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Chapter 25

Screening of Donated Blood for Hepatitis B


25.1 Before the discovery of the 'Australia' (or 'hepatitis-associated') antigen, later renamed the Hepatitis B surface antigen (HBsAg), there were few, if any, settled Scottish National Blood Transfusion Service (SNBTS) protocols to guide practice at donation sessions. Individual Regional Transfusion Directors (RTDs) were free to develop and apply their own policies and practices for the protection of recipients of blood, blood components and blood products from transmission of infection. In the early 1970s, the risk of transmission of viral hepatitis, so far as it was understood, was thought to be mitigated by what were regarded as increasingly sophisticated screening tests for the Hepatitis B virus (HBV) antigen and antibody and these became the main means of protecting the blood supply.

25.2 In this chapter those tests are discussed in an attempt to understand their development and the reliance placed on them at the time. There is no clear end date for the chapter. By the autumn of 1983, attention was moving from non-A, non-B Hepatitis (NANB Hepatitis) to AIDS[1] and the period selected for discussion ends with the emergence of AIDS, growing awareness of the need for protocols on donor selection in that context and implementation of the first structured guidance on donor selection in Scotland. By then a view had emerged that NANB Hepatitis was not a major problem in Scotland and was generally not a serious disease. That view persisted into the late 1980s. Screening for HBV continued, with increasing sophistication, but also with increasing awareness that the results were of little relevance to NANB Hepatitis.

25.3 Historically, the blood collection procedures followed in Scotland in the course of routine donation sessions provide a context for discussing the impact of screening technology and practice. As discussed in Chapter 18, Collection of Blood - General, at the beginning of the reference period those procedures were not well adapted to investigating the health or relevant social factors affecting the prospective donor's suitability to provide blood for transfusion; they relied heavily on volunteered information. In some circumstances, as in collections in prisons, there was particular concern about the reliability of the information provided. Chapter 26, Donor Selection - Higher Risk Donors, discusses some groups of individuals who might have been thought to be unsuitable as donors and the methods adopted to identify members of these particular groups. Apart from interview and visual inspection of prospective donors, emphasis was placed on developing scientific tests to identify blood donations that presented risk and the approach to routine collection procedures can best be understood against that background.

Developing knowledge of Hepatitis B and growing awareness of other hepatitis viruses

25.4 The effectiveness of an approach that relied heavily on technology depended in the first place on knowledge of the risk against which the tests were directed and, secondly, on the relevance of the test results to total risk, as knowledge of the range of infective agents increased. It became increasingly clear from seminal research during and after the mid-1970s that tests developed to identify the Hepatitis B antigen or antibody - the primary technology available - did not detect antigen or antibody associated with NANB Hepatitis viruses which were, by definition, different but as yet uncharacterised. The risk of transmission of NANB Hepatitis could not be managed by testing: whether the risk of transmission of those forms of infection was acceptable was thought to depend on the materiality of the risk to the patient (that is, the severity of the disease) as understood from time to time.

25.5 Knowledge of the natural history of Hepatitis B developed during this period but was not fully understood by the end of it.[2] As was to happen later, following the discovery of the Hepatitis C virus (HCV), it took some years for researchers to match the markers of infection to the liver histology (appearance of liver cells under a microscope) and clinical picture presented by the patient and to the natural history of the disease. By the end of the period, it was known that the Hepatitis B virus damaged the liver cells it invaded and that, at least in the early stages of infection, it was more damaging than the postulated NANB Hepatitis virus(es). A higher proportion of acute Hepatitis B patients had overt clinical illness and jaundice. These signs and symptoms reflected the body's immune response to the virus, proportionate to the virus' attack, and usually would lead to clearance of the virus (in dead liver cells) and, if the virus was completely cleared, regeneration of the liver and restoration of normal liver architecture and function.

25.6 The vast majority of patients with haemophilia who had overt jaundice in the late 1960s and early 1970s did have acute Hepatitis B. A proportion of these patients went on to have chronic liver disease, marked by persistently elevated transaminases,[3] and it was initially thought that these biometric indications were related to their Hepatitis B infection. By the early 1980s, however, it was increasingly understood that most of these patients probably were infected, or co-infected, with NANB Hepatitis. Many had cleared the Hepatitis B virus and recovered from that disease. Their continuing abnormal liver enzyme levels, indicative of liver disease, were due to NANB Hepatitis infection and, in most of those cases at least, as events were to prove, Hepatitis C infection.

25.7 Clinically, there are similarities between the types of infection. Most chronic HBV infections, like infections with NANB Hepatitis/HCV, are insidious, with no obvious acute clinical onset. Also like NANB Hepatitis/Hepatitis C, Hepatitis B acquired in infancy is usually chronic but does not present with any symptoms until the patient is aged in the 30s or later. In each case, infection acquired in later life (over about 50 years of age), if chronic, often progresses to cirrhosis in relatively short periods compared with the 20, 30 or more years typical in younger patients. Both diseases are, however, associated with long periods of developing fibrosis (scarring of the liver) before the stage of cirrhosis is reached. Progression to cirrhosis indicates that not only is there significant fibrosis but also that the normal architecture of the liver has changed to include structurally abnormal nodules. Like NANB Hepatitis/Hepatitis C, a small proportion of carriers of Hepatitis B appear to be 'tolerant' of infection. The virus circulates, and the patients are still carriers of the infection and remain infectious to others, but it never does the 'tolerant' patient any harm.

25.8 As discussed in Chapter 14, Knowledge of Viral Hepatitis 1, the existence of NANB Hepatitis was inferred from observation of hepatitis in patients shown by the best tests available not to have Hepatitis A, Hepatitis B, cytomegalovirus or Epstein-Barr virus infection. Although a test for Hepatitis A was reported in 1973, a screening test for practical application was not available in Scotland until 1978.[4] The Hepatitis B tests available developed and changed over the period are covered in this chapter. From the outset there were tests for Hepatitis B surface antigen (HBsAg) and Hepatitis B surface antibody (anti-HBs). The HBsAg tests indicated whether the patient was currently infectious and might indicate ongoing chronic Hepatitis B liver disease. The anti-HBs test indicated that the patient had been exposed to or infected by Hepatitis B. If HBsAg was absent (and occasionally the two might co-exist) then a positive test for anti-HBs indicated that the patient had previously had Hepatitis B but was now immune and, in the absence of HBsAg, was no longer infectious.

25.9 These tests improved in sensitivity during this period and additional tests were also developed. In the 1980s, tests for the presence of antibody to Hepatitis B core antigen (anti-HBc) were developed, which added to knowledge of the state of infection in patients.[5] Combining the results of the additional tests with a negative HBsAG test, for example, could provide a reliable indicator of past infection and confirm the absence of current infection. Alternatively, where HBsAg had 'faded' from serum, as it might over time, the additional tests could indicate current infectivity (usually chronic) and show that the Hepatitis B virus was still present in the body, even if only in very small amounts.

25.10 As these tests relating to Hepatitis B developed in sophistication and in sensitivity, with growing knowledge of the structure of the Hepatitis B virus well into the 1980s, appreciation of the prevalence of NANB Hepatitis/Hepatitis C increased, and increased knowledge of the implications of infection with the Hepatitis B virus (or group of viruses)[6] became better understood. It is important to bear in mind, however, in considering comments made as the period progressed, that understanding of the absolute and relative reliability of tests also increased over the period. Confidence in the effectiveness of Hepatitis B screening assays to identify blood with the potential to transmit 'viral hepatitis', at least until the early to mid-1980s, reflected a lack of understanding both of the efficiency of the technology in identifying Hepatitis B and of the characteristics of NANB Hepatitis that undermined the usefulness of available screening tests more generally. Comments made early in the period may mislead in presenting an apparent state of knowledge of matters that in fact were established only at a later date.

25.11 The 1973 World Health Organization (WHO) report of the opinions of the expert scientific group on viral hepatitis, discussed in Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.31-14.42, commented that it was generally agreed that not all cases of post-transfusion hepatitis were caused by Hepatitis B infection and that 'as more hepatitis B carriers are eliminated from serving as blood donors, the proportion of cases due to other types of hepatitis will increase'.[7] The comment was speculative, however: the seminal research that led to the conclusion that there were types of viral hepatic disease other than Hepatitis A and B had not yet been published. In a section on 'Changing patterns of infection in certain developed countries', the report noted marked shifts in the age- and sex-specific rates for hepatitis in the USA and some European countries during the previous decade. The patterns of infection noted were not related to blood transfusion or other medical procedures but, rather, suggested a likely association with the illicit use of drugs. It was thought quite possible that, in addition to the increased risk of parenteral transmission,[8] the lifestyles of drug users might increase the level of non-parenteral transmission.[9] The population groups exposed to infection were increasing and the scientific context for the objective testing of blood for agents that might transmit infection was widening. The risks of transmission were accordingly increasing in the absence of effective exclusion policies and practices. In the early and mid-1970s, however, practical steps for eliminating post-transfusion hepatitis were still focused on Hepatitis B and testing for that infection in particular.

The demand for a serological test for Hepatitis B

25.12 The need for screening for hepatitis had been identified at an early date, sometimes generally but more often related to Hepatitis B. In November 1969, a letter to the British Medical Journal (BMJ) reflected a general view:

[U]ntil a reliable serological test for viral hepatitis is available the donor with anicteric hepatitis [hepatitis, that is, that does not present with clinical 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.[10]

25.13 At a meeting of the UK RTDs on 15 October 1969, a contributor from the London School of Hygiene and Tropical Medicine (name redacted but almost certainly Professor Arie Zuckerman) presented a talk on the discovery of the Australia antigen, on methods of detecting it and on its possible relationship with serum hepatitis.[11] In discussion it was agreed that there were few reported cases of Hepatitis B transmission and none of other viral hepatitis transmission in major surgery. Six cases of viral hepatitis transmission related to transfusions of cryoprecipitate, not apparently due to Hepatitis B, had been reported to the Oxford Haemophilia Centre.[12] Testing for the presence of Australia antigen required serum samples containing antibody reacting with the antigen ('anti-sera' or 'reagents'). At that stage, only a handful of such samples had been detected in the UK and testing was therefore largely dependent on gifts of reagents from colleagues in the USA.

