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Chapter 14

Knowledge of Viral Hepatitis 1


14.1 Early developments in knowledge of viral hepatitis were noted in the introduction to Chapter 6 of the Preliminary Report. Key stages were:

  • The discovery, in 1965, of the 'Australia' antigen, HBsAg, the surface antigen to the Hepatitis B virus (HBV), followed by the development of tests for the presence of the antigen, and subsequently other components of HBV, which became generally available from about 1970.[1]
  • The identification of the Hepatitis A virus (HAV) by Dr Stephen Feinstone and others, published in 1973.[2]
  • The realisation in around 1974-75 that Hepatitis A and Hepatitis B, as then understood, could not account for a substantial proportion of cases of post-transfusion hepatitis, and that there had to be another form or forms of viral hepatitis to explain the clinical manifestations of hepatic (liver) dysfunction that were known or becoming known.[3]

14.2 In this Report, it is appropriate to discuss more fully the response of the UK Government and other agencies to the emerging knowledge of viral hepatitis during the period when it presented a threat to NHS patients receiving blood, blood components or blood products in the course of medical treatment.

Understanding the risk: background

14.3 The aim of this part of the Report is to describe what was known at critical stages to scientists, practitioners and relevant authorities, not what 'ought' to have been known or accepted. In this early period, scientific developments were reported that, in time, became generally accepted medical knowledge. Developments can often be best identified and described chronologically, by date of publication, as was done in the Preliminary Report. However, inherent in this approach is a risk of representing as contemporaneous knowledge material that would not, and in some cases could not have, at that time, been known or understood by practitioners generally. Further, published data and discussion will reflect work carried out over a period prior to publication. In general, first publication of a finding or theory is more likely to mark the beginning of critical examination of ideas rather than the date of their general acceptance. Scientists exploring the boundaries of current knowledge inevitably develop theories that may be backed up by limited empirical data. Such theories are perhaps unlikely to meet with immediate acceptance by a critical peer group and even less likely to survive challenge by related, or unrelated, specialists. Scientific orthodoxy may resist novel ideas and inhibit their acceptance. Those with control of the funds necessary for the validation of a theory and the implementation of changes required to give practical expression to emerging ideas are even less likely to be easily satisfied.

14.4 On the other hand, the convention that dictates that scientific ideas are presented tentatively where logical absolutes cannot be sustained should not be taken to undermine the impact of publication. Reputation is a significant factor of the author or authors of published work and of the journals in which they publish. It all makes for difficulty in saying when a given scientific proposition was 'established'. All of these comments are as relevant to the early 1970s as they are today.

The early years

14.5 The revolution in knowledge brought about by the discovery of the 'Australia' (or 'hepatitis-associated') antigen, later renamed the Hepatitis B surface antigen (HBsAg), the isolation of the Hepatitis A virus and the inference of the existence of one or more non-A, non-B Hepatitis (NANB Hepatitis) viruses can best be understood by looking in greater detail than was done in the Preliminary Report at some of the key early publications.

14.6 Until the late 1960s, it was generally understood that 'hepatitis' could be transmitted in water-borne (enteral)[4] form or in blood-borne (parenteral)[5] form. It was thought likely that one or more agents causing enteral (also known as 'infectious') hepatitis were viruses and were different from the one or more agents - also thought probably to be viruses - which caused parenteral (also known as 'homologous' or 'serum') hepatitis. It was known that the development of serum hepatitis was associated with blood transfusion but it was thought that the hazard affected a very small proportion of recipients of whole blood, plasma or plasma products. In the mid-1960s, there was no single test or battery of liver function tests which would reliably distinguish carriers of any putative hepatitis virus from those not affected. The consequences of transmission, as understood at the time, varied:

Some patients suffer no upset from the transmitted virus, some may have only a transient liver dysfunction with or without jaundice and yet others may develop a rapidly fatal hepatic necrosis. The incubation period of infective hepatitis is about 20 to 40 days, whereas that of homologous serum hepatitis is 40 to 160 days.[6]

14.7 The emphasis was on short-term signs and symptoms of infection and the two putative forms of hepatitis were distinguished by their periods of incubation before the appearance of clinical symptoms.

14.8 A similar focus on the short term was reflected in early publications of the findings of haemophilia clinicians. Researchers in 1963 reported 'reactions' to the infusion of human AHG concentrate (a stable concentrate of human antihaemophilic globulin - a precursor to the industrial scale production of Factor VIII concentrates used for the treatment of haemophilia).[7] The reactions ranged from mild headaches to nausea, vomiting and pain. In all cases, the signs and symptoms of the reactions observed were reported to have disappeared quickly after the end of the infusion. These were almost certainly not related to the transmission of infection but rather were transient mild immune reactions to the 'foreign' proteins introduced by the AHG. The 1963 report also discussed three possible cases of homologous serum jaundice. It was said that no permanent harm was caused by the patients' reactions. The authors found that jaundice occurred but there was no firm view as to its cause. As with other adverse patient responses, it was not associated with apprehension of any long-term consequences of infection.

14.9 Blood products were associated with a case of jaundice in a haemophilia patient reported in 1966,[8] and with a second, fatal case following the use of cryoprecipitate reported in September 1969.[9] The 1966 case was described as one of transient jaundice from which the patient recovered after a day of nausea and vomiting. The second case, of fulminant hepatitis (a rapidly progressing form of the disease), in retrospect almost certainly a case of fulminant Hepatitis B, presented after some four months of treatment using a total of 162 units of cryoprecipitate. The patient had developed nausea and continuous vomiting with cold, moist, jaundiced skin. He deteriorated rapidly and died. Post-mortem examination of the liver showed extensive hepatocellular damage. Tests for known viruses were carried out. Apart from a rather high titre (concentration) for cytomegalovirus (CMV), the samples tested were described as normal. Blood tested for serum hepatitis antigen, shortly to be called Hepatitis B antigen, gave a weak positive reaction. The conclusion was that the clinical and post mortem findings were 'fully compatible with a diagnosis of serum hepatitis'.[10]

14.10 The report in 1969 stimulated correspondence. A letter published in the British Medical Journal (BMJ) in November of that year reported a further case with symptoms of nausea, itching and jaundice.[11] Biochemical laboratory tests disclosed high levels of alkaline phosphatase (ALP), and aspartate and alanine transaminase (AST and ALT).[12] A purported causal link between the use of concentrates and viral hepatitis was explicit in the letter but the focus remained on jaundice within a relatively short period after use of concentrates. More generally, the letter identified a need for screening for hepatitis infection to reduce transmission risk. It was recognised that, while careful questioning of donors would exclude those who had experienced clinical jaundice, effective reduction of risk depended crucially on a reliable test. The letter stated:

[U]ntil a reliable serological test for viral hepatitis is available the donor with anicteric hepatitis [hepatitis, that is, without jaundice] will go undetected. Cryoprecipitate will remain a potential source for the transmission of hepatitis virus until previous attacks of this form of hepatitis can be reliably diagnosed or an effective means of sterilization ... is produced.[13]

14.11 The laboratory tests were not treated as diagnostic. The letter envisaged serum or viral hepatitis as a single entity requiring a single reliable serological test.

