‘The Expert Report to the Infected Blood Inquiry: Statistics’ (http://bitly.ws/EAng) found that around 3650 people with bleeding disorders in the UK were infected with HIV or hepatitis viruses through the use of contaminated blood products. In addition, many people (8120) were found to be chronically infected with hepatitis C 10 years or more after receiving contaminated blood transfusions. The Infected Blood Inquiry (https://www.infectedbloodinquiry.org.uk/), which was announced in 2017, published its second Interim Report on 5 April 2023 and is expected to conclude in autumn 2023. CLI caught up with Professor Albert Farrugia (UWA Medical School, The University of Western Australia) to find out more about the safety of blood products and how a tragedy such as this can be avoided in the future when, as with SARS-CoV-19, we are constantly facing new but unknown pathogens.

As in introduction to the topic, could you give a brief summary of what blood/plasma products are used and which diseases/conditions are treated with them, please?

Plasma products are derived from the process of fractionation of large pools of plasma constructed from donations from thousands of individuals. This process has its inception in the work of Professor Edwin Cohn (Harvard University, MA, USA) during the Second World War [1], but has undergone many modifications since then. This industrial process is subject to the oversight of the regulatory agencies in the countries where the products are marketed, and today reflects a global industry with an estimated value of over 20 billion US dollars.

The first product from this process was human albumin solution, which was developed as a blood substitute to treat acute hemorrhage following battlefield injury. Subsequent clinical development of the various fractions resulting from plasma fractionation have focused on rare, chronic diseases characterized by a deficiency of the protein extracted from the process. Examples include hemophilia A and B, which ensue from a congenital deficiency of certain proteins involved in the coagulation of blood following injury. Concentrates of plasma factor VIII or factor IX, which constitute the missing proteins, were used to treat hemophilia from the mid 1960s, although synthetic versions of these proteins, produced by recombinant technology, have now largely substituted plasma-derived products in these conditions. Purified immunoglobulin solutions are crucial in treating patients deficient in the protein, in inherited or acquired deficiencies of IgG which increase the risk of infection. In addition, immunoglobulin may also be used to modulate the immune system in certain autoimmune disorders, particularly a number of severe neurological conditions. There are many more proteins in plasma than there are products, and the industry continues to seek new indications to make the best use of every litre of donated plasma.

Employees working in the plasma purification area (Grifols)

Which diseases are transmitted by blood/plasma products and how does the contamination of those products happen?

Ever since the industry’s inception, the transmission of pathogenic microorganisms by plasma products has been recognized [2]. Hepatitis was known to be transmitted by pooled, unfractionated plasma, before its etiology from various viruses was demonstrated. Early studies showed that the parent product albumin could be rendered safe from hepatitis transmission by heating the final, purified albumin solution before it was made available for treatment. This was possible because the albumin molecule could be protected from the damage accrued from heating by the inclusion of stabilizing excipients in the albumin solution. These excipients are still in use and have no adverse effects on the recipients.

As other proteins, including the ones mentioned above, were developed, the problem of viral transmission continued to be recognized, particularly for the products used to treat hemophilia. Prior to the development of these products 60 or so years ago, this condition imposed a painful and short life on the patients suffering from it. With the availability of these first products, the transmission of hepatitis was reported, and, with the discovery of hepatitis B [3], this virus was shown to be transmitted by concentrates of factor VIII and factor IX. Since it was known that the coagulation factors could not withstand heat treatment in the way albumin could, this procedure was not attempted as a safety measure for many years after the introduction of these products. The lifesaving nature of the products, and the demonstration that most patients who acquired hepatitis B overcame the infection without long-term sequelae, gave the user community – doctors and patients alike – a sense this was an unavoidable result of the treatment.

This sense of complacency bore terrible fruit with the emergence of two other blood-borne viruses which entered the blood supply and the products which were derived from it. This impacted mostly, but not solely, the hemophilia population. The tragic history of the acquired immunodeficiency syndrome (AIDS) epidemic because of the infection of people with hemophilia by human immunodeficiency virus (HIV) has been extensively reviewed [4]. After a decade of continuous improvement in the expectation and quality of life, the hemophilia community was devastated through the infection and the loss of many of its members. The products which saved the community in the 1960s and 70s proved to be its downfall in the 1980s and 90s. concurrently, another hepatitis virus was known to be infecting these patients. It was known that, besides the nosocomially (as well as parenterally) transmitted hepatitis A and the parenterally transmitted hepatitis B, another viral agent, designated as ‘Non A and Non B hepatitis’ (NANBH) was being transmitted through blood and blood products. The virus responsible for most of NANBH was characterized as hepatitis C virus (HCV) in the late 1980s. It was evident that much of the hemophilia population was also infected with this virus. Preliminary studies gave hope that this infection would be more benign than AIDS [5], but these hopes were dashed with accruing evidence that the virus caused chronic liver disease, leading to cirrhosis and mortality in many patients [6].

