV-2 and were therefore potentially excluded from donation. A total of units of blood components were discarded following post donation information. The estimated number of donors deceased (180) and the number of clinically recovered individuals in the same period was also considered. CONCLUSION: This forecasting model can be used to obtain information on blood donors' involvement during future SARS-CoV-2 outbreaks, especially in case of changes concerning epidemiology, incidence by age bracket and geographical distribution and also for new outbreaks of emerging viruses.

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.

Hepatitis E virus infection prevalence among men who have sex with men involved in a hepatitis A virus outbreak in Italy.

BACKGROUND: The routes of hepatitis E virus (HEV) transmission have still not been fully clarified. Here, we evaluated the possibility of sexual transmission of HEV, which remains a highly disputed issue. MATERIALS AND METHODS: Hepatitis E virus sexual transmission risk was assessed by comparing the prevalence of HEV infection in a sample of 196 Italian men who have sex with men (MSM) involved in a multi-country hepatitis A virus (HAV) outbreak, and in 3,912 Italian male blood donors selected from the same regions and provinces as the MSM. Selection of study of participants was motivated by the fact that HEV prevalence among Italian blood donors has been found to vary enormously between different geographical areas. RESULTS: Anti-HEV IgG prevalence was 14.8% and 5.6% in blood donors and MSM, respectively. Adjusted anti-HEV IgG prevalence was significantly lower in MSM than in blood donors (odds ratio [OR], 0.40; 95% confidence interval [CI]: 0.22-0.75; p<0.01), among residents in northern (OR, 0.45; 95% CI: 0.37-0.55; p<0.01) and southern (OR, 0.45; 95% CI: 0.35-0.58; p <0.01) Italy than among residents in Central Italy, while the prevalence was significantly higher in participants over 50 years of age than in those under 50 years of age (OR, 1.83; 95% CI: 1.48-2.27; p<0.01). DISCUSSION: Our findings suggest that sexual intercourse does not have a relevant role in HEV transmission. In particular, sexual transmission of HEV is unlikely to influence the prevalence of HEV infection at population level.

Pathogen reduction of blood components during outbreaks of infectious diseases in the European Union: an expert opinion from the European Centre for Disease Prevention and Control consultation meeting.

Pathogen reduction (PR) of selected blood components is a technology that has been adopted in practice in various ways. Although they offer great advantages in improving the safety of the blood supply, these technologies have limitations which hinder their broader use, e.g. increased costs. In this context, the European Centre for Disease Prevention and Control (ECDC), in co-operation with the Italian National Blood Centre, organised an expert consultation meeting to discuss the potential role of pathogen reduction technologies (PRT) as a blood safety intervention during outbreaks of infectious diseases for which (in most cases) laboratory screening of blood donations is not available. The meeting brought together 26 experts and representatives of national competent authorities for blood from thirteen European Union and European Economic Area (EU/EEA) Member States (MS), Switzerland, the World Health Organization, the European Directorate for the Quality of Medicines and Health Care of the Council of Europe, the US Food and Drug Administration, and the ECDC. During the meeting, the current use of PRTs in the EU/EEA MS and Switzerland was verified, with particular reference to emerging infectious diseases (see Appendix). In this article, we also present expert discussions and a common view on the potential use of PRT as a part of both preparedness and response to threats posed to blood safety by outbreaks of infectious disease.

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.

Platelet-rich plasma for sports-related muscle, tendon and ligament injuries: an umbrella review.