14.12 There was a great deal of uncertainty at the time. The distinction between Hepatitis A and Hepatitis B was not fixed. Dr Rosemary Biggs, a prominent expert at the Oxford Haemophilia Centre, used the terms 'infective hepatitis' and 'viral hepatitis' interchangeably. An editorial in The Lancet in August 1970 cast doubt on the use of the terms 'serum' and 'infectious' to distinguish the two types envisaged at the time.[14] The general state of uncertainty was reflected in a paper presented to the Sub-Committee of Specialists on Blood Problems of the Public Health Committee of the Council of Europe in April 1970, where it was commented that the generally observed distinction between Hepatitis A and Hepatitis B might be artificial.[15]

14.13 For some official purposes, any distinction between infectious hepatitis and serum hepatitis was treated as irrelevant. In the UK, growing awareness of the prevalence of hepatitis led to provision for the notification of cases of the disease.[16] As regards Scotland, the Public Health (Infectious Diseases) Regulations (Scotland) 1932[17] required notification of infective jaundice, then defined to mean spirochaetosis ictero-haemorrhagica (Weil's disease). Those Regulations were amended by the Public Health (Infectious Diseases) (Scotland) Amendment Regulations 1968[18] after which the relevant notifiable disease was simply 'infective jaundice' without further definition.[19] It was intended that all forms of 'infective jaundice' (including 'serum' hepatitis) would be covered. One aim of the regulations was to facilitate a study of the epidemiology of the disease.[20] The scope of the 1968 Regulations is reflected in the incubation periods mentioned in the relevant Scottish Home and Health Department (SHHD) circular.[21] Infective hepatitis was said to have an incubation period of usually 15-40 days, while serum hepatitis was described as occurring less frequently but as a potentially more serious condition with a longer incubation period of usually 60-160 days. The focus was again on 'jaundice' and, apart from differing incubation periods, the symptoms of jaundice did not appear to give rise to any need to differentiate between infective hepatitis and serum hepatitis.

14.14 The official view of the scope of the Regulations was not immediately accepted by all. Dr John Wallace of the Glasgow and West of Scotland Blood Transfusion Service (then and thereafter frequently a member of UK expert advisory groups) wrote to Dr Ian Macdonald of the SHHD, on 27 February 1969 asking for the official position on notification of serum hepatitis.[22] The response was that 'infective jaundice' was notifiable and that that included serum hepatitis.[23] For reporting purposes, then, a distinction between infective and serum hepatitis was not recognised by SHHD in these exchanges but it was agreed that the subject of notification was worthy of further consideration by the Transfusion Directors.[24] The Regional Blood Transfusion Directors subsequently proposed that the notification system should disclose the following:

Patients developing infective jaundice at a relevant period after having had blood or blood products.


Cases where patients are donors and who might have given blood whilst infected.[25]

14.15 The emphasis on a 'relevant period' appears clearly to have implied that the reporting obligation would still extend only to cases of overt, clinical jaundice.

UK research projects and reports

Haemophilia Centre Directors' Report

14.16 The Directors of the (then) 36 Haemophilia Centres of Great Britain decided in 1967 to make a study of the incidence of transfusion hepatitis and inhibitors,[26] described as 'the two most alarming complications of treatment of patients with coagulation defects'.[27] During the years 1969 and 1970, before the ready availability of HBsAg screening tests, data were sought on the varieties and amounts of therapeutic materials used and on the incidence of 'inhibitors and jaundice'. On 5 April 1971 the results were presented to a meeting of the Haemophilia Centre Directors as a 'Report on the progress of the MRC Cryoprecipitate Working Party Survey of the Incidence of Transfusion Jaundice and the Incidence of Inhibitors in Haemophilic and Christmas Disease Patients'. The Inquiry has not found a follow-up from the Medical Research Council (MRC) to this particular report, although, as noted below (paragraphs 14.20-14.23), a Working Party of the MRC conducted its own research on recipients of blood transfusions at a single hospital in or around the same period. The relationship, if any, between this study and the later MRC study is not clear.

14.17 The Haemophilia Centre Directors' report noted that transfusion-transmitted hepatitis was thought to be a viral infection and that there was every reason to suppose that the virus was contained in the various protein fractions used to treat haemophilia and Christmas disease (Haemophilia B), listed as cryoprecipitate, human antihaemophilic globulin and Factor IX concentrate. It stated:

No attempt was made to record sub clinical hepatitis since the important feature from the point of view of these patients is clinical illness.[28]

14.18 Of the 1066 patients reviewed in 1969, 34 had not been treated in the year, reducing the relevant cohort to 1032, in which 29 cases of clinical jaundice were recorded, an incidence of 2.8%. All of those patients were severely affected[29] by haemophilia or Christmas disease. The report contained detailed analyses of the materials used and the relationship between donor exposure and infection. The blood of 60 patients was tested for hepatitis associated antigen and antibody; and 11 tested positive, only one of which developed clinical hepatitis. The view expressed was that the overall low incidence of clinical illness was presumed to be due to the fact that the patients developed immunity in childhood. This led to the incorrect conclusion that patients with coagulation defects were very resistant to clinical infection with HBV. Lack of understanding of the natural history of the disease was a major contributory factor leading to incorrect inferences at this time (1971).

14.19 The results of the study were published by Dr Biggs in 1974.[30] By then, the text had been amended to cover the period 1969-71 and screening for HBV had been instituted. The study included 1837 patients, 62 of whom had 64 instances of clinical jaundice, an incidence of 3.48%. Again, most were severely affected haemophilia or Christmas disease patients. A total of 302 patients were tested by various methods for hepatitis associated antigen and antibody. About 30% were antigen or antibody positive. A smaller proportion was noticeably ill. The emphasis in the paper remained on clinically apparent hepatitis, typically manifested by jaundice.

Blood Transfusion Research Committee Cryoprecipitate Working Party

14.20 As noted above, the MRC Blood Transfusion Research Committee Cryoprecipitate Working Party conducted further research in the early 1970s to look into the relationship between transfusion and hepatitis in the UK. Members of the group included Professor Sheila Sherlock, Professor Ari Zuckerman, Dr William Maycock and Dr John Wallace. Its final report was published in 1974.[31] After excluding several groups of patients who fell out of the study for various reasons, 768 patients who had received blood transfusions at the Central Middlesex Hospital were studied intensively for six months after transfusion, both clinically and by laboratory tests for liver function.

14.21 The overall incidence of icteric and anicteric hepatitis (that is, hepatitis with or without jaundice) was 1%. Of the 768 patients, eight were judged to have developed post-transfusion viral hepatitis on the criteria applied by the group. The study identified 35 other patients who showed 'conspicuous or sustained' elevated liver function (specifically, ALT) test results but were judged not to have symptoms or physical signs suggestive of viral hepatitis. A further 115 patients had ALT rises after transfusion but 'were thought not to have viral hepatitis'.

14.22 In discussing the criteria used for the diagnosis of hepatitis, the report stated:

Liver biopsy may provide incontrovertible confirmatory evidence of hepatitis but this procedure is seldom undertaken. Where liver biopsy was not performed, that is to say in the majority of the survey patients, reliance was placed on clinical evidence and measurement of serum ALT. The duration and degree of elevation of the enzyme that qualify a patient for inclusion in the hepatitis group must be critically examined. Neither a rise in ALT, nor its magnitude, is a specific indication of hepatitis. In some previous studies a transaminase level was arbitrarily defined below which a diagnosis of hepatitis was not made ... In the present survey no such arbitrary lower limit was set. However, if other factors were present which might have caused the enzyme rise these patients were not considered to be suffering from viral hepatitis; it was accepted that these other factors were a more likely cause of the liver damage ... This rigid exclusion of all patients having other possible causes for their liver damage may have contributed to the low incidence of hepatitis in the present study.[32]

14.23 Other possible causes of an underestimate were also explored.

14.24 By 1974, the tests available for HBsAg and antibody to Hepatitis B (anti-HBs) remained relatively insensitive. The work of the MRC group was carried out in an era when overt clinical jaundice was still regarded as a good marker of 'post-transfusion hepatitis'. The existence of non-A, non-B Hepatitis (NANB Hepatitis) had yet to be reported and, therefore, the incidence of post-transfusion NANB Hepatitis virus infection could not have been, and was not, discussed. Though understandable in context, the firm exclusion of raised ALT without other clinical manifestations of infection as a diagnostic feature of viral hepatitis, even where there was no other indicator of liver inflammation, was to have a significant and continuing impact on the understanding in the UK of viral hepatitis generally.