25.14 The introduction of tests for the Australia antigen was discussed at the UK RTD meeting on 11 March 1970:

There were several aspects of the problem which would affect any decisions made regarding the general introduction of tests for this antigen: (i) Although the antigen appears to be associated with serum hepatitis and not with infectious hepatitis, it has not yet been shown to be the cause of the former disease although a causal association seems very probable. (ii) If all donors were screened and those with positive tests for Australia antigen were removed from the panel, it was estimated that the incidence of hepatitis might be diminished by about 40 per cent (iii) the antibody containing anti-sera (at present all of human origin) necessary for testing were scarce, of varying potency and possibly of differing specificity (iv) the most reliable method of detecting the Australia antigen was not yet established, (v) the overriding need was to obtain supplies of anti-sera, preferably of animal origin and to establish a reference preparation of anti-serum.[13]

25.15 The meeting agreed that, in the circumstances, a more precise definition of the status of the Australia antigen and of the methods of detecting it should be awaited before planning to screen donors and also that, if routine testing were to be introduced, it should be on a national (UK-wide) basis because of the possible medico-legal significance of the procedure. Extracts from the minutes of the meetings on 15 October 1969 and 11 March 1970 were later appended to the minutes of the first meeting of the Medical Research Council (MRC) Working Party on Post-Transfusion Hepatitis on 14 February 1980.[14]

25.16 There had been significant international public health interest in the screening of blood for hepatitis infection before the reference period, but also a great deal of uncertainty. The uncertainty in the UK, and in Europe as a whole, 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.[15] The paper noted a close association between hepatitis and the Australia antigen but commented that a similar close association between hepatitis and the relative antibody was less well established. The paper stated:

Because of the obvious implications ... it should be considered whether introduction of routine screening should not be deferred until more is known about the nature of the antigen or antigens and the corresponding antibody or antibodies and their relationship to hepatitis.[16]

25.17 There were technological and practical difficulties in the way of universal screening, according to that advice. In April 1970, however, the burden of the advice submitted to the sub-committee was uncompromising: donations should be tested by effective methods of screening when supplies of antisera were assured and infected blood should not be used. A 1970 WHO bulletin similarly recommended the detection and exclusion of blood donors carrying Australia antigen.[17]

25.18 The major Scottish Blood Transfusion Centres in Edinburgh and Glasgow were engaged in research into screening tests in 1970. Systematic study of virus transmission by therapeutic blood products had begun in Edinburgh in the 1960s while in Glasgow research was a direct response to the WHO bulletin.[18] In each case the available tests were found to be lacking in sensitivity[19] for detection of the Australia antigen.

25.19 The published sources, and indeed the Scottish research, appear to have left open a number of questions. The Council of Europe report recognised, in common with other contemporaneous opinion, that the available testing methods would not detect all Hepatitis B antigen-positive donations. Anticipating a point that was to be developed later, as tests became more sensitive, among the patients found negative on the Australia antigen test there would be an increasing proportion of hepatitis caused by 'other' transmissible agents in infected blood samples. It appears to have been clearly understood that there was no assay to detect these groups: other means would have to be relied upon.

25.20 The problem of reducing the risk of transmission of the Australia antigen by blood and blood derivatives was discussed at a meeting convened by the Department of Health and Social Security (DHSS) on 20 July 1970, where competing views were noted.[20] One view was that screening should be introduced as and when possible, notwithstanding that the methods and reagents used would not be uniform. The other was that attempts to institute screening should not be pressed until much more was known about the Australia antigen and methods of testing for it; and that routine screening should not be introduced except on a national scale with uniform methods of testing and reagents. After extensive discussion, in which it was suggested by one participant that donors whose blood contained antigen or antibody should be permanently excluded from donation, it was recommended that the DHSS should facilitate in every way it could the testing of blood donations for the presence of the Australia antigen and its antibody. The discussion concluded:

As long as antisera for testing were scarce it would not be possible to organize testing on a national scale. The Department might therefore consider starting testing in a few centres ... to test the feasibility of routine screening .... It was agreed that each donation from a given donor should be tested and that the donor should be excluded if antigen or antibody were found. At present it seemed that such a donor should be permanently excluded.[21]

25.21 In the light of this recommendation, a further group was set up by the DHSS, the Scottish Home and Health Department (SHHD) and the Welsh Office in September 1970 under the chairmanship of Dr William Maycock: the Advisory Group on Testing for the Presence of Australia (hepatitis-associated) antigen and its antibody (the Maycock Group). Its terms of reference were:

To advise the Health Departments on:

i 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;

ii the provision of reagents, choice of methods and whether, and if so, what kind of, training facilities are required;

iii the scale of accommodation, staffing, equipment and other services necessary to implement the group's proposals.[22]

25.22 The Maycock Group held its first meeting on 5 October 1970.[23] By then, partial screening of donations had already started in some regions. In the Glasgow and the West of Scotland RTC, partial testing was introduced for a six month period in 1970[24] and was implemented in full in the region on 13 October 1970.[25] In a note of discussions with a commercial supplier dated 10 November 1970, it was recorded that commercial supplies of anti-serum for testing were available.[26]

25.23 The first report of the Maycock Group was available (probably in draft) in September 1971.[27] It recommended that Regional Transfusion Centres (RTCs) should begin testing at the earliest possible date using immunodiffusion, complement fixation or immunoelectro-osmophoresis technology at the Director's discretion.[28] It was agreed that donors should be excluded if antigen or antibody were found in their blood.[29] It was estimated that testing for the presence of the Australia antigen and its antibody would reduce the incidence of serum hepatitis by about 25%, given the relatively insensitive nature of the tests.[30] The proposal for screening was implemented throughout Scotland by the end of 1971 or early 1972.[31]

25.24 Testing to screen for the Australia antigen was introduced for all blood donations in the rest of the UK from December 1972.[32]

25.25 There was, however, a degree of scepticism on the part of some Scottish scientists at this time. John Watt, Director of the Protein Fractionation Centre (PFC), and colleagues presented a paper on plasma fractionation at a Joint Symposium held by the Royal College of Physicians of Edinburgh and the Royal Society of Edinburgh in February 1972.[33] They discussed hepatitis transmission and the identification by Dr Baruch Blumberg and others of the 'hepatitis associated antigen' (HAA - another term for the 'Australia antigen', HBsAg). They commented:

A screening programme which results in identification of HAA carriers among blood donors, even if such identification be less than totally accurate, is bound to reduce the incidence of infection in recipients of whole blood, cellular components and whole plasma. However, it is equally certain that such screen procedures, unless they be absolutely infallible, will not greatly influence the infectivity of plasma products. This must remain the province of the fractionator and the characteristics of his technology until such time as screening systems are capable of identifying HAA presence in dilutions at least six orders of magnitude greater than can presently be detected .... Many commercial fractionators and some state organisations process pools containing as many as 30 000 donations of plasma; one unidentified infected donation would be enough to make the whole of such a pool suspect.[34]

25.26 Chemical processing to inactivate pathogens, in the absence of infallible screening methodology, was identified by fractionators as the solution to virus transmission. Professor John Cash, who would become the Medical and Scientific Director of the SNBTS, referred to a range of screening techniques and commented:

This work clearly implies that the routine screening of donor blood for Australia antigen will decrease the total incidence of post-transfusion hepatitis. Although the urgency and importance of this approach cannot be overemphasised, the degree of protection offered remains uncertain, as the final analysis will be dependent upon the prevalence of antigen-positive donors in a community, which can vary widely (Prince 1970), the quality of the methods used to detect the antigen and the frequency of other potential hepatotoxic agents in the donor population.[35]

25.27 Professor Cash discussed a range of clinical practices that might reduce the risk of virus transmission and commented on the tests available for the Australia antigen. He said that the recent introduction of total donor screening in Scotland was a major step forward but left much still to be done. More sensitive tests were required and there was a need for improved facilities and for a national reference laboratory for the supply of standardised reagents. He concluded:

[W]e must not assume that the elimination of all antigen-positive units will solve the post-transfusion hepatitis dilemma. Current evidence strongly suggests that the present limitations, which have been calculated to represent a detection rate as low as 25 per cent, cannot be entirely explained on insufficient sensitivity of existing methods, and that other agents are responsible for a significant proportion of the problem.[36]

25.28 In May 1972, the Maycock Group published a revised report in which it repeated its recommendation that RTCs should begin, at the earliest possible date, to test all blood donations for the presence of the Australia antigen and its antibody using, initially, an immunoelectroosmophoretic method of testing.[37] The report noted that knowledge of all aspects of the Australia antigen was accumulating very rapidly and that its recommendations should be regarded as interim and subject to modification at a later date.[38]

25.29 Leaving aside the reservations of Scottish scientists noted at paragraph 25.25 about the effectiveness of screening in relation to large-pool plasma products, there was concern expressed in Scotland in October 1972 about the delay in introducing more sensitive screening tests for Australia antigen and its antibody.[39]

25.30 The 1973 WHO report identified the tests available and commented on them.[40] With regard to effectiveness, it stated:

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. The effect the introduction of more sensitive techniques will have on the rate of post-transfusion hepatitis is not yet clear, but preliminary evidence suggests that it will not be great. A further significant reduction in the rate of post-transfusion hepatitis may require the development of biological tests for the hepatitis B virus, as well as a better understanding of the complex etiology of this form of the disease. 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.[41]

25.31 On that assessment of the situation, the techniques then available were not very sensitive in detecting Hepatitis B and failed to detect an important proportion of cases of that type of infection, though 30% effective screening was an improvement on the Maycock Group's estimate of 25%. Further, the detection rate left unexplained other cases of post-transfusion hepatitis. As events were to prove, those included the non-A, non-B form or forms of hepatitis postulated after 1974.[42] Following Stephen Feinstone's identification of the Hepatitis A virus (HAV) and subsequent confirmation by 1978 that its mode of infectivity was enteral and not parenteral, HAV could be excluded as a cause of post-transfusion hepatitis. There were two remaining variables: the sensitivity of existing screening tests for Hepatitis B and the range of non-B agents capable of transmitting infection. The interaction of these variables was little understood.

25.32 What was increasingly understood, however, was that the problem of transfusion-associated transmission of hepatitis was more widespread than had been appreciated previously. In addition to the increasing prevalence of infection among new population groups (see paragraph 25.11 above) the report also commented:

Hepatitis B antigen has now been found in all components of plasma that are derived by the Cohn method of fractionation from plasma known to contain the antigen.... It is important to exclude antigen-positive plasma from the pool to be used for preparing blood derivatives for clinical use.[43]

25.33 The risk to patients with coagulation deficiencies who required replacement therapy was recognised. There was also a need to protect transfusion patients from infected blood and blood components.

25.34 The Maycock Group was reconvened on 6 December 1973. Its second report, dated September 1975, noted that by that date the antigen had become known as the 'Hepatitis B surface antigen' (HBsAg) and that information about the subject continued to accumulate very rapidly. During this phase of its operations, improved serological assays for HBsAg were being developed and applied routinely in the UK, including Scotland. The second report stated:

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, while confirming ... that those donors whose blood is HBsAg positive should be permanently excluded from the panel and their donations rejected for clinical use, we now recommend that donors whose blood contains anti-HBs may be retained on the panel and their donations used clinically.[44]

25.35 The second report of the Maycock Group was approved by the Minister of State in October 1975 and endorsed by the Standing Medical Advisory Committee (SMAC) at their meeting on 11 November 1975.[45] The recommendation was reflected in the advice of the National Blood Transfusion Service in 1977;[46] 1983;[47] and 1985.[48] The clinical use of blood containing antibodies to Hepatitis B, without detectable antigen, was now recommended.