BACKGROUND: Platelet-rich plasma (PRP) has been used in different non-transfusion indications due to its role in tissue regeneration and healing. The aim of this overview of systematic reviews (umbrella review) is to provide a summary of the existing research syntheses related to PRP use for sports-related muscle, tendon and ligament injuries. MATERIALS AND METHODS: Literature searches were performed in MEDLINE, Embase, and Cochrane Library to identify systematic reviews focusing on PRP use for sports-related muscle, tendon and ligament injuries. The methodological quality of included studies was assessed using the checklist for systematic reviews and research syntheses developed by the Joanna Briggs Institute and the GRADE assessment. RESULTS: Twenty-two studies met the inclusion criteria. Five studies evaluated PRP use for acute muscle injury, and 17 evaluated PRP use for tendon and ligament injury. Studies were heterogeneous in terms of the dose and number of PRP injections, and the control groups. Three of the 5 reviews evaluating acute muscle injury concluded that PRP had no effect on the outcomes considered. One review shows superior efficacy of rehabilitation exercise compared to PRP. One review shows that PRP may result in an earlier return to sport for acute grade I-II injury. Eight out of the 17 reviews evaluating PRP for tendon and ligament injuries show a statistically significant (p<0.05) difference in pain and/or function outcome measures favouring PRP compared to controls, although most of the observed differences were small. Adverse events data and quality of life outcomes were rarely analysed or reported in the included studies and were considered clinically insignificant. DISCUSSION: In most of the included reviews, the available evidence was judged to be of low/very low quality due to risk of bias, inconsistency and imprecision, thus making the level of certainty of these findings low and not adequate to support the general use of PRP in this setting.

The use of platelet-rich plasma in oral surgery: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate the benefit of platelet rich plasma (PRP) in oral surgery. MATERIALS AND METHODS: We performed a systematic search of the literature. The GRADE system was used to assess the certainty of the body of evidence. RESULTS: We found 21 randomised controlled trials that met our inclusion criteria: 12 studies included patients with periodontal defects, five studies focused on healing of extraction sockets, three studies on sinus lift augmentation, and one study on periapical osseous defects. However, for the quantitative synthesis (meta-analysis), we evaluated "periodontal defects" studies only, since for other clinical contexts the number of studies were too low and the procedural heterogeneity was too high to allow pooling of data. PRP-containing regimens were compared to non-PRP-containing regimens. Primary outcomes for the evaluation of periodontal defects were probing depths, clinical attachment level, gingival recession, and radiographic bone defect. It is not usually clear whether or not the use of PRP compared to controls affects "probing depth" at long-term follow up; the between group differences were small and unlikely to be of clinical importance (i.e., very low quality of evidence). For the other outcomes analysed ("clinical attachment levels", "gingival recession", "bony defect"), we observed a very slight marginal clinical benefit of PRP compared to controls. The available evidence for these comparisons was rated as low quality as most of the studies selected showed inconsistency, imprecision, and risk of bias. DISCUSSION: Evidence from a comparison between the use in oral surgery of PRP-containing regimens compared to other regimens not-containing PRP was of low quality. The results of the meta-analysis, limited to studies in patients with periodontal defects, document that PRP was slightly more effective compared to controls not-containing PRP.

Patient Blood Management: a revolutionary approach to transfusion medicine.

Patient Blood Management (PBM) is a multimodal, multidisciplinary approach adopted to limit the use and the need for allogeneic blood transfusion in all at-risk patients with the aim of improving their clinical outcomes. Although PBM usually refers to surgical patients, its clinical use has gradually evolved over the last few years and it now also refers to medical conditions. This review will critically analyse the current knowledge on the use of PBM programmes in surgical and non-surgical patients.

Serum eye drops for the treatment of ocular surface diseases: a systematic review and meta-analysis.