14.25 These studies represented significant initiatives in hepatitis research in the late 1960s and early 1970s. The approach adopted towards the identification of viral hepatitis in those studies would characterise UK research for a considerable period. As a result, in retrospect, the true incidence of post-transfusion hepatitis was underestimated. Dr Harvey Alter and Dr Leonard Seeff later analysed the data relating to the patients reported in the MRC Working Party study and concluded, in retrospect, that 80% of those with sustained elevated liver function test results had NANB Hepatitis, although in the original report the patients were not judged to have had 'post-transfusion hepatitis', as there defined, at all.[33] Arithmetically, if the report's assessment of HBV infection had been sound, the proportion of patients with NANB Hepatitis would have been even higher than indicated by Alter and Seeff.

14.26 The MRC report represented the views of Professor Zuckerman and Professor Sherlock, both recognised at the time as authoritative commentators. In December 1975, the SNBTS Directors agreed with the main recommendations of the report when it was presented by Dr Wallace, a member of the group from the Glasgow and the West of Scotland Blood Transfusion Service.[34] In light of later knowledge, the MRC study was not a sound basis upon which one could draw conclusions about the prevalence of post-transfusion hepatitis in the UK, though it clearly represented informed opinion at the time. In his evidence to the Inquiry, Dr Brian McClelland, South East Scotland Blood Transfusion Service, stated that when he read the 1974 report in the early 1980s he realised that it did not tell transfusionists and others what they needed to know.[35] His efforts aimed at promoting research into the prevalence of post-transfusion NANB Hepatitis, against the resistance generated by established views, are discussed in Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis. The erroneous conclusion drawn from the study, that post-transfusion hepatitis was rare in the UK, persisted until 1980 and was promoted even later by some experts.

14.27 At the same time as these studies were taking place, there were also developments at the UK Government level and internationally.

The Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen: First Report

14.28 The Department of Health and Social Security (DHSS) responded promptly to advice received in July 1970[36] that it should give any assistance it could in instituting testing for the 'Australia' antigen. In September 1970 the three territorial Health Departments appointed the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen, to advise them on 'the organisation of and responsibility for testing blood donations and other specimens of blood for Australia (hepatitis-associated) antigen and its antibody in the hospital service' and related matters.[37] The initial members of the advisory group included some who would play a central role in the development of policy advice in the UK: Dr Maycock, the chairman, Dr David Dane,[38] Professor Albert Marmion (Edinburgh University Medical School), Dr Wallace (Glasgow and West of Scotland Blood Transfusion Service) and Dr, later Professor, Zuckerman.

14.29 The Group published a first (revised) report in May 1972.[39] It set out the understanding of viral hepatitis of this group of experts at that date:

The association between the [hepatitis associated/Australia] antigen and serum hepatitis, commonly accepted as the most frequent form of hepatitis observed following the injection of blood and blood products, is well-established and the antigen can now be detected by a variety of laboratory tests .... Australia antigen appears not to be associated with infectious hepatitis which may also be transmitted by blood and blood products.[40]

14.30 It was suggested that the 'hepatitis agent' might be less widely dispersed in the UK than in some other countries but it was nonetheless recommended that testing, for both the antigen and its antibody, should be introduced generally. The principal recommendations included:

[T]he Regional Transfusion Centres should begin, at the earliest possible date, to test all blood donations for the presence of Australia (hepatitis-associated) antigen and its antibody....


[A] donor found to be antigen or antibody positive should not be allowed to continue as a donor of blood intended for clinical use.[41]

World Health Organization Scientific Group on Viral Hepatitis 25-30 September 1972

14.31 Professor Zuckerman was a member of the Secretariat of the World Health Organization (WHO) Scientific Group on Viral Hepatitis, a body composed of eminent international experts, including Professor Marmion of Edinburgh. The report 'Viral Hepatitis', Number 512 of the Technical Report Series, set the scene more widely and reflected an international understanding of the position.[42] The Introduction to the report indicated that the focus for the group was on viral Hepatitis A, epidemic or infectious hepatitis, and viral Hepatitis B, serum hepatitis. In comparison with the group's earlier reports, in 1953 and 1964, it was stated:

[B]ecause of the discovery of the Australia antigen in 1961[43] and its subsequent recognition as a specific marker of infection with the agent of viral hepatitis B, there has been great progress in the understanding of the clinical, epidemiological and immunological behaviour of this form of the disease. Relatively speaking there has been much less progress in the understanding of viral hepatitis A but there have been some advances ....[44]

14.32 The report noted the change in terminology, from reference to 'Australia' as a descriptive term in describing the antigen and antibody, to the abbreviations 'HB Ag', and 'HB Ab', explaining that:

The terminology of the actual disease is more difficult. The general term viral hepatitis refers, by common usage, to hepatitis caused by two presumptive viruses, although it is recognised that other viruses may also be implicated.

It is proposed that the common forms of viral hepatitis be subdivided principally on epidemiological grounds, taking into consideration the presence of hepatitis B antigen, into:

Viral hepatitis type A,


Viral hepatitis type B.

There is substantial historical, epidemiological, and experimental evidence to suggest that these two types of hepatitis are caused by antigenically distinct agents. It is appreciated that it is not possible to allocate every patient with hepatitis to one of these two groups and that viral hepatitis infections exist that are due to other agents, only some of which have been recognised. This is a problem frequently confronting epidemiologists, clinicians, and pathologists that will only be resolved when the different etiological agents of hepatitis have been identified.[45]

14.33 The clear inference from this discussion is that, while there were other aetiological agents, it was understood that the common forms of hepatitis were caused by what was called 'viral hepatitis type A' and HBV, although the Hepatitis A virus was not isolated until 1973. The characterisation of the most common forms of hepatitis as comprising (only) two aetiological groups was soon to be undermined.

14.34 The discovery of the Hepatitis B surface antigen, HBsAg, and demonstration of its persistence, resulted in the re-examination of theories and to the conclusion that HBV had a worldwide distribution similar to that previously attributed only to Type A. The report noted that there was developing understanding that not all cases of post-transfusion hepatitis were caused by HBV infection. It continued:

The proportion due to hepatitis B or other undesignated agents probably varies with the circumstances. However, as more hepatitis B carriers are eliminated from serving as blood donors, the proportion of cases due to other types of hepatitis will increase.[46]

14.35 The report also commented:

The present widely employed techniques for detecting hepatitis B antigen in blood are thought to be capable of preventing approximately 30% of cases of post-transfusion hepatitis .... Cases not due to virus B are thought to be due to a variety of causes, including Hepatitis A virus, cytomegalovirus, and other, as yet unidentified agents.[47]

14.36 These comments were an early and explicit recognition that there might indeed be other viruses, in addition to HBV, responsible for post-transfusion hepatitis.

14.37 At the same time as the understanding of the serology and epidemiology of HBV infection was developing, the use of needle biopsy of the liver was becoming much more routine. Hence, for the first time, attempts could be made to correlate serological, biochemical and clinical features of a disease, Hepatitis B, with pathological features seen in the liver.