25.36 In the introduction to its third report, published in 1981, the Maycock Group again emphasised the rapidity with which information on the subject had been accumulating and the need to avoid regarding its recommendation as final.[49] It is appropriate to emphasise that there was rapid change throughout the 1970s. The deliberations and subsequent advice of the Maycock Group were based on the premise that Hepatitis B antigen-positivity remained the principal transfusion-related risk of transmission of hepatitis, although a challenge of that position was already emerging. On 3 August 1974 The Lancet published the important paper by Dr Alfred Prince and his colleagues which suggested that, in the USA, 'a large proportion of long-incubation post-transfusion hepatitis is unrelated to hepatitis B and that control of post-transfusion hepatitis will require identification of a hepatitis virus(es) type C'.[50]

25.37 The advice of the Maycock Group was not universally applauded. In a reply to the Group's second report, a representative of the Royal College of Physicians (RCP) commented as follows:

I do however have some misgivings about discontinuing the current practice of permanently excluding from the panel, donors with a past history of jaundice or hepatitis. Even with the most sensitive techniques false negatives may occur, and furthermore transfusion hepatitis may be caused by viruses other than Hepatitis B for which at present no tests are available (the existence of Hepatitis C was postulated recently). Although the chance that such individuals might transmit hepatitis is admittedly remote, the risk is there and not worth taking unless it can be shown that many donors are being lost to the panel in this way - what are the figures for such rejections at present[?][51]

25.38 A draft reply dated July 1976 from the DHSS to the RCP noted that the Maycock Group's recommendation agreed with a recommendation contained in the 1975 WHO Report. The draft considered the historic background of the exclusion of donors with a history of jaundice and noted the developments in the knowledge of and testing for HBsAg. It stated that no evidence had been collected yet in the UK to substantiate the presence of the postulated 'Hepatitis C' and concluded that, for these reasons, it was proposed to retain the recommendation of the Maycock Group that donors with a history of jaundice should no longer be permanently excluded from donating.[52]

25.39 The DHSS distributed the second report of the Maycock Group with an accompanying circular to all regional health authorities and other bodies in England and Wales in November 1976, intimating Ministers' acceptance of the report subject to reservations and recommending implementation.[53] The circular drew attention to the Group's recommendation that the practice of permanently excluding donors with a history of jaundice could be discontinued, provided that HBsAg was not detected by a reversed passive haemagglutination assay (RPHA), or a test of equal sensitivity, and that the donor had not suffered from hepatitis or jaundice during the previous 12 months.

25.40 Meantime, by about 1974 all blood donated in Scotland was screened for the presence of Hepatitis B surface antigen and anti-Hepatitis B by counter-immunoelectrophoresis (CIEP) or immunoelectro-osmophoresis (IEOP) (the 'second generation' tests).[54] The technology was still, in routine application, dependent on human observation. Dr Brian Dow, Glasgow and the West of Scotland BTS, explained the process as it was applied in 1974.[55] A sugar derived from seaweed (agarose gel) was spread on glass plates where it formed a milky coloured surface. Test samples were added, typically in three 'wells'. Each plate comprised a reagent in one well, for example a specimen from a donor known to have Hepatitis B surface antigen-positive blood; the test sample in the middle well; and a second reagent in the third, ie a sample from a donor known to have anti-HBs. If the test sample had HBs antibody, the application of an electric current would develop a visible white line (a 'precipitin line') in the gel between the test sample and the sample with Hepatitis B surface antigen by osmosis. The same process would disclose anti-HBs, if the test sample had it, by a precipitin line in the other direction.

25.41 The test was not very sensitive and required a far greater concentration of antigen or antibody for detection than the next generation of tests.[56] Dr Dow thought, however, that Glasgow had achieved a higher rate of reduction in post-transfusion hepatitis than indicated in the first Maycock Group report, achieving 30-50% success as against the 25% estimated by the report.[57] Success depended on observation by the technician, the quality of the reagents[58] and the reference laboratory back-up available.[59] Good technicians were required as identifying the precipitin line was a subjective exercise and technicians differed in their interpretations.[60] To achieve the level of success it had, Glasgow made sure that a supply of good reagents was available and had used the same reagents consistently from about 1970.[61]

25.42 In England, Dr Rosemary Biggs published a report of the Haemophilia Directors' study in 1974, indicating that testing had reduced the incidence of infection in donations but also pointing to the insensitivity of the available tests.[62] Referring for comparison to an earlier report[63] from 1972 by Dr John Wallace and others, Glasgow, she wrote:

The incidence of the Hepatitis B virus in the donor population was of the order of 1 per 800 donations at the time that these observations were made. Since then the screening of all donors for Hepatitis B antigen has been instituted and the incidence of samples grossly contaminated with Hepatitis B virus is now certainly less. Screening, however, is unlikely to remove all infected samples because more than one virus is involved and because the screening method is not sufficiently sensitive to detect all samples infected with Hepatitis B virus.[64]

25.43 At this time, the Glasgow and Edinburgh Blood Transfusion Services were actively engaged in research into the development and application of screening techniques and continued to develop test technology. Information on research in Edinburgh was passed to the Maycock Group following a meeting of the Central Consultative Committee on 14 October 1974.[65]

25.44 The second report of the Maycock Group, published in September 1975, described the principles of testing and commented that 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 was established. It noted that blood and blood products could also transmit other forms of hepatitis which did not appear to be associated with the presence of HBsAg.[66] The results of testing by various techniques were set out and the incidence of icteric hepatitis (hepatitis, that is, accompanied by clinical jaundice) was discussed. The likely outcome of testing was noted:

Several studies in [the] USA have shown that exclusion of HBsAg positive donors diminishes the incidence of hepatitis B in transfused patients. Although comparable surveys in UK have not yet been reported, it seems likely that exclusion of HBsAg positive donors here will also be associated with a diminution in the number of cases of hepatitis B transmitted by blood and blood products.[67]

25.45 The report commented that infection with Hepatitis B was associated with the appearance in the serum of a specific surface antigen, HBsAg, and its homologous antibody, anti-HBs. A second antigen-antibody system, the Hepatitis B core, appeared to be intimately related to the infection.[68]

25.46 The report also noted that published information showed 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.[69] This led to the recommendations on donor management discussed above.[70]

25.47 Notwithstanding this advice, the report stressed that a negative result for antigen and antibody, even by the most sensitive of the available methods of testing, did not necessarily imply the absence of an infective agent or agents.[71] Having reviewed the methods available, the Group recommended that RPHA should be adopted by RTCs in place of CIEP to screen every blood donation for the presence of HBsAg.[72]

25.48 The emphasis at this stage was firmly on HBsAg identification. The confidence shown in recommending the selection of a specific method implied a step change in knowledge of Hepatitis B at about the beginning of the reference period. The history of developing scientific knowledge over the period would suggest that there was a perception that there had been significant progress, although the prevailing understanding of the virus was still incomplete. It appears that there was growing confidence in the effectiveness of the screening process to reduce, if not totally eliminate, the risk of transmission of Hepatitis B. The Maycock Group's second report noted:

In the light of the developments which have occurred since the publication of our last Report we no longer consider that CIE should be the recommended technique for the routine screening by RTCs for the presence of HBsAg. The choice for a replacement method lies, in our view, between RPH and RIA .... RIA is, admittedly, more sensitive than RPH, but even so cannot be relied upon to detect HBsAg in every donation in which it is present. In our opinion the extra degree of sensitivity which RIA affords is outweighed by the considerable advantages which RPH offers in other, no less important, respects .... We therefore recommend that RPH should be adopted as soon as possible by all RTCs in place of CIE to screen every blood donation for the presence of HBsAg....[73]

25.49 'Third generation' HBsAg screening tests were introduced from 1975.[74] The Maycock Group noted that RPHA showed a 50% improvement in sensitivity over CIEP and approached the sensitivity of the best available test, radioimmunoassay (RIA). Dr Harvey Alter and colleagues reported on retrospective re-testing of samples previously tested by CIEP by RIA. They found that three of four patients who developed Hepatitis B infection, but were negative by CIEP, tested positive by RIA.[75] With the third-generation tests, from 1975, the process was increasingly automated: there was progressively less 'art' and more 'science' in testing. Tests, thought at the time to be sensitive and accurate, were beginning to be widely available for infections with Hepatitis B. Research and development continued and further improvements in the sensitivity of screening methods for HBsAg and anti-HBs continued to be made thereafter.

25.50 Progress on consultation of the second report of the Maycock Group was reported in a memorandum by TE Dutton, DHSS, dated 16 March.[76] It recorded that the report was approved by the Minister of State in October 1975 and endorsed by the SMAC at their meeting on 11 November 1975, as already noted, and provided a summary of responses. Although consulted, the RTDs' responses (if any) were not summarised.[77] A copy of the memo was appended to a memo sent by Dr Archibald McIntyre, SHHD, on 24 March 1976, to Dr McCreadie, Dr Graham Scott and others.[78] It recorded that in Scotland sensitive tests for the detection of HBsAg were being used in all five RTCs.

25.51 Until the adoption of the third-generation tests, testing for Hepatitis B was not efficient. In addition, there were no tests for hepatitis agents other than Hepatitis B. A practical assay for Hepatitis A was not available in Scotland until 1978. The inability to identify what came to be called the NANB Hepatitis viruses had, as a necessary corollary, the inability to develop any screening test or assay that would enable the exclusion of infected donations from the source materials used as whole blood, blood components or in the manufacture of blood products. (It is important to emphasise, however, that the developing knowledge that there was a form or were forms of hepatitis that did not have the characteristics of Hepatitis A or Hepatitis B logically had to mean that the most effective tests for Hepatitis A or Hepatitis B, which had to reflect the identifying characteristics of those diseases, could not detect NANB Hepatitis). Increased confidence in the sensitivity of the tests for HAV and HBV hence led to increased confidence in the existence of other 'non-A, non-B' Hepatitis virus(es). In time, a major debate would take place over the use of 'surrogate' tests for NANB Hepatitis.[79] For the time being, however, there was no means of identifying any NANB Hepatitis transmissible agent in blood.