The community of patients receiving immunoglobulins have also suffered from viral infections conveyed by their treatment products. Viral transmission had not been seen in these patients for several decades after the introduction of the first products, leading to the assumption that viruses were eliminated from the products by the manufacturing process without any other measures being needed. This was shown to be a vain hope in the late 1970s when hyperimmune immunoglobulin used to treat rhesus negative women transmitted NANBH, later shown to be HCV, to East German women given a local product, an episode replicated in Ireland a few years later. In the 1980s and 90s, HCV was also transmitted by normal immunoglobulin given to immunodeficient patients [7]. The consequences of these infections on the patients mirrored those with hemophilia. The consequences of these epidemics in plasma product recipient communities had profound consequences on the plasma industry and all the stakeholders in this landscape, consequences which were reflected in the series of inquiries in various countries attempting to assess the reasons behind these tragic occurrences. The word ‘scandal’ has been continuously bandied in this context. I tend to stay away from this judgmental attitude, as, both as an active member of the sector during many of the years in which these events unfolded, and, also, as a patient myself dependent for many years on plasma products, I tend to see the issue in its totality, which is complex and not able to be resolved through the allocation of blame. Of more importance are the events which reversed this disaster and made plasma products as safe as they are today.

What are the steps taken to ensure safety of blood and plasma products and what lessons have been learnt from the infected blood problems in the 1970s/80s?

The key factor contributing to the viral epidemics was the absence of the kind of viral inactivation measure which made albumin safe. The epidemics accelerated the development of such viral inactivation measures which were introduced into the manufacture of coagulation factor concentrates and immunoglobulins over the 1980s and 90s. Concurrently, donor selection and testing procedures contributed to the safety of blood transfusion but the need to manufacture plasma derivatives from an industrial sized plasma pool meant that the determining factors were inactivation procedures introduced into the manufacturing scheme [2]. This has been confirmed repeatedly over this millennium, as the various pathogens which entered the blood supply and infected the recipients of transfusions have failed to infect the communities of plasma products, despite the lack of selection and testing procedures in many instances. These infections include viruses such as West Nile virus, dengue virus and others. It is incredible to note that plasma product treatments are now safer than standard blood transfusions, a reversal of the situation fifty years ago. For this reason, there can be no respite in ensuring that viral inactivation and similar procedures are maintained and refined when necessary.

What steps are still needed to improve blood/plasma product safety? Is there anything that you would like to see happen in the blood-product industry?

I suggest that the lessons of the plasma industry should be recognized by the transfusion sector and that pathogen reduction technologies for fresh blood components such as red cells, platelets and plasma be introduced without further delay. I am aware that the state of the art in these technologies is not as advanced as with plasma products but I feel that delaying implementation until the technologies are perfect and able to deal with all the agents in all the components is ill-advised and fails to absorb the learnings of the plasma sector.

Given that we have just emerged from a pandemic caused by a new pathogen, we have perhaps been nudged out of a position of possible complacency. How can the risk of transmission of a new – as yet unknown – pathogen in blood products be minimized, and so prevent another contamination disaster like that of HIV?

I reiterate the need for pathogen reduction. The ability to face any epidemic with the knowledge that its penetration into the blood supply, which is quasi-inevitable, will not affect patients, should be enough to support the required investments.

References

1. Cohn EJ. The history of plasma fractionation. In: Advances in military medicine, pp364–443. Little, Brown and Co 1948.
2. Farrugia A. The evolution of the safety of plasma products from pathogen transmission—a continuing narrative. Pathogens 2023;12(2):318 (https://www.mdpi.com/2076-0817/12/2/318).
3. Blumberg BS, Alter HJ, Visnich S. A ‘new’ antigen in leukemia sera. JAMA 1965;191(7):541–546
(https://jamanetwork.com/journals/jama/article-abstract/654843).
4. Evatt BL. The tragic history of AIDS in the hemophilia population, 1982–1984. J Thromb Haemost 2006;4(11):2295–2301 (https://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2006.02213.x).
5. Mannucci PM, Colombo M, Rizzetto M. Nonprogressive course of non-A, non-B chronic hepatitis in multitransfused hemophiliacs. Blood 1982;60(3):655–658 (https://doi.org/10.1182/blood.V60.3.655.655).
6. Makris M, Preston FE, Rosendaal FR, et al. The natural history of chronic hepatitis C in haemophiliacs. Br J Haematol 1996;94(4): 746–752 (https://doi.org/10.1046/j.1365-2141.1996.02343.x).
7. Yap PL. Intravenous immunoglobulin and hepatitis C virus: an overview of transmission episodes with emphasis on manu-facturing data. Clin Ther 1996;18(Suppl B):43–58 (https://www.clinicaltherapeutics.com/article/S0149-2918(96)80195-0/pdf).

The expert

Professor Albert Farrugia PhD
UWA Medical School, The University of Western Australia, 6009 Perth,
Australia

Email: albert.farrugia@uwa.edu.au