14.38 The report defined a 'carrier state' of Hepatitis B, which might be associated with liver damage, as a persistent state in individuals in whom the antigen had been detected repeatedly for more than three months. A proportion of carriers had been found to have liver abnormalities ranging in severity from minor changes in the nucleus of the cell to severe hepatitis and cirrhosis:

Two forms of the chronic disease can be distinguished, persistent and aggressive. Clinically, chronic persistent hepatitis is a mild, benign disease, while chronic aggressive hepatitis tends to conform to the clinical syndrome of chronic active hepatitis, in which liver cell dysfunction is often severe and the prognosis is poor. However, considerable overlap exists between the clinical categories and their pathological counterparts. Aggressive changes may be seen in the course of uncomplicated acute viral hepatitis, but the prognosis in these cases is usually excellent.

Chronic persistent hepatitis is characterized ... by preserved lobular architecture, portal inflammatory infiltration, and slight or no fibrosis. It is not always preceded by a recognizable acute illness, and malaise, hepatomegaly and minor abnormalities of liver function are the clinical features. There is no progression to cirrhosis and the prognosis is good.[48]

14.39 Discussing prevalence among blood donors, the report stated:

Great variations in the prevalence of hepatitis B antigen in apparently healthy blood donors have been found in different parts of the world. Prevalence also varies with such factors as the socioeconomic status and sex of the donor, whether he is a volunteer or paid, and whether he lives privately or in an institution. Antigen has been detected most frequently in males in the younger age-groups.[49]

14.40 Further, the picture was changing at that stage:

During the past decade marked shifts in the age- and sex-specific rates for hepatitis have been observed in the USA and some European countries. These changes were subsequently found to be due to an increase in the number of Hepatitis B infections, particularly among males within the 15-29-year age group. The infections were not related to blood transfusion or other medical procedures. These features, together with the loss of seasonal peaks and the increasingly large proportion of urban cases suggested a likely association with the illicit use of drugs. It is quite possible that in addition to the increased risk of parenteral transmission, the mode of life of drug abusers may increase the level of non-parenteral transmission.[50]

14.41 In addition to discussion of the epidemiology of hepatitis, the paper commented on changing perceptions of the relevance of a history of jaundice. Limited surveys had shown that the prevalence of Hepatitis B antigen was no higher amongst blood donors with a past history of jaundice than in those without such a history:

Studies of Hepatitis B infection among volunteers and those naturally infected with the virus suggest that a greater proportion of individuals who have had a mild or inapparent infection become chronic carriers of the antigen than those who have had a more severe illness. For this reason exclusion from blood donation of individuals with a clinical history of hepatitis B infection, but who do not have detectable antigen, may not materially reduce the frequency of hepatitis among the recipients of blood.[51]

14.42 Dr McClelland commented that the 'more sensitive techniques' referred to in the report were actually 'very insensitive' and failed to detect many cases of Hepatitis B. In addition, while noting that there might be 'as yet other unidentified agents', the paper did not develop the risk that one or more might be responsible for significant transmission of infection. Dr McClelland said that the paragraph 'slightly confounded' the extent to which the techniques missed cases of Hepatitis B and their inability to detect non-B cases.[52] This was, nevertheless, an important juncture. The report was authoritative. It drew attention to the existence of a 'carrier state' and associated chronic liver disease, at least for HBV, which was not necessarily associated with a history of clinical jaundice. It provided a remarkable and, in many ways, prescient summary. It was the beginning of a move away from the exclusion of donors with a relatively distant history of hepatitis.[53] By 1973, therefore, to some extent at least, the idea that most post-transfusion hepatitis was attributable to HBV was already beginning to be superseded.

The Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen: Second Report

14.43 The WHO 1973 report was cited in an article on Hepatitis B in hospitals, published in 1974 by Dr Wallace and others.[54] The article quoted the suggestion that individuals with a history of overt hepatitis may not have a high incidence of HBsAg and commented that Dr Wallace had recently published evidence[55] supporting that contention. It was to have a more direct impact on the second report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen. The Group was reconvened on 6 December 1973 and reported in September 1975.[56] By then there had been a considerable advance in knowledge, including a second WHO technical paper, number 570, published in 1975.[57]

14.44 Membership of the Advisory Group in 1975 comprised, among others, the individuals already mentioned in paragraph 14.28 as members of the original 1970 group. By that stage, the Australia (hepatitis-associated) antigen had become universally known as the Hepatitis B surface antigen. The second Advisory Group report discussed current knowledge of the antigen, HBsAg, its homologous antibody, anti-HBs, and the Hepatitis B core antigen-antibody system which was by then becoming recognised. The report stated:

The association between the presence of HBsAg in donor blood and the occurrence of HBsAg positive hepatitis in the recipients after an incubation period of 40-180 days is established. Blood and blood products can also transmit other forms of hepatitis which do not appear to be associated with the presence of HBsAg.[58]

14.45 This second topic was not developed. It was thought likely that exclusion of HBsAg-positive donors would diminish the number of cases of Hepatitis B transmitted in blood and blood products, as it had in the USA.[59] It was also thought, on the basis of published reports, that the incidence of Hepatitis B in recipients of antibody-positive blood was no greater than that of recipients of blood in which neither HBsAg nor anti-HBs was demonstrable. The recommendations were amended to confirm the exclusion from clinical use of blood found to be HBsAg-positive but to recommend that donors whose blood contained anti-HBs might be retained on the panel and their blood used clinically.

14.46 By the date of the second report, it was understood that Hepatitis B antibodies did not necessarily signal recovery from infection. The available evidence suggested that core antibodies might not be protective and that they were present in persistent carriers of HBsAg.[60] The association between HBsAg in donor blood and the occurrence of HBsAg-positive hepatitis in recipients was established.[61]

14.47 The paragraphs from the WHO 1973 report are substantially paraphrased in the observations that:

Published reports show that the incidence of hepatitis B in recipients of antibody positive [blood] is no greater than that of recipients of blood in which neither HBsAg nor anti-HBs is demonstrable. Therefore... we now recommend that donors whose blood contains anti-HBs may be retained on the panel and their donations used clinically.


We have given much thought to the problem of donors with a history of jaundice but in whom neither HBsAg nor anti-HBs is detected. We are not aware of any evidence that a relationship exists between a history of jaundice in donors and the occurrence of icteric or anicteric hepatitis in recipients of their blood. We therefore recommend that the practice of permanently excluding from the panel donors with a history of jaundice should be discontinued provided that HBsAg is not detected by reversed passive haemagglutination or a test of at least equal sensitivity... and that the donor has not suffered from hepatitis or jaundice during the previous twelve months.[62]

14.48 Individuals positive for HBsAg were to continue to be excluded from blood donation.


The Joint Symposium of the Royal College of Physicians of Edinburgh and the Royal Society of Edinburgh

14.49 Scottish experts were represented on the panels reporting nationally and internationally, discussed above. In addition, there was more local study. A joint symposium was held in 1972 by the Royal College of Physicians of Edinburgh and the Royal Society of Edinburgh. The report of the joint symposium provides a base line for assessing Scottish views on many aspects of the topics under review at the start of the reference period.[63] The symposium was largely concerned with blood transfusion and therefore reflected a particular interest within the medical community related to the use of blood and blood products. The discussion also had wider relevance, however.