25.52 Similar views were expressed in other countries. A study in Finland of carriers of Hepatitis B antigen and transfusion hepatitis was published in 1974.[80] The report stated that in most series in the literature only 40-60% of cases of post-transfusion hepatitis could be traced to a donor with HBsAg. The report listed a number of possible reasons for that, including, with reference to the paper by Prince and others in 1974 already mentioned at paragraph 25.36, that some cases of post-transfusion hepatitis might be caused by a virus not yet known.[81] It concluded:

The present series suggests that screening by the counter-immunoelectrophoresis [CIE] method will reduce the number of cases of transfusion hepatitis by about a third, to which the radioimmunological method [RIA] will add 10-20 per cent. It seems that the solution of the transfusion hepatitis problem demands more sensitive and more specific HBAg testing methods that are expressly suited for routine screening, as well as methods for the demonstration of other infectious viruses in the blood.[82]

25.53 In his evidence to the Inquiry, Professor Leikola of the Finnish Red Cross Blood Transfusion Service said:

[It] was realised that not all Hepatitis B cases were recognised by [the HBsAg] test, that a good part of the people that were screened were negative with the new test but were still carrying the Hepatitis B virus and [it] was known that it was a serious disease.

In addition to that, [there] was the possibility [of] other viruses existing and probable existence of other viruses.[83]

25.54 In 1975, the Glasgow Blood Transfusion Centre introduced RIA testing for HBsAg and continued to use that technique until about 1977-78.[84] The relative effectiveness of the test was to become an issue in Scotland in and after 1976. The Maycock Group's recommendation in favour of RPHA was challenged by Glasgow transfusion experts and scientists who thought that, while the RPHA test approached the effectiveness of RIA, it ultimately fell short of it.[85] Dr Dow agreed that certain RIA tests developed 'in-house' (apparently a reference, for example, to the RIA favoured by the Blood Transfusion Service in England and Wales) tended to be relatively slow and tedious, taking two or three days to complete, but noted that Glasgow used a commercial test that was quick to carry out, being completed within four hours.[86]

25.55 By letter to Dr McIntyre dated 22 June 1976, Dr Wallace, Glasgow & West of Scotland BTS and a member of the Maycock Group, advised that his region had continued to research the use of RIA with the cooperation and financial support of Abbott Laboratories and the agreement of General Jeffrey (National Medical Director of the SNBTS). They had found that the RIA test was more sensitive in detecting HBsAg positive donors than the RPHA method.[87]

25.56 Dr Wallace provided evidence that the RIA test was more effective. On the basis of a study conducted to assess the sensitivity of RIA and RPHA tests it had been established that, in a nine month period using RPHA, seven HBsAg-positive donations identified by RIA had not been detected. He referred to a Fatal Accident Inquiry involving the transmission of Hepatitis B to a patient who had died and a second case where the patient had survived: each had involved false negative reactions on RPHA testing. Dr Wallace was concerned about the lack of sensitivity of the RPHA test which, he implied, might lead to further deaths if it were to continue to be used. He referred to the possibility of informing the Scottish Legal Office or his own Defence Union if a way could not be found to maintain a sensitive method of testing donations. He sought additional funding to continue screening with the Abbott RIA test after withdrawal of commercial support.[88]

25.57 In a memorandum dated 28 June 1976, Dr McIntyre referred Dr Scott to Dr Wallace's letter.[89] He stated that Dr Wallace had been involved in the 'problems of hepatitis' right from the beginning and knew that Hepatitis B was 'only the tip of the iceberg'. In his evidence to the Inquiry, Dr Scott explained the SHHD's view: 'Well, we knew that there were other hepatitis agents involved that hadn't emerged then. Non-A non-B. Nobody had developed a test for the other forms of hepatitis'.[90] It is implicit in the letter that SHHD medical officials had also been aware that Hepatitis B was 'only the tip of the iceberg'.

25.58 In other respects, Dr McIntyre expressed concern about what he perceived to be 'professional blackmail' in the letter from Dr Wallace. It seems that Dr McIntyre interpreted Dr Wallace's letter as containing a thinly-veiled threat that, if he was not given funding to continue with his study, he would report his misgivings to the professional medical and other authorities. Dr Scott replied to Dr McIntyre to the effect that the Maycock Group, of which Dr Wallace was a member, took account of the sensitivities and cost of the different tests and had recommended that testing by RPHA be introduced.[91] The SHHD had control of the budget and the issue was effectively disposed of on the basis of comparative cost.

25.59 The Inquiry has been unable to recover a copy of the SHHD's response to Dr Wallace but the nature of the response is indicated in a subsequent letter dated 26 July 1976 by Dr Wallace to Chief Administrative Medical Officers in his region in which he noted:

The reply from SHHD states that RPHA is the recommended method of testing and is the method which should be employed in this region after the middle of August 1976. Accordingly, RIA testing of donations for the presence of HBsAg will cease on 14 August, 1976, and thereafter RPHA will be the method used for total screening. In the light of the evaluation it is estimated that in the course of one year from 9 to 16 donors who are chronic carriers of HBsAg detectable by RIA will not be detected by RPHA.[92]

25.60 Dr Dow took up this issue in his written statement and in oral evidence.[93] Glasgow was, at this time, at the forefront of Hepatitis B testing.[94] He said that RPHA testing was a less sensitive test than Glasgow's (Abbott) RIA test. The RIA would identify a lower level of virus infectivity and, as a corollary, exclude a higher percentage of infected donations.[95] Dr Wallace had written to the west of Scotland haematologists because of his concerns about sensitivity, having been forced to use the less sensitive RPHA test because he was not funded for the RIA test. While RIA was in use, no confirmed cases of HBsAg post-transfusion infection were reported; after the change, four cases were reported in a year.[96]

25.61 Mr Barr, Dr Dow and others wrote up the Glasgow work and published in 1979.[97] The paper reflected the strong views held at the time. It noted that since 1970 all blood donations in the west of Scotland had been screened for the presence of HBsAg. The method of testing in the first five years was CIEP. In that period, several cases of proven viral Hepatitis B transmission were notified, consistent with the known sensitivity of the test. In the final year of the study period, 1975-76, 8589 plasma pools were tested by a long incubation RIA method and four positive results were obtained. These four examples of HBsAg were RPHA-negative and RIA-positive and it was considered possible that was an underestimate, as factors such as neutralisation and dilution of HBsAg in the plasma pools could have influenced the number of positive results obtained. They reported that, among the three RPHA systems they had tested, there was remarkable variation in both sensitivity and specificity. The Abbott Diagnostics (Auscell) test appeared to be the most sensitive and specific, although it did fail to detect some antigen-positive donations. The British Wellcome Diagnostics (Hepatest) test was cheaper. From one year of testing using RIA, 12 of the antigen-positive donations detected by RIA failed to give a positive reaction when tested by RPHA. The conclusion was that finding RPHA-negative/RIA-positive carriers was not a rare event, an indication of the relative insensitivity of RPH assays.

25.62 Notwithstanding the Glasgow experts' reservations, the Maycock Group's recommendations were consistent with international thinking at the time, which recognised RPHA and RIA as equally acceptable. In 1976, the International Society of Blood Transfusion published a guide to the Hazards of Blood Transfusion.[98] It stated:

Tests for HBsAg ... are now available. Although these will detect no more than about 50% of hepatitis B virus carriers, no blood or blood product should be transfused unless the donor is known to have been negative for HBsAg. It is recommended that each blood donation should be tested by such a method as counter-immunoelectrophoresis [CIE] or, preferably, radioimmunoassay (RIA) or reverse passive haemagglutination (RPHA).[99]

25.63 The guide noted that the incidence of Hepatitis B was not known and was likely to vary from area to area. The report did not express a preference between RIA and RPHA: a sensitivity rate of 50% was expressed as a general feature of the available tests. Dr Wallace's preference for the Abbott RIA did not receive support from the guide. By the date of publication, with government support, the Maycock recommendations had taken effect as noted above.

25.64 There were, however, continuing issues. There was interest in collecting data relating to all forms of adverse reaction to factor products as production increased at the PFC and concentrates became available. The clinical value of the products required reporting and study. There was a report of adverse reactions to the PFC intermediate Factor VIII, at a meeting of the SNBTS Directors on 1 July 1976.[100] A specific batch, batch 127, had caused reactions in Aberdeen and in Edinburgh.[101] Dr David Dane[102] had shown that the product was free of HBsAg 'at conventional test limits (and a bit beyond)'. Edinburgh and south east Scotland had found that (uniquely, according to the minute) the batch had contained no antibody to HBsAg. At a meeting of the SNBTS Directors on 4 October 1976,[103] the investigation of two suspect batches, including batch 127, by Dr Cash and Dr Dane, using a more sensitive test, was reported.[104] Batch 127 was thought to have contained one positive HBsAg donation. From the context it appears that the 'adverse reaction' reported was jaundice. It was agreed to receive information about Dr Dane's more sensitive test for examination.

25.65 It is of interest, in assessing contemporaneous attitudes, that a question was raised at the SNBTS Directors meeting in October, apparently by Mr Watt, whether it was of real value to investigate patients who developed jaundice following the administration of Factor VIII. Mr Watt thought that it was not justified on grounds of cost effectiveness. Dr Cash and Dr Charles Cameron, East of Scotland BTS, prevailed: investigation would continue. It was thought that Edinburgh in particular had benefited by changing their technology to meet the situation that had arisen from the investigation of batch 127. More generally, the episode is an indication that the differences of opinion between fractionators and clinicians that had been expressed in the early 1970s had not been resolved.

25.66 In his book Blood Transfusion for Clinicians (1977), Dr Wallace observed:

The recognition of HBsAg as a marker for the infective agent of type B hepatitis introduced the possibility of testing every blood donation for the presence of HBsAg. Considerable discussion ensued as to the benefits resulting from the costly, and time-consuming procedure of total screening. Some authorities stated that the exclusion of HBsAg positive donors would at best reduce the incidence of post-transfusion hepatitis by only 25 per cent. The inability to prevent 75 per cent of cases of transfusion-transmitted hepatitis was considered to be multifactorial:

i. the methods of detecting HBsAg by large scale screening were the relatively insensitive immunodiffusion (ID) and counterimmunoelectrophoresis (CIEP) techniques.

ii. it was suspected that HBsAg was not homogeneous, and that different subtypes would make detection difficult.

iii. other infective agents might transmit hepatitis: these included virus A, CMV, EBV and viruses not yet identified, such as the predicted virus C.

iv. the use of absolutely fresh untested donations: some clinicians considered that fresh blood had clinical merit and insisted on its use.

v. a route of transmission other than transfusion: it was recognized that various hepatitis viruses could be transmitted by parenteral routes other than transfusion and by close contact.

