Albert Farrugia

The Risk of HIV, HBV, HCV and HTLV Infection Among Musculoskeletal Tissue Donors in Australia

In Australia, there are no current national estimates of the risks of transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or human T‐lymphotrophic virus (HTLV) by musculoskeletal tissue transplantation. We determined the prevalence rates of antibodies against HIV (anti‐HIV), HCV (anti‐HCV) and HTLV (anti‐HTLV) and Hepatitis B surface antigen (HBsAg) for 12 415 musculoskeletal tissue donors from three major bone tissue banks across Australia for the period 1993–2004. The prevalence (per 100  000 persons) was 64.44 for anti‐HIV, 407.13 for HBsAg, 534.63 for anti‐HCV and 121.88 for anti‐HTLV. The estimated probability of viremia at the time of donation was 1 in 128  000, 1 in 189  000, 1 in 55  000 and 1 in 118  000, respectively. With the addition of nucleic acid amplification testing (NAT), the probability of donor viremia would be reduced to 1 in 315  000 for HIV, 1 in 385  000 for HBV and 1 in 500  000 for HCV. The prevalence of HIV, HBV, HCV and HTLV although low, are higher among musculoskeletal tissue donors than among first‐time blood donors. The risks associated with musculoskeletal donation will be reduced with NAT, though further cost analysis is required prior to its implementation.

Plasma fractionation issues

Procurement and processing of human plasma for fractionation of therapeutic proteins or biological medicines used in clinical practice is a multi-billion dollar international trade. Together the private sector and public sector (non-profit) provide large amounts of safe and effective therapeutic plasma proteins needed worldwide. The principal therapeutic proteins produced by the dichotomous industry include gamma globulins or immunoglobulins (including pathogen-specific hyperimmune globulins, such as hepatitis B immune globulins) albumin, factor VIII and Factor IX concentrates. Viral inactivation, principally by solvent detergent and other processes, has proven highly effective in preventing transmission of enveloped viruses, viz. HBV, HIV, and HCV.

Variant Creutzfeldt-Jakob disease transmission by plasma products : assessing and communicating risk in an era of scientific uncertainty

A substantial body of animal data indicates that transmissible spongiform encephalopathies (TSEs) are transmitted through blood. These data have been augmented in the past year by reports that two recipients of red cells from donors with variant Creutzfeldt–Jakob disease (vCJD) in the United Kingdom have acquired this infection. Most of the blood donations collected in countries affected by bovine spongiform encephalopathy (BSE) and vCJD also contribute plasma to fractionation pools. Thus, a number of batches of fractionated products have included plasma from donors who developed vCJD. On the basis of public health strategies influenced, in part, by risk assessments, the UK and the French authorities have instituted measures for recalling products and informing patients of the estimated risks. It is therefore relevant to review the principles used by authorities in generating risk assessments for the transmission of TSEs by blood and blood products. While the general principles are fairly straightforward, the final assessments are very dependent on the magnitude of several key parameters, which are, largely, still unknown. A critical determinant of final product risk is the extent to which the plasma fractionation process will contribute to eliminating the infectious prion agent. Therefore, regulatory and industry measures to characterize fractionation processes for their capacity to eliminate prions are to be strongly encouraged. In the interim, an understanding of the principles used to generate risk assessments should contribute to an enhanced ability to address this threat to patient safety. Authorities should recognize that adequate communication is an integral part of good risk‐management practices.

Globalisation and blood safety

Globalisation may be viewed as the growing interdependence of countries worldwide through the increasing volume and variety of cross-border transactions in goods and services, and also through the more rapid and widespread diffusion of technology. Globalisation is not just an economic phenomenon, although it is frequently described as such, but includes commerce, disease and travel, and immigration, and as such it affects blood safety and supply in various ways. The relatively short travel times offered by modern aviation can result in the rapid spread of blood-borne pathogens before measures to counteract transmission can be put in place; this would have happened with SARS if the basic life cycle of the SARS virus included an asymptomatic viraemia. This risk can be amplified by ecological factors which effect the spread of these pathogens once they are transferred to a naïve ecosystem, as happened with West Nile Virus (WNV) in North America. The rationalization and contraction of the plasma products industry may be viewed as one aspect of globalisation imposed by the remorseless inevitability of the market; the effect of this development on the safety and supply of products has yet to be seen, but the oversight and assurance of a shrinking number of players will present particular challenges. Similarly, the monopolization of technology, through patent enforcement which puts access beyond the reach of developing countries, can have an effect on blood safety. The challenges presented to blood safety by globalisation are heightening the tensions between the traditional focus on the product safety - zero risk paradigm and the need to view the delivery of safe blood as an integrated process. As an illustration of this tension, donor deferral measures imposed by globalisation-induced risks such as vCJD and WNV have resulted in the loss of the safest and most committed portion of the blood donor population in many Western countries, leading to an increased risk to safety and supply. It is only through an appreciation of the basic needs of transfusion medicine, including the enunciation of appropriate principles to manage, rather than eliminate, risks, that the challenges imposed by globalisation may be overcome.