14.50 Dr Robert Cumming, Regional Director of the Edinburgh and South East Scotland Blood Transfusion Service at the time, gave an introductory talk.[64] He discussed the prevention of adverse effects of transfusion, highlighting improvements in the equipment for handling blood, processing procedures and changes in practice aimed at minimising the traditional risks of incompatibility and bacterial contamination. However, diminishing risks of incompatibility had been offset by an increase in immune-system based risks arising from repetitive transfusion.[65] He referred to, but did not discuss, the detection of diseases transmissible by blood. He emphasised the need for greater knowledge of the dangers inherent in the intensive use of 'potent therapeutic agents of biological origin'.[66]

14.51 Professor Alexander Douglas, Regius Professor of Medicine at Aberdeen University, discussed the use of plasma coagulation factors. His comments on possible adverse effects of therapy were brief:

Side-effects to factor VIII include febrile reactions, the transmission of serum hepatitis and the induction of antibodies to factor VIII .... Using human factor VIII preparations the risk of hepatitis is proportional to the number of donations involved in the material given. In the production, for example, of cryoprecipitate the blood should be screened for Australia antigen.[67]

14.52 On the other hand, while plasma therapy for Haemophilia B patients was associated with non-specific reactions, in Scotland prothrombin therapy (for Haemophilia B) using concentrated materials was thought to be problem-free.[68]

14.53 These contributions by Dr Cumming and Professor Douglas reflected similar interests to those investigated by Dr Biggs. Dr Wallace promoted the advantages of pasteurised albumin product (Plasma Protein Solution) as the product of choice thanks to the heating process involved in its manufacture.[69] It could be presented in stable liquid form as Stable Plasma Protein Solution (SPPS), pasteurised at 60°C for 10 hours, and in that form it was said to be free from the risk of transmitting viral diseases, thus eliminating the hazard of hepatitis. He noted that in general surgery there was progress towards the use of blood components in preference to whole blood. A policy of total fractionation (the division of blood in to its component parts) was advocated as the ideal towards which transfusion services should aim.

14.54 However, it was in the presentation of Dr John Cash,[70] then Deputy Director of the Edinburgh and South East Scotland Blood Transfusion Service, that the risk of hepatitis transmission was most clearly identified.

14.55 By way of introduction, he wrote:

Although the medical profession has long recognised the concept that there are no therapeutic roses without thorns, there is no doubt that the dangers of blood transfusion, in all its forms, have yet to be fully defined. However, in the ardour of therapeutic endeavour, we are frequently guilty of forgetting those hazards which have already been well documented ....

Recent data published by the Registrar General (1971) would suggest that the numbers of deaths attributable to blood transfusion are comparable to those complicating general anaesthesia. Almost 50 per cent of the post-transfusion deaths were due to hepatitis. While not intending to underemphasise the importance of incompatible red cell, white cell and platelet transfusions, allergic reactions to plasma proteins, systemic effects of bacterial pyrogens and heavily contaminated blood and blood products, air embolism, citrate intoxication and haemosiderosis, the magnitude of the hepatitis problem and the recent explosion of highly productive research in this area is so great that it seems appropriate on this occasion to consider this particular feature of safety in some detail.[71]

14.56 Apart from demonstrating considerable literary panache, Dr Cash's assessment of the problem of hepatitis, as then understood, placed it squarely before the medical profession in Scotland. His discussion is, therefore, of particular importance in defining the scope of general knowledge of the risk at this time. He continued:

In 1965, Blumberg et al (1965) reported that sera from two multi-transfused haemophiliac patients formed precipitin lines in the micro-Ouchterlony gel diffusion test when tested against serum from an Australian aborigine. The substance in this serum did not appear to be the usual lipoprotein and was tentatively labelled 'Australia antigen'. Subsequent studies revealed that the presence of Australia antigen was closely associated with viral hepatitis (Blumberg et al, 1967; Blumberg et al, 1968; Prince 1968), and that virus-like particles could be isolated from antigen-positive sera (Bayer et al. 1968). Confirmation of these findings came from all over the world along with the observation by Okochi and Murakami (1968) which clearly indicated that hepatitis frequently followed the transfusion of antigen-positive blood.

These primary observations heralded an explosive research effort in which clinicians, biochemists, geneticists, microbiologists and immunohaematologists have all made important contributions.[72]

14.57 After citing a range of publications on specific issues, which emphasised the familiarity of the NHS in Scotland at this early stage with world-wide research, Dr Cash proceeded:

From the early beginnings of this work, debate has gone on as to whether Australia antigen is responsible for serum hepatitis alone or both infectious hepatitis and the serum form of this disease. Recent work has shown that the classical long incubation (serum) form, while more commonly acquired by the parenteral route, can also be transmitted orally. This suggests that Australia antigen is responsible for the classical serum hepatitis and sporadic cases of infectious hepatitis and that other agents are casually [sic - causally] related to epidemic infectious hepatitis (Simon 1971). However, there seems little doubt that the agents responsible for the epidemic variety can be transmitted parenterally and, therefore, by means of blood transfusion (Koff and Isselbacher 1968).

In 1968, Okochi and Murakami first suggested a possible relationship between hepatitis and the administration of Australia antigen-positive blood. This observation was confirmed by Gocke and Kavey (1969) and both groups have confirmed and extended their original findings (Gocke et al. 1970; Okochi et al. 1970).[73]

14.58 This review was written before Feinstone and Prince's work enabled the provision of markers for HAV and before the publication of evidence for one or more NANB Hepatitis viruses that followed.[74] It appears that, while the presentation contained a number of assertions not ultimately established, the medical profession in Scotland was made aware that (i) there was a causal relationship between transfusion and hepatitis infection; (ii) the Australia antigen/HBsAg was not solely responsible for the transmission of hepatitis infection; and (iii) post-transfusion hepatitis was fatal in some cases. In common with other parts of the UK, some trends in research that were to mark step changes in understanding of viral hepatitis in the USA were not taken into account.[75] It nevertheless appears to be clear that, at the beginning of the reference period, the NHS in Scotland was aware of international research on Hepatitis B and, indeed, was participating in it.

Local research

14.59 Scottish scientists had certainly played a part in developing knowledge of viral hepatitis, however. By 1970, the Blood Transfusion Centres in Edinburgh and Glasgow had started research on hepatitis.[76] In the case of the Glasgow study, this was a direct response to the 1970 WHO Bulletin recommending the detection and exclusion of blood donors carrying Australia antigen.[77] The study distinguished donors tested for the first time and those returning who had previously tested negative. The reported incidence of 0.115% for the general donor population on first testing was in agreement with the general level of about 0.1% for unpaid donors in the USA and in Western Europe. The Glasgow researchers recognised that their test was relatively insensitive and commented that it was 'too early to assess the full significance of total screening ...'. A contemporaneous study on behalf of the National Blood Transfusion Service (NBTS) for England and Wales found that the incidence of Hepatitis B antigen in donations from new general public and factory donors in 1973 was 1:1107 (0.09%).[78] Routine blood screening for what became known as HBsAg and its antibody, Anti-HBs, was instituted in 1974.

14.60 In Edinburgh, systematic study of bleeding patterns in haemophilia patients began in the 1960s and 1970s and progressed to the study of risks of virus transmission, initially focused on HBV.[79] These studies continued into the 1980s.[80] They were initiated by Dr Howard Davies of the Edinburgh Haemophilia Centre and Dr John Peutherer, a virologist; Professor Christopher Ludlam became involved when he succeeded Dr Davies.[81] During the early 1970s it was found that, despite screening, about 10% of susceptible patients became infected each year with HBV but that only a tiny proportion of these became infective HBV carriers.[82] Until the end of the 1970s, screening tests for HBsAg were not sensitive enough to detect all blood donations infected with HBV.