The prevention of even 25 per cent of cases of post-transfusion hepatitis was however regarded as statistically impressive.[105]

25.67 Dr Wallace referred to the work of Dr Prince and others in the USA that concluded that an infective agent other than Hepatitis B was involved in causing post-transfusion hepatitis.[106] He wrote:

Evidence from the USA indicates that a long incubation form of hepatitis other than type B exists, and this has been named type C or 'non-A non-B'. Present evidence on this infection in Britain is scanty, but most cases of post-transfusion hepatitis seem to be type B, although some cases with relatively short incubation periods are associated with type A or CMV or EBV infections. It may be that at present type C infection is rare in Britain. More evidence on this subject will emerge as RPHA and RIA are introduced as the method of testing donations for HBsAg.


While type B hepatitis seems to be the form of post-transfusion hepatitis most commonly encountered in Britain, it would be advantageous to recognize markers for the infective agents of 'non-B' hepatitis, such as type A and type C, if the latter really exists.[107]

25.68 The book was written in 1976 and published in 1977. It reflected Dr Wallace's views at a time when he would clearly have thought that the choice between RIA and RPHA was open for discussion by the Maycock Group and when the prospects for both test formats seemed promising. In addition, the text must have been written shortly before it became clear that Hepatitis A was not a material cause of post-transfusion hepatitis.

25.69 Commenting on the position at 1977, the date of publication, Dr McClelland, who became a consultant in the Edinburgh and South East of Scotland Blood Transfusion Service in 1977 and Director in 1979, was less sanguine.[108] In his written evidence,[109] he pointed to two apparent underlying assumptions: (i) that testing donations with a very sensitive test for HBsAg and removing all donations with positive test results would virtually exclude the risk of transfusion-transmitted Hepatitis B and (ii) that, provided Hepatitis B transmission was avoided, the blood would be safe. He commented that this seemed somewhat at odds with the statements that referred to 'other infective agents that might transmit hepatitis, such as the predicted virus C' and with the fact that Hepatitis B screening was thought to detect only 25% of cases of post-transfusion hepatitis. In his written statement, Dr McClelland said:

I think this apparent inconsistency must be a reflection of the prevailing sense at the time that hepatitis, if not due to Hepatitis B virus, was not a serious condition.[110]

25.70 He expanded on these matters in oral evidence. He was asked whether, at the time of publication of Dr Wallace's book, he would have shared that 'prevailing sense'. He replied:

I have found this very confusing when I read it again because it seemed to be saying several conflicting things. I would not have shared that view. I do think that, lying in back of this is something which I think came through to me in reading a lot of this material again, that there was a very strong sense within the UK that non-A non-B hepatitis wasn't a big problem in the UK.

There was clearly awareness that it was a big problem in the United States, that is in spite of the fact that the only prospective study of transfusion-transmitted hepatitis that was done for many years was organised by the Medical Research Council in the UK and published in 1974. The data, [were] actually interpreted as saying that it wasn't a problem apart from Hepatitis B. Non-A non-B hepatitis wasn't a problem but actually, if you look at the data for five minutes, it actually clearly is a problem and that, you know, coming from a group of eminent academics seems - again, I had real difficulty understanding that when I looked at it again.

It does seem to me that there must have been a very strong received belief that somehow non-A non-B hepatitis just wasn't a problem in the UK sufficient to cause highly intelligent people doing research study to actually really ignore their own findings and interpret them quite inappropriately, in my view. So I think that sort of attitude, the power of that sort of attitude must underlie this statement of Dr Wallace. It's speculation.[111]

25.71 It would seem reasonable to assume that Dr Wallace's book reflected accepted knowledge among senior practitioners in Scotland, and among experts throughout the UK, at the beginning of Dr McClelland's career in transfusion medicine. As already noted, Dr Wallace was a member of the Maycock Group. On the other hand, Dr McClelland's interest in transfusion-transmitted viruses was engaged by US research, including the report of the Transfusion-Transmitted Viruses Study and the work of Dr Jay Hoofnagle and others.[112] For him, the view that somehow NANB Hepatitis was not a big problem in the UK was inconsistent with the knowledge that only 25% of cases of post-transfusion hepatitis could be explained by Hepatitis B and that other (known) causes including Epstein-Barr virus were not significant. In his view, the data could be interpreted as indicating NANB Hepatitis was quite a large problem: there was quite strong evidence that something was going on.

25.72 A similar view to Dr McClelland's was taken in Finland. In his evidence to the Inquiry, Professor Leikola was asked about his understanding of NANB Hepatitis in the mid-to-late 1970s and replied:

Well, I would say that after summer 1978, when I came back from my sabbatical year in America, when I was not involved in these cases at all - but after that I think that it became clear in our minds that there is definitely a virus, or maybe maximum two viruses, causing hepatitis that is like Hepatitis B and unlike Hepatitis A.

However, in those circumstances we also were feeling that, yes, it may cause a disease. It is mentioned in this article[113] that in most cases the disease is mild and non-symptomatic and there were very little means to avoid [it] because we did not know any particular risk groups, even though it's clearly referred in this article that in most cases it is related to some parenteral contact with blood, either by tattooing, needle sharing or transfusion. But, yes, I would say that at that time, 1978, 1979, 1980 it became clear to us that such a disease exists.[114]

25.73 The views of Dr McClelland and Professor Leikola reflected the influence of developing thought in the USA, where it was recognised that there was a significant prevalence of NANB Hepatitis. At this stage there were few reported NANB Hepatitis cases in Scotland.

25.74 In relation to reported cases, Dr Dow said that, although he was aware of reports elsewhere in the world, he was not aware of NANB Hepatitis in Scotland until 1979 when Dr Follett, the Head of the Hepatitis Reference Laboratory, raised the issue with Dr Ruthven Mitchell, Director of the Glasgow and West of Scotland BTS.[115] In 1979, Dr Follett had a reliable test for Hepatitis A which had become available during 1978 (five years after Feinstein and others reported the isolation of the Hepatitis A virus) and could differentiate acute cases of Hepatitis A and B, allowing for effective screening for both viruses. The balance - outstanding cases of post-transfusion hepatitis - became potential non-A non-B cases. He had identified a few cases of post-transfusion hepatitis which, following testing, were found to be definitely neither Hepatitis B nor Hepatitis A. Again this evidence pointed to a material change of position shortly after the date of Dr Wallace's book, coinciding in time with Dr McClelland's appointment as consultant. It appears that the risk of transmission of NANB Hepatitis, previously recognised in theory, was becoming acknowledged as an existing risk in Scotland by the end of the 1970s.

25.75 On 5 May 1979 The Lancet published a paper by Robert Galbraith and colleagues on an outbreak of HBsAg-negative hepatitis in a renal unit at Fulham Hospital, London, in 1968-70.[116] The paper explained that to clarify the aetiology of the outbreak serological tests for antibody to HAV were carried out retrospectively on serum samples obtained at the time of the outbreak.[117] The authors concluded:

Overall these results must indicate that the development of chronic liver disease was not related to hepatitis A infection and that this outbreak falls into the category of [NANB] hepatitis. More and more data point to this as the cause of a substantial proportion of cases of post-transfusion hepatitis negative for HBsAg and to its role in the subsequent development of chronic liver disease.[118]

25.76 In August 1979 Dr Ajay Chaudhuri and others reported on patients thought to have viral hepatitis admitted to the Infectious Diseases Units at Ruchill and Belvedere Hospitals, Glasgow, in 1976 and 1977.[119] During that two-year period, 164 patients with viral hepatitis were admitted to these hospitals. Of these patients, 52 were positive for Hepatitis B antigen, with males still greatly outnumbering females and with most cases in the 16-29 year age group. The authors noted: 'As in previous years, drug abuse was associated with the largest number of cases, with 22 patients admitting use of intravenous narcotic drugs with shared syringes and needles. They were mostly men (19 male: 3 female) in their twenties'. In the 112 patients who were HBsAg-negative, a diagnosis of non-B hepatitis was made with, in the majority of these patients, epidemiological findings and clinical course suggesting a diagnosis of Hepatitis A.

25.77 In a discussion of non-A, non-B Hepatitis the authors noted:

In four patients with non-B hepatitis, hepatitis developed within 2-6 months of transfusion of blood products. Three male haemophiliacs and a female patient with Christmas disease had received numerous transfusions of factor VIII and cryoprecipitate. These four patients and also two drug addicts with hepatitis had no evidence of hepatitis B infection, nor of hepatitis A infection nor of infection with cytomegalovirus, nor EB virus. At present they are classified as cases of [NANB] hepatitis. Evidence from other countries suggests that a virus (or viruses) may be associated with this type of hepatitis and that a carrier state is possible. With laboratory tests now permitting definitive diagnosis of hepatitis A virus infection, as well as hepatitis B, in 1979 it should be possible to determine the prevalence of [NANB] hepatitis in the general population in West Scotland.[120]

25.78 It appears, therefore, that there was an attitude in the UK among some experts that persisted into 1979, that NANB Hepatitis, particularly following blood transfusion, was common in the USA but that it had not become a major problem in the UK generally and in Scotland in particular. This attitude was to find an echo five or six years later in early responses to the arrival of HIV/AIDS in the USA. Attitudes were, however, changing by the end of the decade, under the influence of US research. Dr McClelland and the west of Scotland experts were taking a fresh look at the issue and research in this country picked up pace.

25.79 In 1978 Dr Rosemary Biggs, the Director of the Oxford Haemophilia Centre, published the second edition of her textbook, The Treatment of Haemophilia A and B and von Willebrand's Disease. One of the four complications that was said to arise from treatment with plasma fractions was the transmission of an infective organism, in particular hepatitis, to the patient.[121] Dr Biggs identified infective hepatitis, virus A and virus B, as transmissible agents, distinguishing them in the first place by their respective incubation periods and secondly discussing modes of transmission. The text proceeded:

Donor testing is important but at present no testing procedure will eliminate all samples infected with hepatitis B virus. The very high incidence of HBsAg in the blood of commercial donors means that even when the known positive samples are excluded, the blood products made from commercial donor blood are liable to be more infective than similar products made from volunteer donor blood.

A rather high proportion of haemophilic patients who develop hepatitis have no serological evidence of hepatitis B virus infection. These patients may have hepatitis A for which no serological tests are at present available. They may also have long incubation type hepatitis the causative agents for which have as yet not been identified. They may even develop jaundice for other reasons, for example haemolytic response to the infusion of blood group antibodies.[122]

25.80 The book was probably written in 1977, when Dr Biggs may not have been aware of research in the west of Scotland. It would be 1978 before Dr Follett, for example, had a reliable test for Hepatitis A. Dr Biggs' book recognised, however, that the 'long incubation type' hepatitis might have infected the haemophilia community.