When do tissues and cells become products? – Regulatory oversight of emerging biological therapies

Although therapeutics derived from biological sources have been subjected to regulatory oversight for some time, the products used in transplantation procedures have historically been exempt from this oversight. These products have been viewed as being part of medical practice rather than as the result of mainstream pharmaceutical manufacture. Furthermore, their unique source makes them difficult to assess in traditional regulatory systems based on the␣tenets of pharmaceutical quality control. With the␣increasing use of transplantation therapies to both replace dysfunctional organs and to influence genetic and metabolic processes, public health concerns on these therapies have increased. In addition, it is recognized that therapeutic claims for some of these interventions need to be properly assessed. These considerations have led the established regulatory agencies of the developed world to develop new regulatory paradigms for the products of transplantation practice. While a number of concerns have driven these developments, the minimization of infectious disease risk remains the paramount driver for introducing these regulatory systems. More than the regulation of medicines and medical devices manufactured in traditional pharmaceutical modes, the regulation of cell and tissue products is intimately linked to areas of public health policy and funding. This places regulators in a challenging position as they attempt to reconcile their roles as independent assessors with the needs of the overall public health framework. This is particularly difficult when considering measures which may affect access to life saving therapies. Regulators have recognized the need to assess these therapies through systems which incorporate consideration of risk-benefit ratios and include mechanisms for transparent and accountable release of products when full compliance to traditional concepts of manufacturing practice is not possible.

Comparison of the risk of viral infection between the living and nonliving musculoskeletal tissue donors in Australia

Screening of musculoskeletal tissue donors with nucleic acid testing (NAT) for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has been implemented in the United States and other developed nations. However, in contrast to the donor demographics in the United States, the majority of Australian musculoskeletal tissue donations are primarily from living surgical donors. The objective of our study was to determine and compare the risk of viral infection associated with musculoskeletal tissue donation from living and nonliving donors in Australia. We studied serum samples from 12 415 consecutive musculoskeletal tissue donors between 1993 and 2004. This included 10 937 surgical donations, and 1478 donations obtained from postmortem organ donation patients and cadaveric donors. Current mandatory retesting of surgical donors 6 months postdonation reduces the risk of viral infection by approximately 95% by eliminating almost all donors in the window period. The addition of nucleic acid amplification testing for nonliving donors would similarly reduce the window period, and consequently the residual risk by approximately 50% for hepatitis B virus, 55% for HIV, and 90% for HCV. NAT, using appropriately validated assays for nonliving donors, would reduce the residual risk to levels comparable to that in living donors (where the 95% reduction for quarantining pending the 180‐day re‐test is included).

Theoretically estimated risk of severe acute respiratory syndrome transmission through blood transfusion during an epidemic in Shenzhen, Guangdong, China in 2003

Abstract Background Severe acute respiratory syndrome (SARS) is a newly recognized infectious disease that caused an outbreak in south China in 2003. The cause of SARS was identified as a novel coronavirus (CoV). The existence of asymptomatic seroconvertors and the detection of the SARS-CoV RNA in plasma during the course of infection all suggest that SARS could, as least theoretically, be transmitted by transfusion. An estimate of the risk of SARS transmission through blood transfusion will contribute to decisions concerning blood safety monitoring and may be useful in the design of strategies to decrease the risk of transfusion-transmitted infections. Study design and methods Case onset dates from the 2003 Shenzhen SARS epidemic and investigational results from Taiwan on viremia in humans are used to estimate the number of cases that were viremic throughout the epidemic. Estimates of the asymptomatic-to-clinically confirmed SARS-CoV infection ratio, the proportion of asymptomatic infections reported in a seroprevalence survey in Hongkong, and the population size of Shenzhen are used to infer the SARS-CoV transfusion–transmission risk. Statistical resampling methods are used. Results Based on data from Shenzhen, Hongkong and Taiwan, the maximum and mean risk (per million) of SARS-CoV transmission from donors in Shenzhen were estimated as 23.57 (95% CI: 6.83–47.69) and 14.11 (95% CI: 11.00–17.22), respectively. The estimated risk peaked on April 02, 2003. Conclusions Although there are currently no confirmed reports of the transmission of SARS-CoV from asymptomatic individuals, recent research data indicate that transfusion-transmitted SARS-CoV is at least theoretically possible. Although the risk is low, with its rapid spread of the disease, appearance of alarmingly high infectivity and high fatality rate, public health authorities need to consider strategies for blood donor recruitment and virus inactivation during an epidemic to further ensure blood safety.

Flow-Cytometric Method for the Quantitation of the Fc Function of Intravenous Immunoglobulin Preparations

Objectives: We have developed and optimised a new flow‐cytometric method for the measurement of the Fc function of intravenous immunoglobulin (IVlg) preparations, which is important in predicting the effector function of immunoglobulin (Ig) in such preparations. Materials and Methods: Ig was bound to a monocytic cell line, THP‐1 with FcγRl and FcγRll cell surface receptors, and the bound Ig detected by FITC‐conjugated F(ab)2 fragment of rabbit anti‐human IgG. Results: Validation studies showed that Ig bound to the cell line through the Fc portion. The method detected alterations in Fc function caused by reduction with dithiothreitol or by storage. The method was reproducible (CV<11%) and a limited comparison study showed that it correlated with the European Pharmacopoeia reference method. Conclusions: This technically simple method is suitable for the quantitation of the Fc function of Ig preparations.

The Cambridge Healthtech Institute's 9th Annual Conference on Blood Safety.

This article summarises, and provides a personal commentary on, the Cambridge HealthTech Institute’s Conference on Blood Safety in February 2003. Most of the converging areas which contribute to this field were amply covered at the conference by speakers of a high calibre and international standing.