14.61 The incidence of anti-HBs in haemophilia patients suggested that a significant proportion had become infected by HBV. Dr Biggs' 1974 paper, discussed above (paragraph 14.19), recognised that factor concentrates generally were associated with a risk of transmitting hepatitis.[83] Others were more definite in their conclusions. Writing in 1974, Dr Donald Buchholz said that, 'hepatitis reigns supreme as the major cause of transfusion-associated disease'.[84]

14.62 Dr Biggs' 1974 review also noted that post-transfusion hepatitis was caused by several viruses which might occur in donor plasma and hence in the various protein fractions used to treat haemophilia and Christmas disease. The ability to identify both the Hepatitis B antigen and antibody enabled scientists to estimate the proportion of cases of post-transfusion hepatitis associated with Hepatitis B, within the limits of sensitivity and specificity of the tests available from time to time.

Research in the United States of America

14.63 It is appropriate at this point to take note of research that had not entered into the UK reports already discussed. Research projects in the USA in the early to mid-1970s, led by Alter, Aach, Knodell and Seeff, led to a conclusion by 1974-75 that Hepatitis B, the main focus of attention in the UK, was responsible for only a low proportion of transfusion-associated hepatitis. This research is discussed in more detail in the next chapter (Chapter 15, Knowledge of Viral Hepatitis 2).

14.64 The Hepatitis A virus, responsible for most enteric hepatitis was identified in 1973 by Feinstone and others.[85] At that time, however, there were still no blood tests to detect either its presence in the blood or the fact that an individual had been exposed to the virus but subsequently cleared it. That development would come in 1974-75. At the beginning of the reference period, in 1974, scientists were approaching a critical change in understanding that would lead to the identification of forms of hepatitis that were neither form A nor form B, but that stage had not yet been reached.

Towards non-A, non-B Hepatitis/Hepatitis C

14.65 Following the opinion that Hepatitis B accounted for a relatively small proportion of cases of post-transfusion hepatitis, doubts grew on epidemiological grounds over whether Hepatitis A could account for the majority of cases of post-transfusion hepatitis as was implied in earlier discussion.[86] In 1974, Alfred Prince and others suggested that a substantial proportion of post-transfusion hepatitis cases were caused neither by the Hepatitis A virus nor by the Hepatitis B virus and they suggested the existence of an additional hepatitis virus or viruses which would require 'identification of a hepatitis virus(es) type C'.[87] It was to be long before the term 'Hepatitis C' entered the vocabulary but Dr Prince and colleagues had clearly noted the need for differentially identified types of hepatitis virus in their original work.

14.66 The identification of the specific Hepatitis A virus by Stephen Feinstone's team provided a basis for proof of Prince's hypothesis.[88] Serological analysis in 1975 of stored sera from the earlier studies revealed that none of the cases of transfusion-associated hepatitis could be attributed to HAV.

14.67 Following this work, the expression 'non A, non B hepatitis' (frequently abbreviated to 'NANBH' or 'NANB Hepatitis') was coined as a collective term for hepatitis from which, at that time, Hepatitis A and Hepatitis B, as well as CMV and Epstein-Barr virus (both of which can cause liver inflammation), had been excluded.[89] In due course, and much later, further research led to the identification of the Hepatitis C virus as the principal cause of the condition described.[90] As at 1974, knowledge of HAV, HBV and NANB Hepatitis infection was not developed and was not widely disseminated. Awareness of the risk of viral infection from blood and blood products was relatively unrefined and unsophisticated.

14.68 There is a serious risk, in citing the work of researchers such as Feinstone and Prince, of giving the impression that their ground-breaking research immediately entered the common currency of general medical knowledge and informed clinical practice. That would be as unfair as it would be unrealistic. The view that there were only two relevant hepatitis viruses had support in the UK in the 5th edition of Professor Sherlock's book, Diseases of the Liver and Biliary System, published in 1975. The book can be taken to provide an authoritative description of the state of knowledge available to the medical profession in the UK generally in 1974-75.[91] Hepatitis A was not identified as a separate cause of concern; despite Professor Sherlock's observation that the disease might be transmitted parenterally, it was not thought to be associated with transfusion.[92] Hepatitis B was described as a 'long incubation disease'. It was said to be spread classically by therapeutic administration of blood and blood products but could also be spread orally and sexual spread was considered likely.[93] The 5th edition contained no reference to the NANB Hepatitis virus.

Diseases of the Liver and Biliary System (1975)

14.69 Professor Sherlock's description of the clinical course of hepatitis included the following comments:

Hepatic involvement, particularly to the extent of jaundice, is an infrequent complication of rather a common virus infection. The picture varies widely, ranging from slight malaise to a severe and fatal disease culminating in hepatic coma ....

In general, type A and type B hepatitis run the same clinical course. Type B tends to be more severe and may be associated with a serum sickness-like syndrome. The relationship of type B to chronic liver disease has been established ....

The severity is very variable. The mildest attack is without symptoms and marked only by a rise in serum transaminase levels. If it is of type B there is transient HBAg positivity. Alternatively, the patient may still be anicteric but suffer gastro-intestinal and influenzal-like symptoms ....

The usual icteric attack in the adult is marked by a prodromal period usually about 3 or 4 days but even up to 2 or 3 weeks.


The prodromal period is followed by darkening of the urine and lightening of the faeces. This heralds the development of jaundice and symptoms decrease .... Appetite returns and abdominal discomfort and vomiting cease. Pruritus [itching] may appear transiently for a few days.


The adult loses about 10 lb weight. A few vascular spiders may appear transiently.

After an icteric period of about 1-4 weeks the adult patient makes an uninterrupted recovery .... After apparent recovery lassitude and fatigue persist for some weeks. Clinical and bio-chemical recovery is usual within 6 months of onset.[94]

14.70 Professor Sherlock noted the possibility of prolonged jaundice, also followed by complete recovery, and commented on 'post-hepatitis syndrome' as a condition leaving the patient feeling 'below par' for weeks or months.[95] She commented that chronic persistent hepatitis, chronic active hepatitis, post-hepatitic scarring and cirrhosis could all develop.[96] Of these, the author described chronic persistent hepatitis as benign. She continued:

Chronic active hepatitis often proceeds to or is associated with cirrhosis. Chronic active hepatitis also has many causes. The mechanism by which hepato-cellular necrosis proceeds in any individual to chronic active hepatitis and finally to the irreversible stage of cirrhosis is in most instances unknown. Knowledge of the factors determining this course would give the key to the development of cirrhosis.[97]

14.71 For comparison, the observations of Prince and others in their 1974 paper are noteworthy. The authors suggested, albeit tentatively, that there were long-term risks associated with Hepatitis B and non-B viruses:

Long-term complications of acute hepatitis-B infection, such as chronic hepatitis, cirrhosis, and hepatoma, have been reported to follow mild anicteric infections more frequently than severe icteric cases; consideration must thus also be given to the possibility that non-B hepatitis may play a role in the aetiology of some forms of chronic liver disease.[98]

14.72 Notwithstanding these differences, Professor Sherlock's analysis would have been understood by most, if not all, clinicians in the UK to be an authoritative exposition of knowledge of viral hepatitis at the beginning of the reference period.