25.81 Work on identifying the extent of NANB Hepatitis in the west of Scotland, begun in the late 1970s, was continued by Dr Dow, Dr Follet, Dr Mitchell and Professor Norman Grist (University of Glasgow) with grant support from the Scottish Hospital Endowments Research Trust.[123] However, a full prospective study would have been wide-ranging and expensive and was not undertaken.[124] Throughout 1980-1985, Dr Dow carried out ALT[125] testing on a sporadic basis, using prison sessions. Prison sessions were an obvious target as prisoners had already been shown to have a high incidence of Hepatitis B and NANB Hepatitis was also thought to be blood-borne. People with haemophilia, intravenous drug users and renal dialysis patients were also obvious populations.[126]

25.82 Thus, while established UK transfusion experts (including those practising in Scotland) were sceptical, at this stage, of the frequency of one or more non-B blood borne-viruses, some transfusion doctors and haemophilia doctors were implicitly acknowledging that such viruses were probably by no means rare, even if their apparent pathological importance had yet to be appreciated.

25.83 It was suggested in Dr Biggs' book that mildly affected haemophilia patients who had never or rarely been transfused should not receive large-pool commercial concentrates. Rather, Dr Biggs suggested, they should be given cryoprecipitate or small-pool concentrates. Dr Biggs concluded, however, that treatment with concentrates should not be withheld from severely affected patients because of the danger of hepatitis since 'the danger of death from haemorrhage and crippling' was of 'more immediate importance'.[127] (There was no mention of NANB Hepatitis in the book, apart from what might be inferred from the passage quoted.)

25.84 It seems likely that Dr Biggs' book, which was presented as 'an authoritative and up-to-date guide for haematologists, physicians and surgeons who care for haemophilia patients', would have had a wide circulation among clinicians, as would Dr Wallace's book of the year before. Dr McClelland's retrospective review of Dr Wallace's book left him confused. In the case of Dr Biggs' book, the lack of comment on the work of Feinstone and others on testing for Hepatitis A from 1973 onwards,[128] or on the application of the test reported by Alter and others in The Lancet in 1975,[129] might similarly be questioned. On the other hand, it is likely that, typically, textbooks for practitioners report generally accepted science, and it is right to bear in mind that there can be a significant gap between the level of understanding and what can be gleaned in retrospect from a wide reading of specialised professional literature.

25.85 On 20 August 1978 the Haemophilia Centre Directors' Hepatitis Working Party, chaired by Dr Craske, produced a report which discussed the pilot project initiated by Dr Craske to investigate the incidence of chronic liver disease in patients treated with Hemofil (a brand of commercially produced Factor VIII) in 1974-75.[130] Under the heading 'Prevention of Virus Infections', the report expressed doubts about screening tests for HBsAg:

Screening tests for HBsAg

Further studies have been carried out over the past year with batches of factor VIII suspected of having been contaminated with hepatitis B virus .... Since 1975, all batches of concentrate known to be associated with cases of acute hepatitis B have been negative for HBsAg by radioimmunoassay. However, despite improved donor screening in the USA, cases of overt hepatitis B still occur associated with every brand of large pool factor VIII, including NHS factor VIII.

It is evident, therefore, that screening tests for HBsAg are not sensitive enough to detect all donor plasma infected with hepatitis B virus, even when the concentrate is prepared from donations of plasma from volunteer donors.


Efforts are being made to increase the sensitivity of screening tests, but it seems unlikely that this will significantly reduce the incidence of hepatitis B from the present level.[131]

25.86 By 1979, therefore, the position in Scotland can be summarised as follows:

  • It was known that the best available screening tests for Hepatitis B still failed to detect a significant minority of Hepatitis B-infected donations.
  • It was known that NANB Hepatitis had been found in the Scottish population by the exclusion of Hepatitis A and B by Dr Follett and his group using tests covering both infections which were available from 1978.
  • There was still no screening test for NANB Hepatitis infection.
  • The prevalence of NANB Hepatitis infection was not known.
  • There was a clear need for further relevant research.

25.87 The detection rate on screening for Hepatitis B was probably over 80%, and the risk of transfusion-transmitted Hepatitis B was reduced accordingly. However, for large-pool concentrates screening was virtually ineffective having regard to the likelihood of the pool containing infected donations that had escaped detection on screening.

The early 1980s

25.88 There was official recognition of the need for further research early in 1980. An undated internal DHSS note, probably circulated in early 1980, commented on the reasons for a proposal to set up an Advisory Group on Viral Hepatitis. The purpose of this group was to advise on the public health aspects of hepatitis.[132] The context, reflecting knowledge of hepatitis infection among officials, is, however, relevant. The introduction to the note narrated that three and possibly more agents were known to cause viral hepatitis, with differences in their mode of spread and other epidemiological features. Increased knowledge had led to an even greater awareness of the problems which were arising. The note stated: 'At present hepatitis B presents the majority of problems and is responsible for the majority of enquiries but [NANB] hepatitis is already becoming a major source of concern'.[133]

25.89 The terms of reference proposed for the new Advisory Group were to advise the Chief Medical Officers (CMOs) of the Health Departments of the UK on all aspects of communicable hepatitis. The most important problems anticipated were related to: health and safety for NHS staff in direct contact with individuals who were carriers of Hepatitis B antigens; risks to patients from NHS staff; prevention and control of hepatitis; hazards associated with equipment; and hazards associated with blood and blood products in particular. It marked the beginning of a new phase in official recognition that there were public health issues relating to transmission of hepatitis. It is significant, however, that Hepatitis B was still identified among the most important problems. NANB Hepatitis was noted as becoming a cause for concern but was not included in the list of the most important problems in the field.

25.90 As appears from the discussion in Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis, other groups among the several that became active in the early 1980s were more relevant for present purposes, although provision was made for cross-representation of membership and the sharing of minutes of meetings.[134] The evidence indicates that a more structured approach was taken by the Health Departments to obtaining advice from this stage on.

25.91 In 1981 the Maycock Group published its third report.[135] While the report mainly dealt with testing for Hepatitis B, it also noted:

[NANB] hepatitis viruses are a common cause of [post-transfusion hepatitis] in the United States and are thought to have been responsible for cases of [post-transfusion hepatitis] in the UK. Hepatitis due to these viruses is common among haemophiliacs and follows the administration of imported, and occasionally of British Factor VIII and Factor IX. There is evidence for the occurrence of sporadic cases of [NANB] hepatitis in the general adult population and in association with cryoprecipitate therapy in the UK.

There are at the present time no screening tests for detecting [NANB] hepatitis viruses in blood donations.[136]

25.92 In oral evidence relating to donations collected in European penal institutions in the period 1975-83, Professor Leikola commented that he believed that many Europeans thought at the time that the problem of intravenous drug use in prisons was much smaller as compared to the problem in US institutions.[137] He went on to comment more generally:

Most of the research on Hepatitis B was done in the United States. Therefore I think that the investigators were readily willing to accept that the denial of using intravenous drugs was true. Secondly, in the 1970s it was well established that the occurrence of hepatitis virus was more common in prisoners as compared to the population at large. Wallace et al, 1972, assumed that the high incidence may be related to social habits and hygiene. This assumption was more or less copied to the later report by Barr and others in 1981. At the time when Wallace et al wrote their report, probably 1971, knowledge on the routes of infection was not as clear as it was later. Hepatitis A virus in contrast to Hepatitis B virus is water-borne and an infection could be related to poor hygiene. Other more realistic thoughts about the aetiology of Hepatitis B were expressed by Dr Helske in 1973.[138]

Discussion and Comment

25.93 Testing blood donations for infection at the beginning of the reference period was still relatively rudimentary and was necessarily related to contemporaneous knowledge of the risks of transmitting disease by use of human blood, blood components and blood products. Developing knowledge of these risks is a major topic for this Inquiry and is dealt with, in relation to hepatitis, in Chapters 14-16, Knowledge of Viral Hepatitis 1 to 3.[139]

25.94 There is a degree of artificiality in separating out topics such as the developing knowledge of the risk of transmitting disease, particularly hepatitis, donor selection, technological change and even manufacturing capacity. Similarly, a strict chronological account of events would fail to capture the atmosphere of medical and scientific research and development at the beginning of the reference period. Reference to the events of the preceding decade in particular, and some earlier events, has been required. In particular, setting out the evidence on a simple chronological basis would not present a satisfactory historical perspective, therefore a more analytical approach has been adopted. Chapter 18, Collection of Blood - General will deal with collection procedures generally and in particular the exclusion of individuals with a history of hepatitis or of transfusion. In this chapter, the emphasis is on the relevance of the early assays for infection with hepatitis viruses to donor exclusion policies.

25.95 The difference of opinion illustrated by the controversy over the adoption of RPHA technology in preference to RIA set out in paragraphs 25.54-25.56 demonstrates that there was active research into the best available methods and that two groups of scientists took different views at the time. In Dr Wallace's view, the less sensitive test was selected but the Maycock Group's recommendation for that test was supported by relevant expert opinion, in the UK and internationally, and cannot be criticised as inappropriate. Of course, the emphasis was on Hepatitis B at a time when there was evidence suggesting that NANB Hepatitis was a threat that was not addressed by either test.

25.96 It is clear that until the early to mid-1970s there was a strand of belief that, once screening for Hepatitis B had been dealt with, the problem of post-transfusion hepatitis would have been solved.[140] It was thought, correctly as events were to show, that there is no chronic carrier state for Hepatitis A infection which, in any case, is almost never transmitted by transfusion. Until 1973 or 1974 (depending on whether one has regard to the most advanced research) only Hepatitis B was relevant to transmission. The methods of detection of Hepatitis B until then were, however, inefficient. Two factors emerged in the mid-1970s. First, it was realised that the assays available were not able to detect all cases of Hepatitis B infection due to a significant problem of false negatives. Secondly, it was generally agreed that not all cases of post-transfusion hepatitis were caused by Hepatitis B type infection and that, as more Hepatitis B carriers were eliminated from serving as blood donors, the proportion of cases due to other types of hepatitis would increase.[141]

25.97 The original rationale for the exclusion from donation of individuals with a clinical history of hepatitis was based on evidence that some of them remained infectious long after the apparent resolution of their illness. It was thought that most were Hepatitis B patients. That was correct up to a point: most haemophilia patients in the 1960s and 1970s had been infected with Hepatitis B. It may have been an acceptable view more generally so long as only the Hepatitis A and Hepatitis B viruses were believed to exist. Once it was realised that more efficient tests were throwing up an increasing proportion of cases that were not Hepatitis B or Hepatitis A, however, there was a problem, obvious with the benefit of hindsight at least. When two potential causes of disease were increased to three, there could be no logical basis for a view that all cases of continuing illness were associated with the first two identified, and with them alone, to the exclusion of the newly postulated virus. It was never suggested that NANB Hepatitis was a 'new' virus in the sense of a virus affecting humans for the first time (as was to be suggested in the case of HIV); rather, it was an undiscovered virus of undetermined epidemiology. The early HBsAg assays identified 25-30% of 'hepatitis' cases as associated with Hepatitis B. That left a very large balance of cases that might have been associated with Hepatitis A, Hepatitis B or NANB Hepatitis: they were all cases of 'hepatitis', generally defined. In the light of later scientific developments, and perhaps even in the light of contemporaneous US literature, Dr McClelland's concerns about Dr Wallace's views were well founded. After 1979, with more sensitive tests for Hepatitis B and routine testing for Hepatitis A becoming available, the identification and definition of NANB Hepatitis cases among all cases of hepatitis would become much more clear cut.