BACKGROUND: The use of blood-derived eye drops for topical treatment of ocular surface diseases has progressively increased in recent years. MATERIALS AND METHODS: To evaluate the use of serum eye drops in ocular surface disorders, we performed a systematic search of the literature. RESULTS: In this systematic review, we included 19 randomised controlled trials (RCTs) investigating the use of serum eye drops in 729 patients compared to controls. For the quantitative synthesis, we included only 10 RCTs conducted in patients with dry eye syndrome comparing autologous serum to artificial tears. At 2-6 weeks, no clear between-group differences in Schirmer test (MD 1.05; 95% CI: -0.17-2.26) and in fluorescein staining (MD -0.61; 95% CI: -1.50-0.28) were found (very low-quality evidence, down-graded for inconsistency, serious risk of biases, and serious imprecision). Slightly higher increase in tear film break-up time (TBUT) scores in autologous serum compared to control (MD 2.68; 95% CI: 1.33-4.03), and greater decrease in ocular surface disease index (OSDI) in autologous serum compared to control (MD -11.17; 95% CI: -16.58 - -5.77) were found (low quality evidence, down-graded for serious risk of bias, and for inconsistency). For the Schirmer test, fluorescein staining and TBUT, data were also available at additional follow-up timing (2-12 months): no clear between-group differences were found, and the quality of the evidence was graded as low/very-low. CONCLUSIONS: In patients with dry eye syndrome, it is unclear whether or not the use of autologous serum compared to artificial tears increases Schirmer test and fluorescein staining scores at short-term and medium-/long-term follow up. Some benefit at short-term follow up for the outcome of TBUT and OSDI was observed, but the quality of the evidence was low.

Emicizumab for the treatment of haemophilia A: a narrative review.

One of the most serious complications of the treatment of severe haemophilia A is the development of alloantibodies against exogenous factor VIII (FVIII). Inhibitors render factor replacement therapy ineffective, exposing patients to a remarkably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in newer haemostatic therapies that are not based on the replacement of the deficient FVIII. This review will focus on the most interesting among these innovative therapies, emicizumab, and will provide an update on its current stage of clinical development.

Perioperative hemostatic management in the cirrhotic patient: a position paper on behalf of the Liver Intensive Care Group of Europe (LICAGE).

Recent data demonstrated that amongst patients undergoing elective surgery the prevalence of cirrhosis is 0.8% equating to approximately 25 million cirrhotic patients undergoing surgery each year worldwide. Overall, the presence of cirrhosis is independently associated with 47% increased risk of postoperative complications and over two and a half-increased risk of in-hospital mortality in patients undergoing elective surgery. In particular, perioperative patients with chronic liver disease have long been assumed to have a major bleeding risk on the basis of abnormal results for standard tests of hemostasis. However, recent evidence outlined significant changes to traditional knowledge and beliefs and, nowadays, with more sophisticated laboratory tests, it has been shown that patients with chronic liver disease may be in hemostatic balance as a result of concomitant changes in both pro- and antihemostatic pathways. The aim of this paper endorsed by the Liver Intensive Care Group of Europe was to provide an up-to-date overview of coagulation management in perioperative patients with chronic liver disease focusing on patient blood management, monitoring of hemostasis, and current role of hemostatic agents.

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%.

Prevention and management of acute reactions to intravenous iron in surgical patients.

Absolute or functional iron deficiency is the most prevalent cause of anaemia in surgical patients, and its correction is a fundamental strategy within "Patient Blood Management" programmes. Offering perioperative oral iron for treating iron deficiency anaemia is still recommended, but intravenous iron has been demonstrated to be superior in most cases. However, the long-standing prejudice against intravenous iron administration, which is thought to induce anaphylaxis, hypotension and shock, still persists. With currently available intravenous iron formulations, minor infusion reactions are not common. These self-limited reactions are due to labile iron and not hypersensitivity. Aggressively treating infusion reactions with H1-antihistamines or vasopressors should be avoided. Self-limited hypotension during intravenous iron infusion could be considered to be due to hypersensitivity or vascular reaction to labile iron. Acute hypersensitivity reactions to current intravenous iron formulation are believed to be caused by complement activation-related pseudo-allergy. However, though exceedingly rare (<1:250,000 administrations), they should not be ignored, and intravenous iron should be administered only at facilities where staff is trained to evaluate and manage these reactions. As preventive measures, prior to the infusion, staff should inform all patients about infusion reactions and identify those patients with increased risk of hypersensitivity or contraindications for intravenous iron. Infusion should be started at a low rate for a few minutes. In the event of a reaction, the very first intervention should be the immediate cessation of the infusion, followed by evaluation of severity and treatment. An algorithm to scale the intensity of treatment to the clinical picture and/or response to therapy is presented.