Knowledge of blood-borne hepatitis at the outset of the reference period: Summary

14.73 Knowledge of blood-borne hepatitis was rudimentary in the early 1970s. The results of reported studies were just beginning to make an impact on thinking among scientists at the leading edge of research. Among clinicians generally, Professor Sherlock's views would have been definitive of the state of knowledge. In other respects, there was uncertainty:

  • The work of Blumberg and others initiated a new era of research but knowledge of hepatitis and the forms recognised at the time remained incomplete.
  • Routine (fairly sensitive) testing for HBsAg in all donor blood meant that from this time new cases of post-blood transfusion hepatitis caused by HBV would become rare in the UK, although that would become clear only later.
  • Early surveys with relatively insensitive tests suggested that the prevalence of HBsAg positivity was about 1:1000 of the donor population in Scotland and England.
  • The fact that at least 20% of haemophilia patients treated with clotting factor had markers of past infection with HBV was recognised.
  • Serum markers of HBV in routine use were still confined to HBsAg - correctly thought to be an indicator of potential infectivity - and anti-HBs - correctly thought to indicate past infection with HBV and to indicate immunity from further infection as well as lack of infectivity.
  • Understanding of the natural history of HBV infection, and particularly of the groups at risk of developing chronic HBV infection, was still poorly developed.
  • Factor therapy had become more and more popular with haemophilia patients and their doctors[99] and there was a consequent significant increase in demand on the supply of blood from which these factors were extracted.[100]

14.74 Matters that were just beginning to be reported yet had a significant impact on knowledge in the UK were:

  • Recognition that HBV accounted for only a relatively small proportion of cases of post-transfusion hepatitis was beginning to be reported.
  • HAV had been discounted as a cause of most post-transfusion hepatitis infections following Feinstone's characterisation of the virus and the development of serological tests for it.
  • The term NANB Hepatitis was coined for hepatitis from which, at that time, HAV and HBV, CMV and Epstein-Barr virus had been excluded as causative agents.
  • Prince and colleagues had already reported that long term complications of acute Hepatitis B infection, such as chronic hepatitis, cirrhosis and hepatoma, appeared to have followed mild anicteric infections more frequently than severe icteric cases.
  • However, the prevalence of what would become NANB Hepatitis was not known, and there was no understanding of its natural history or of its epidemiology.

1 Preliminary Report paragraphs 6.12-6.14

2 Ibid paragraphs 6.22-6.23

3 Ibid paragraphs 6.28-6.32

4 Strictly speaking, an enteral infection is one spread through the introduction of a pathogen to the gastrointestinal tract.

5 Again, strictly speaking, a parenteral infection is one spread by a means other than by the introduction of a pathogen to the gastrointestinal tract and, in this general way, does not refer only to blood-borne infections. Medical literature of the time, however, used the term parenteral, at least as regards hepatitis, to mean 'blood-borne' and this usage is retained here.

6 Grant, 'Complications of Blood Transfusion', The Practitioner, 1965; 1166:184-5 [LIT.001.5542] at 5547

7 Maycock et al, 'Further Experience with a Concentrate Containing Human Antihaemophilic Factor', British Journal of Haematology, 1963; 9:215 [LIT.001.0063]. Dr Maycock and three of his colleagues were, at the time, associated with the Lister Institute of Preventative Medicine. One colleague was associated with the laboratory at Lewisham Hospital, London.

8 Del Duca & Eppes, 'Hepatitis Transmitted by Antihemophilic Globulin, New England Journal of Medicine, 1966; 965 [PEN.018.1455]

9 Whittaker & Brown, 'Serum Hepatitis in a Haemophiliac', British Medical Journal, 6 September 1969 [LIT.001.0248]

10 Ibid [LIT.001.0248]

11 Fitzpatrick & Kennedy, 'Serum Hepatitis in a Haemophiliac', British Medical Journal, 1 November 1969 [LIT.001.0249]

12 These proteins, synthesised in liver cells and normally present in low levels in the blood, become elevated when the liver is disordered by virus infection or other hepatic disorders.

13 Fitzpatrick & Kennedy, 'Serum Hepatitis in a Haemophiliac', British Medical Journal, 1 November 1969 [LIT.001.0249]

14 'More about Australia Antigen and Hepatitis', The Lancet, 15 August 1970 [DHF.002.7334]

15 Paper Submitted to the Sub-Committee of Specialists on Blood Problems of the Public Health Committee of the Council of Europe on the Subject of Hepatitis Associated Antigen and the Antibody to It [DHF.001.1745]

16 Professor Zuckerman had pressed for notification in 1966 as essential for the measurement of the scale of post-transfusion hepatitis in the UK. See Zuckerman, 'Blood Transfusion and Infectious Hepatitis', British Medical Journal, 1966; 1136 [LIT.001.0247]

17 S.I. 1932/1047

18 S.I. 1968/1493

19 SHHD Health and Welfare Services Circular No. 26/1968 dated 27/09/1968 [SGH.002.3268]

20 Memorandum [SGH.002.3266]. In the event, the regulations were ineffective for that purpose. See Chapter 3, Statistics, paragraphs 3.9-3.13

21 Memorandum [SGH.002.3266]

22 Dr Wallace's Letter [SGH.002.3256]

23 SHHD Reply to Dr Wallace's Letter [SGH.002.3255]

24 Ibid [SGH.002.3253]

25 Undated letter to Dr Gordon [SGH.002.3248]; Extract from Minutes of Meeting of Regional Directors on 06/05/69 [SGH.002.3249]

26 Inhibitors are antibodies to Factor VIII. Haemophilia patients, particularly at this time, who developed inhibitors faced additional challenges in terms of therapeutic practice, as infusion of Factor VIII was not possible without serious risk.

27 Appendix to Agenda for a Meeting of Haemophilia Centre Directors on 5 April 1971 entitled 'Report on the progress of the MRC Cryoprecipitate Working Party survey of the incidence of transfusion jaundice and Factor-VIII Antibodies in Treated Patients with Haemophilia and Christmas Disease' [DHF.001.1811] at 1812.

28 Appendix to Agenda for a Meeting of Haemophilia Centre Directors 05/04/71 entitled 'Report on the progress of the MRC Cryoprecipitate Working Party survey of the incidence of transfusion jaundice and Factor-VIII Antibodies in Treated Patients with Haemophilia and Christmas Disease' [DHF.001.1811] at 1812

29 See Chapter 2, Patients at Risk, paragraphs 2.24-2.27 for a discussion of the classification of haemophilia in to 'mild', 'moderate' and 'severe' categories.

30 Biggs, 'Jaundice and antibodies directed against factor VIII and IX in patients treated for haemophilia or Christmas disease in the United Kingdom', British Journal of Haematology, 1974; 26: 313-329 [LIT.001.0099]

31 Medical Research Council Working party on Post-Transfusion Hepatitis, 'Post-transfusion hepatitis in a London hospital: results of a two-year prospective study', Journal of Hygiene Cambridge, 1974; 73:173-188 [LIT.001.0116]

32 Ibid [LIT.001.0116] at 0127

33 Zuckerman and Thomas (eds), Viral Hepatitis: Scientific Basis and Clinical Management 1993; page 472, table 29.2. Ironically, it is possible that the MRC approach was influenced by the views of Professor Zuckerman.

34 Minutes of the SNBTS Directors' Meeting of 17 December 1975 [SNF.001.0011] at 0013

35 Day 63, page 71

36 Note of a Meeting held on 20 July 1970 to Discuss the Problems of the Hepatitis Associated Antigen in Relation to Blood Transfusion and Associated Matters [DHF.001.1751]

37 Revised (first) Report of the Advisory Group on Testing for the Presence of Australia (Hepatitis Associated) Antigen and its Antibody [DHF.001.1980] at 1983

38 Dr Dane led the team of scientists who, in 1970, discovered the complete Hepatitis B virus.

39 Revised (first) Report of the Advisory Group on Testing for the Presence of Australia (Hepatitis Associated) Antigen and its Antibody [DHF.001.1980] at 1983

40 Ibid [DHF.001.1980] at 1984

41 Ibid [DHF.001.1980] at 2000

42 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization Technical Report Series, No. 512, 1973 [SGH.002.9746]

43 1961 is the date noted, but accurate dates for 'discovery' range from 1965 to 1967. See the quotation from Dr Cash at paragraph 14.56, below.