25.98 The natural history of NANB Hepatitis was assumed to be mild, or benign, until biopsy evidence began to change perceptions of its seriousness. It can now be seen that the assumption was wrong. The facts, however, are clear: for a significant period after the discovery that there had to be one or more viruses causing hepatitis that was neither type A nor type B, many experts thought that NANB Hepatitis was a mild or benign condition. The confusion and complexity arising from co-infection by both Hepatitis B and NANB Hepatitis, mentioned at the outset of this chapter, in many cases 'cloaked' any NANB Hepatitis infection for a period. Hepatitis B causing more overt clinical illness allied with the relatively un-symptomatic nature of NANB Hepatitis infection in most cases provides at least part of the answer to the problem.

25.99 So far as positive identification of NANB Hepatitis viruses is concerned, the technology had not been developed: it was not developed until the very end of the 1980s. There was nothing that could have been done to identify the virus or viruses. In time, the dangers presented by NANB Hepatitis infection were recognised. As indicated in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985, Patrick Mollison's textbook on blood transfusion medicine indicated a view in 1983 (the end of the current period of discussion) that NANB Hepatitis was as a rule symptomatically mild, though a majority of patients had abnormal liver enzyme results and 10% of liver biopsies showed evidence of cirrhosis. Knowledge of the risk was beginning to emerge. Whether anything could have been done to reduce risk, while making available therapeutic materials for treatment of coagulation defects, blood and blood components for transfusion, short of the development of an effective assay, is discussed in Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis.

25.100 The proposal to set up an Advisory Group on Viral Hepatitis, together with the Maycock Group and the MRC and BTS initiatives (discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985) indicate a more structured approach by the Health Departments and National Health Service agencies to obtaining advice on hepatitis generally from the early 1980s onwards. The developments are best understood in the context of specific topics. In general, however, it is clear that the early years of the 1980s marked a change in the appreciation of the nature of the risks of transmission of viral hepatitis. Hepatitis B remained a significant problem. The importance of NANB Hepatitis was beginning to be appreciated.


25.101 In about 1983, on the eve of the AIDS epidemic as it was to develop in the UK, Hepatitis B was known to be a disease with potentially serious outcomes for patients. It was known that HAV was almost never transmitted by blood, while HBV was not the only hepatitis virus that presented risk of transfusion-transmitted hepatic disease. However:

  • Screening tests for Hepatitis B remained imperfect and were still believed to fail to identify a significant minority of Hepatitis B infected donations.
  • Samples testing negative for Hepatitis B (and, where tested for Hepatitis A, also negative for that infection) necessarily still included an unknown proportion that were infected with Hepatitis B and an unknown proportion that were infected with NANB Hepatitis or both.
  • The exact proportion of donations infected with NANB Hepatitis could not be determined by exclusion using existing screening tests for Hepatitis A and Hepatitis B.
  • There was no serological or other screening test for the NANB Hepatitis agent of transmission.
  • Knowledge of the prevalence of NANB Hepatitis in the UK, including Scotland, was at a very early stage of development.
  • Because of the emphasis on clinical symptoms and overt jaundice as indications of viral hepatitis, NANB Hepatitis was thought to be rare in Scotland.
  • NANB Hepatitis was generally thought to have a benign prognosis.
  • The risks for the patient that might be associated with the transmission of NANB Hepatitis were thought to be low relative to the risks associated with the conditions for which they required blood transfusion in surgery or in medical treatment of their primary conditions.

1 See, in particular, Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis, and the discussion of the work of the Working Party on Transfusion Transmitted Hepatitis below.

2 See Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985 and, in particular, the successive editions of Diseases of the Liver and Biliary System by Dame Sheila Sherlock referred to therein.

3 Typically alanine transaminase (ALT), a protein synthesised in liver cells. Normally present in low levels in the blood, ALT becomes elevated when the liver is disordered.

4 See paragraph 25.74 below.

5 Tests for anti-HBc were supplemented by tests for the antigen using specific immunoglobulins, Immunoglobulin M (IgM) and Immunoglobulin G (IgG). The test for anti-HBc became of interest as a possible 'surrogate marker' for NANB Hepatitis and is discussed in that context in Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis. The anti-HBc and IgM tests indicated whether the patient had ongoing infection. The IgG test indicated whether the patient had been exposed to or infected with Hepatitis B. It is not necessary, for present purposes, to discuss the nature of these tests in detail.

6 As with HCV (see Chapter 13, Knowledge of Viral Hepatitis Now, paragraph 13.14), HBV is divided into a number of different genotypes (and subgenotypes) with distinct properties.

7 The group met in Geneva on 25-30 September 1972. Their report, dated 1973, was published in 1975 as 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization technical Report Series, No. 512 [SGH.002.9746] at 9754. See, also, at 9762 where it was noted that '[t]he 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. The effect the introduction of more sensitive techniques will have on the rate of post-transfusion hepatitis is not yet clear, but preliminary evidence suggests that it will not be great... 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'. See, also, Dr McClelland - Day 9, pages 106-108

8 Parenteral transmission typically refers to a blood-borne route of transmission. See Chapter13, Knowledge of Viral Hepatitis Now, footnote 5 for a fuller discussion of the term.

9 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization Technical Report Series, 1975; No. 512 [SGH.002.9746] at 9755. Strictly speaking, an enteral infection is one spread through the introduction of a pathogen to the gastrointestinal tract. 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.

10 Fitzpatrick and Kennedy, 'Serum hepatitis in a haemophiliac', British Medical Journal, 1 November 1969; 299 [LIT.001.0249]

11 Minutes of meeting [DHF.002.7801]. At this period the expressions 'Australia/Australian antigen' (Au), 'Hepatitis Associated Antigen' (HAA), and 'Australian (Hepatitis Associated) Antigen' are used interchangeably, all superseded by the term 'Hepatitis B surface antigen' (HBsAg). See the second report of the Maycock Advisory Group, [SGH.003.0079] at 0083, for a wider range of terminology. In this chapter, 'Australia antigen' and 'Hepatitis B surface antigen /HBsAg' are used, except where it facilitates cross-reference to a source of evidence to use an alternative. See Chapter 14, Knowledge of Viral Hepatitis Now, for a discussion of the term 'serum hepatitis' (and the associated term 'infectious hepatitis' referred to below).

12 Minutes of MRC Working Party on Post-Transfusion Hepatitis, 14 February 1980 [DHF.002.4845] at 4846

13 Minutes of UK RTD meeting [DHF.002.7782] at 7786

14 Minutes of MRC Working Party on Post-Transfusion Hepatitis, 14 February 1980 [DHF.002.4845] at 4849-50

15 Paper [DHF.001.1745]

16 Ibid [DHF.001.1745] at 1746

17 See 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]

18 Chapter 14, Knowledge of Viral Hepatitis 1, paragraph 14.59

19 'Sensitivity' is a function of the test's ability to capture all cases of infection with the target pathogen. 'Specificity' is a function of the test's ability to identify only the target pathogen.

20 Note of DHSS meeting [DHF.001.1751]

21 Ibid [DHF.001.1751] at 1755

22 Report of the Advisory Group on Testing for the Presence of Australia (hepatitis-associated) Antigen and its Antibody, 1971 [SNB.002.1339] at 1341

23 Ibid [SNB.002.1339] at 1341

24 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]

25 Memorandum from Dr Wallace, dated 6 September 1971 [SGH.002.9885]

26 Memorandum dated 10 November 1970 [DHF.001.1791]

27 Memorandum from Dr Wallace's Memo dated 6 September 1971 [SGH.002.9885]

28 Report of the Advisory Group on Testing for the Presence of Australia (hepatitis-associated) Antigen and its Antibody, 1971 [SNB.002.1339] at 1346

29 Ibid [SNB.002.1339] at 1362

30 Ibid [SNB.002.1339] at 1343; the Bulletin of the World Health Organization, 1970, as reported in 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]. On the relatively low sensitivity of the early Hepatitis B IEOP tests see also: Report of the Advisory Group on Testing for the Presence of Australia (hepatitis-associated) Antigen and its Antibody, 1971 [SNB.002.1339] at 1345-46; Note by Dr Macdonald, SHHD, of a meeting at the DHSS on 20 July 1970 on Hepatitis and the Australia Antigen [SGH.002.3155]; Cash, 'Principles of Effective and Safe Transfusion' Proceedings of the Royal Society of Edinburgh. (B) 71 (Supplement), 5, 1971/72 [PEN.002.0559] at 0566, 'While it is accepted that the CIEOP technique is basically simple it is full of pitfalls ... and liable to give false-positive and negative results. Both of these events could have serious consequences on the donor and recipient respectively'.

31 Cash, 'Principles of Effective and Safe Transfusion', Proceedings of the Royal Society of Edinburgh (B) 71 (Supplement) 5, 1971/72 [PEN.002.0559] at 0565: Dr Cash refers to the 'recent' introduction of screening in his talk in February 1972.