Budget impact of implementing platelet pathogen reduction into the Italian blood transfusion system.

BACKGROUND: Despite improvements in blood donor selection and screening procedures, transfusion recipients can still develop complications related to infections by known and emerging pathogens. Pathogen reduction technologies (PRT) have been developed to reduce such risks. The present study, developed whithin a wider health technology assessment (HTA) process, was undertaken to estimate the costs of the continuing increase in the use of platelet PRT in Italy. MATERIALS AND METHODS: A multidisciplinary team was established to perform the HTA and conduct a budget impact analysis. Quantitative data on platelet use were derived from the 2015 national blood transfusion report and from the Italian Platelets Transfusion Assessment Study (IPTAS). The current national fee of 60 Euro per platelet PRT procedure was used to quantify the costs to the Italian National Health Service (INHS). The analysis adopts a 3-year time-frame. In order to identify the impact on budget we compared a scenario representing an increased use of PRT platelets over time with a control scenario in which standard platelets are used. RESULTS: Progressive implementation of PRT for 20%, 40% and 66% of annual adult platelet doses could generate an increase in annual costs for the INHS amounting to approximately 7, 14 and 23 million Euros, respectively. Use of kits and devices suitable for the treatment of multiple adult platelet doses in one PRT procedure could lower costs. DISCUSSION: In order to fully evaluate the societal perspective of implementing platelet PRT, the increase in costs must be balanced against the expected benefits (prevention of transfusion-transmissible infections, white cell inactivation, extension of platelet storage, discontinuation of pathogen detection testing). Further studies based on actual numbers of platelet transfusion complications and their societal cost at a local level are needed to see the full cost to benefit ratio of platelet PRT implementation in Italy, and to promote equal treatment for all citizens.

Efficacy of platelet-rich plasma as conservative treatment in orthopaedics: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate the benefit of platelet-rich plasma (PRP) in non-surgical orthopaedic procedures. MATERIAL AND METHODS: We searched the Cochrane Wounds Specialized Register, CENTRAL, MEDLINE (through PUBMED), Embase, and SCOPUS. We also searched clinical trials registries for ongoing and unpublished studies and checked reference lists to identify additional studies. RESULTS: We found 36 randomised controlled trials (2,073 patients) that met our inclusion criteria. The included studies mostly had small numbers of participants (from 20 to 225). Twenty-eight studies included patients with lateral epicondylitis or plantar fasciitis. PRP was compared to local steroids injection (19 studies), saline injection (6 studies), autologous whole blood (4 studies), local anaesthetic injection (3 studies), dry needling injection (3 studies), and to other comparators (4 studies). Primary outcomes were pain and function scores, and adverse events. On average, it is unclear whether or not use of PRP compared to controls reduces pain scores and functional score at short- (up to 3 months) and medium- (4-6 months) term follow-up. The available evidence for all the comparisons was rated as very low quality due to inconsistency, imprecision, and risk of bias in most of the selected studies. There were no serious adverse events related to PRP injection or control treatments. CONCLUSIONS: The results of this meta-analysis, which documents the very marginal effectiveness of PRP compared to controls, does not support the use of PRP as conservative treatment in orthopaedics.

Factors affecting the quality, safety and marketing approval of clotting factor concentrates for haemophilia.

Selecting therapeutic products for the treatment of haemophilia follows the process of obtaining market approval of products submitted to the scrutiny of a regulatory agency. In well-resourced countries, key decisions on whether a product is sufficiently safe and of high quality are made by highly expert and well-resourced agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In countries lacking such agencies, well-informed decisions can still be made through an appreciation of the key issues affecting the quality, safety and efficacy of haemophilia products. A number of well-established principles may then be applied in order to make a choice. In this review, reflecting principles outlined by the World Federation of Hemophilia, we outline the key features in determining the acceptability of therapeutic products for haemophilia in order to ensure an optimal choice in all the environments providing haemophilia care.

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.