44 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization Technical Report Series, No. 512, 1973 [SGH.002.9746] at 9750

45 Ibid [SGH.002.9746] at 9751-9752

46 Ibid [SGH.002.9746] at 9754

47 Ibid [SGH.002.9746] at 9762

48 Ibid [SGH.002.9746] at 9757

49 Ibid [SGH.002.9746] at 9761

50 Ibid [SGH.002.9746] at 9755

51 Ibid [SGH.002.9746] at 9761

52 Day 9, page 108

53 Day 9, page 106

54 Payne, Barr and Wallace, 'Hepatitis B antigen (HBAg) and its antibody (HBAb) in hospital patients', Journal of Clinical Pathology, 1974; 27:15-129 [PEN.002.0830]

55 Wallace et al, 'Total Screening of Blood Donations for Australia (Hepatitis Associated) Antigen and its Antibody', British Medical Journal, 11 March 1972 [SGH.002.9831]

56 Second Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody [SGH.003.0079]

57 'Viral Hepatitis: Report of a WHO Meeting' World Health Organization Technical Report Series, No.570, 1973 [LIT.001.3272]

58 Second Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody [SGH.003.0079] at 0083

59 Ibid [SGH.003.0079] at 0084

60 Ibid [SGH.003.0079] at 0083

61 Ibid [SGH.003.0079] at 0083

62 Ibid [SGH.003.0079] at 0084-0085

63 Proceedings of the Royal Society of Edinburgh Section B (Biology) 1972; vol 71 Supplement [PEN.002.0407]

64 Ibid [PEN.002.0407] at 0408

65 This phenomenon was to re-emerge in the 'antigen overload' theory, developed in the early 1980s as an alternative to the 'infective agent' theory of AIDS. See Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1.

66 Proceedings of the Royal Society of Edinburgh Section B (Biology) 1972; vol 71 Supplement [PEN.002.0407] at 0410.

67 Douglas, 'Plasma Coagulation Factors', Proceedings of the Royal Society of Edinburgh 1972; Section B (Biology), vol 71 Supplement [PEN.002.0575] at 0578

68 Ibid [PEN.002.0575] at 0579

69 Wallace, 'New Approaches to the Supply of Blood and Plasma', Proceedings of the Royal Society of Edinburgh 1972; Section B (Biology) vol 71 Supplement [PEN.018.1026] at 1029

70 Cash, 'Principles of Effective and Safe Transfusion', Proceedings of the Royal Society of Edinburgh 1972; Section B (Biology), vol 71 Supplement [PEN.002.0559]

71 Ibid [PEN.002.0559] at 0563

72 Ibid [PEN.002.0559] at 0563

73 Ibid [PEN.002.0559] at 0564

74 Feinstone et al, 'Hepatitis A: Detection by Immune Electron Microscopy of a Viruslike Antigen Associated with Acute Illness', Science, 1973; 182:1026 [PEN.010.0110]

75 See paragraph 14.63 et seq below

76 Dr McClelland - Day 9, pages 20-22

77 Wallace et al, 'Total Screening of Blood Donations for Australia (Hepatitis Associated) Antigen and its Antibody', British Medical Journal, 11 March 1972 [SGH.002.9831]

78 'Frequency of HBAg and Anti-HBAg Exported by RTCs New General Public and Frequency Donors and in Donors in Armed Forces and in Prison Borstals and Similar Institutions' [SGH.001.7095]

79 Edinburgh Haemophilia and Thrombosis Centre - Appendix to Professor Ludlam's Witness Statement [PEN.012.0351]; Burrell et al, 'Antibody to hepatitis B surface antigen in haemophiliacs and their household contacts,' Journal of Clinical Pathology, 1974; 27:323-325; Burrell, 'Antibody to hepatitis B surface antigen in haemophiliacs on long term therapy with Scottish Factor VIII', Journal of Clinical Pathology, 1978; 31:309-12. Abstract at [SNB.008.2073]

80 Edinburgh Haemophilia and Thrombosis Centre - Appendix to Professor Ludlam's Witness Statement [PEN.012.0351]; Stirling et al, 'Liver function in Edinburgh haemophiliacs: a five year follow-up', Journal of Clinical Pathology, 1981; 34:17-20 [LIT.001.0748]

81 Professor Ludlam Day 44, page 7; Edinburgh Haemophilia and Thrombosis Centre - Appendix to Professor Ludlam's Witness Statement [PEN.012.0351]

82 Day 44, page 6; Stirling et al, 'Incidence of Infection with Hepatitis B virus in 56 patients with haemophilia A 1971 - 79', Journal of Clinical Pathology, 1983; 36:577-80. Abstract at [SNB.008.2056]

83 Biggs, 'Jaundice and antibodies directed against factor VIII and IX in patients treated for haemophilia or Christmas disease in the United Kingdom', British Journal of Haematology, 1974; 26: 313-329 [LIT.001.0099]

84 Buchholz, 'Blood Transfusion: Merits of Component Therapy', The Journal of Pediatrics, 1974; 84: 165 [LIT.001.0141] at 0145

85 Feinstone et al, 'Hepatitis A: Detection by Immune Electron Microscopy of a Viruslike Antigen Associated with Acute Illness', Science, 1973; 182:1026 [PEN.010.0110]

86 Preliminary Report, paragraph 6.28

87 Prince et al, 'Long-Incubation Post-Transfusion Hepatitis Without Serological Evidence of Exposure to Hepatitis-B Virus', The Lancet, 3 August 1974 [LIT.001.0363]

88 Though published first, Feinstone's work is said to have been later in date (see, for example, Viral Hepatitis: Scientific Basis and Clinical Management ed Zuckerman and Thomas: 1993 page 470) but this must be questioned in view of the citation in the Prince paper of one paper read at the 6th symposium of the American Red Cross in May 1974. See the Preliminary Report, paragraph 6.29.

89 See, for example, Alter et al, 'Clinical and serological analysis of transfusion-associated hepatitis', The Lancet, 1975; 2: 838-841 [LIT.001.3926] where Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) were excluded as causal agents of NANB Hepatitis.

90 Identified by the Chiron Corporation in spring 1988 and announced on 10 May 1988. See Chapter 16, Knowledge of Viral Hepatitis 3 - 1986 Onwards. In the mid 1970s, the position was not clear. A letter to The Lancet of 16 November 1974 by Fiala and others of California and two Abbott workers, Overby and Ling, in response to Prince, suggested that more work was required on the possible role of cytomegalovirus in hepatitis. Fiala et al, 'Ctytomegalovirus in non-B post-transfusion hepatitis', The Lancet, 16 November 1974 [LIT.001.3930]

91 Later editions remained authoritative while Professor Sherlock was general editor.

92 Sherlock, S. Diseases of the Liver and Biliary System, 5th ed. 1975, Blackwell, Oxford, page 305

93 Ibid page 306

94 Ibid page 321-322 (emphasis in original)

95 Ibid page 324

96 Ibid page 333

97 Ibid page 390

98 Prince et al, 'Long-Incubation Post-Transfusion Hepatitis Without Serological Evidence of Exposure to Hepatitis-B Virus', The Lancet, 3 August 1974 [LIT.001.0363] at 0368

99 In 1974 Peter Jones, a Haemophilia specialist, published Living with Haemophilia (Lancaster: Medical and Technical Publishing Co. Ltd). This was written as an introductory guide to haemophilia for haemophilia patients and their families, and reflected the contemporaneous views of haemophilia groups.

100 See Spencely & Cash, 'Factor VIII replacement in the treatment of haemophilia A - a simple illustration of a need-supply-demand spiral', British Journal of Preventative Medicine, 1974; 28: 71 [LIT.001.0149]

15. Knowledge of Viral Hepatitis 2 - 1975 to 1985 >