32 A v The National Blood Authority, (2001) 3 All ER 289, paragraph 8, [PEN.017.0302] at 0308

33 Watt et al, 'New Developments in Large-scale Plasma Fractionation', Proceedings of the Royal Society of Edinburgh (B) 71 (Supplement), 3, 1971/72 [PEN.002.0538]. See Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.49-14.59

34 Watt et al, 'New Developments in Large-scale Plasma Fractionation', Proceedings of the Royal Society of Edinburgh (B) 71 (Supplement) 3, 1971/72 [PEN.002.0538] at 0551

35 Cash, 'Principles of Effective and Safe Transfusion', Proceedings of the Royal Society of Edinburgh (B) 71 (Supplement) 5, 1971/72 [PEN.002.0559] at 0564

36 Ibid [PEN.002.0559] at 0564

37 Revised Report of the Advisory Group on Testing for the Presence of Australia (Hepatitis-Associated) Antigen and its Antibody [DHF.001.1980] at 2000

38 Ibid [DHF.001.1980] at 1983

39 Minutes of SHHD Central Consultative Committee on Blood Transfusion meeting on 10 October 1972 [SGH.001.0690]

40 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization Technical Report Series, 1979; No. 512 [SGH.002.9746] at 9758-60

41 Ibid [SGH.002.9746] at 9762

42 Dr McClelland - Day 9, pages 106-108

43 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization technical Report Series, 1979, No. 512 [SGH.002.9746] at 9761

44 Second Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody [SGH.003.0079] at 0084

45 Memorandum from TE Dutton to Dr Waiter dated 16 March 1976 [SGF.001.2841] at 2842

46 Memorandum on the Selection etc of Blood Donors 1977 [SNB.002.5348] at 5350

47 Guidance for the Selection etc of Blood Donors 1983 [SGF.001.0377] at 0388

48 Guidance for the Selection etc of Blood Donors 1985 [DHF.001.8931] at 8943

49 Third Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody [DHF.003.0037] at 0042

50 Prince et al, 'Long-incubation post-transfusion hepatitis without serological evidence of exposure to hepatitis-B virus', The Lancet, 3 August 1974; 241 [LIT.001.0363]. Professor Cash said: 'I saw Alfred Prince in my 1969 visit to the States, he gave me a small vial of Australia antigen in New York and I brought it back, and that was the first beginnings of testing for Australia antigen, certainly in Scotland. This was an outstanding group'. Day 10, page 101

51 Second Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen, comment by Royal College of Physicians [DHF.001.2819] at 2823 (emph. orig.)

52 Final draft reply to the Second Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen [DHF.001.2819]

53 Health Services Development - Hepatitis B Surface Antigen - letter to Regional Health Authorities [DHF.001.2898]. Ministerial approval in October 1975 had been followed by extensive external consultation. See memo dated 24 March 1976 [SGF.001.2841]

54 Dr Dow - Day 8, page 83. Glasgow and Edinburgh used different test methods. By the end of 1984, Edinburgh used a haemaggluntination inhibition technique, see [SGF.001.2786]

55 Dr Dow - Day 8, pages 84-87

56 Dr Dow explained that the IOEP test detected down to 1 microgram per ml of HBV surface antigen whereas current tests would get down to picogram levels: a thousand times the number of individuals with HBV surface antigen would be detected. But that did not necessarily increase the numbers detected, because most were detected by IOEP in the first place, and only a few additional individuals were picked up by RIA, the more sensitive test, when it was introduced, and later developments. Day 8, pages 100-102.

57 Dr Dow - Day 8, pages 95-96

58 Ibid page 90

59 Ibid page 69

60 Ibid pages 85-86. See Dr Helske's paper [LIT.001.3562] at 3576: 7 out of 124 positive samples were detected by one technician only of two reading the plates independently.

61 Dr Dow - Day 8, pages 90-91

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

63 Wallace et al, 'Total screening of blood donations for Australia (hepatitis associated) antigen and its antibody', British Medical Journal, 11 March 1972; 663 [SGH.002.9831]

64 Biggs, 'Jaundice and antibodies directed against Factors VIII and IX in patients treated for haemophilia or Christmas Disease in the United Kingdom', British Journal of Haematology, 1974; 26:313 [LIT.001.0099] at 0100

65 Extract from CCC minutes [SGF.001.2786]

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

67 Ibid [SGH.003.0079] at 0084

68 Ibid [SGH.003.0079] at 0083

69 Ibid [SGH.003.0079] at 0084

70 Ibid [SGH.003.0079] at 0090. The report also made particular recommendations relating to the use of blood and plasma donated by donors who were born or had lived in endemic malarial areas. These were related to the risk of transmission of malaria and are not relevant for present purposes.

71 Second Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody [SGH.003.0079] at 0086

72 Ibid [SGH.003.0079] at 0089

73 Ibid [SGH.003.0079] at 0089

74 Dr Dow - Day 8, pages 117-118

75 Alter et al, 'Clinical and serological analysis of transfusion-associated hepatitis', The Lancet, 1 November 1975; 838-841 [LIT.001.3926]

76 Mr Dutton's memo of 16 March 1976 [SGF.001.2841] at 2842

77 Scottish National Blood Transfusion Services, 'Donor Selection Policies and Procedures', September 2010 [PEN.010.0365] at 0370

78 Dr McIntyre's minute of 24 March 1976 to Dr McCreadie and others [SGF.001.2841]

79 See Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis.

80 Helske, 'Carriers of Hepatitis B antigen and transfusion hepatitis in Finland', Scandinavian Journal of Haematology, 1974; Supplement No 22 [LIT.001.3562] at 3563

81 Ibid [LIT.001.3562] at 3606-07

82 Ibid [LIT.001.3562] at 3563

83 Professor Leikola - Day 13, pages 93-94

84 Dr Dow - Day 8, pages 111-112

85 Ibid pages 115-116

86 Ibid page 116

87 Dr Wallace's letter of 22 June 1976 [SGF.001.2836]

88 Ibid [SGF.001.2836] at 2837-38

89 Dr McIntyre's minute to Dr Scott dated 28 June 1976 [SGF.001.2834]

90 Day 11, page 153

91 Dr McIntyre's minute to Dr Scott dated 28 June 1976 [SGF.001.2834] containing handwritten note by Dr Scott dated 29 June 1976

92 Dr Wallace's letter of 26 July 1976 [SGF.001.2827]. See also Barr et al, 'HBsAg detection - results of comparative large scale testing of blood donations', Medical Laboratory Sciences, 1979; 36:109 [PEN.013.0393] at 0397 in which the authors compared the RPH and RIA methods of detecting HBsAg and observed that the '[f]inding of RPHA negative RIA positive HBsAg carriers therefore appears not to be a rare event. It is likely that a considerable number of such donors exist and can transmit type B hepatitis.'

93 Dr Dow's statement on the acceptance of blood from 'higher risk' donors [WIT.003.0094] at 0097

94 Dr Dow - Day 8, pages 114-115

95 Ibid page 112

96 Ibid pages 113-114

97 Barr et al, 'HBsAg detection - results of comparative large scale testing of blood donations', Medical Laboratory Sciences, 1979; 36:109 [PEN.013.0393]

98 ISBT Guide 2. Hazards of Blood Transfusion, International Society of Blood Transfusion, Paris 1976 [DHF.001.2692]

99 Ibid [DHF.001.2692] at 2703

100 Minutes of SNBTS Directors Meeting, 1 July 1976 [SGF.001.0282]

101 Ibid [SGF.001.0282] at 0285

102 A member of the Maycock Group, Dr Dane led the team of scientists who, in 1970, discovered the complete Hepatitis B virus.

103 Minutes of SNBTS Directors Meeting, 4 October 1976 [SGH.001.1320]

104 Ibid [SGH.001.1320] at 1321. (The reference to 'batch 124' in the header to this paragraph appears to be a typographical error).

105 Wallace, J. Blood Transfusion for Clinicians, Churchill Livingstone, 1977 [LIT.001.3058] at 3100-01

106 Ibid [LIT.001.3058] at 3110

107 Ibid [LIT.001.3058] at 3111-12

108 Dr McClelland - Day 9, page 50

109 Dr McClelland's statement on the acceptance of blood from 'higher risk' donors [WIT.003.0072]

110 Ibid [WIT.003.0072] at 0079

111 Day 9, pages 44-45

112 Ibid page 55

113 Berman et al, 'The chronic sequelae of non-A, non-B Hepatitis', Annals of Internal Medicine, July 1979; 91:1 [LIT.001.0189]

114 Day 13, pages 71-72

115 Dr Dow - Day 8, page 129

116 Galbraith et al, 'Non-A non-B hepatitis associated with chronic liver disease in a haemodialysis unit', The Lancet, 5 May 1979; 951 [LIT.001.0395]. C.f. an earlier report of the same outbreak, which made no mention of the possibility that the outbreak may have been caused by NANB hepatitis: Galbraith et al, 'Chronic liver disease developing after outbreak of HBsAg-negative hepatitis in haemodialysis unit', The Lancet, 8 November 1975; 886 [PEN.013.1426]. In his evidence to the Inquiry, Professor Cash spoke of a fatal outbreak of hepatitis at the renal dialysis unit in Edinburgh in 1969-70 having, once Hepatitis C tests became available, been shown to have been caused by both Hepatitis B and Hepatitis C: Day 10, pages 102-103

117 In his evidence to the Inquiry, Dr Dow explained that although the Hepatitis A virus had been identified in 1973, it was not until about 1978 that reliable tests for Hepatitis A became available: Day 8, pages 130-131

118 Galbraith et al, 'Non-A non-B hepatitis associated with chronic liver disease in a haemodialysis unit', The Lancet, 5 May 1979; 951 [LIT.001.0395] at 0397

119 Chaudhuri et al, 'Viral hepatitis in Glasgow 1976-1977', CDS 79/8, viii [PEN.002.0511]

120 Ibid [PEN.002.0511] at 0513

121 Biggs, R. The Treatment of Haemophilia A and B and von Willebrand's Disease, 1978, Blackwell Scientific Publications, Oxford, page 181

122 Ibid page 181

123 Dr Dow's statement on the acceptance of blood from 'higher risk' donors [WIT.003.0094] at 0098

124 Ibid [WIT.003.0094] at 0099

125 Dr Dow's research refers to SGPT, serum glumatic-pyruvic transaminase, another term for alanine transaminase, ALT.

126 Dr Dow - Day 8, pages 149-150

127 Biggs, R. The Treatment of Haemophilia A and B and von Willebrand's Disease, 1978, Blackwell Scientific Publications, Oxford, pages 186-187

128 Ibid. Book jacket.

129 Alter et al, 'Clinical and serological analysis of transfusion-associated hepatitis', The Lancet, 1 November 1975; 838-841 [LIT.001.3926]

130 Report of the Haemophilia Centre Directors' Hepatitis Working Party - 1978 [SNB.001.7192]

131 Ibid [SNB.001.7192] at 7197-98

132 See Minutes of the MRC Working Party on Post-Transfusion Hepatitis of 14 February 1980 which anticipated the early formation of the DHSS Advisory Group [PEN.017.1710]

133 DHSS note 'Advisory Group on Hepatitis' [DHF.002.9099]

134 For example with the UK Working Party on Transfusion-Associated Hepatitis [PEN.017.1716]

135 Third Report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody: 1981 [DHF.003.0037]

136 Ibid [DHF.003.0037] at 0045-46

137 Day 13, page 74

138 Ibid pages 74-75

139 See also Chapters 23 and 24 on viral inactivation of blood products; Chapter 25 on screening donated blood for HBV; Chapter 27 on surrogate testing for NANB Hepatitis; and Chapter 31 on screening for HCV.

140 Dr McClelland - Day 9, pages 106-107

141 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization Technical Report, Series 1979, No. 512 [SGH.002.9746] at 9754 and 9762

26. Donor Selection - Higher Risk Donors >