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Informed consent for blood transfusion: should the possibility of prion risk be included?
Informed Consent for Blood Transfusion: Should the Possibility of Prion Risk Be Included? Jason Hart, Brendan Leier, and Susan Nahirniak The emergence of bovine spongiform encephalopathy (BSE) in British cattle has received significant media attention since its discovery in 1986. Transmission of this prion from cattle to humans has been documented, and the BSE prion is believed to be the causative agent for variant Creutzfeldt-Jakob disease (vCJD). Evidence of this spread is a significant threat to public health, and, although there has never been a proven case, there is a theoretical risk of transmission between humans by blood transfusions. In addition, recent animal studies have documented spread in this fashion, raising the question of whether vCJD should be included as part of informed consent for blood transfusions. The process of informed consent requires disclosure of material risks,
defined as the risks that a reasonable person, under such circumstances, would want to know. Consent should, therefore, include the risks of a transfusion reaction, as well as the known infectious risks of blood. It should also include the unknown or theoretical risks of blood transfusions because full disclosure of even remote risks preserves the patient/physician trust relationship, which if breached, is very difficult to mend. Given the high level of public awareness, the potential lethality of the infection, and the theoretical risk of transmission by blood, vCJD can be considered a material risk, and consequently, it is reasonable to include it in the informed consent process. © 2004 Elsevier Inc. All rights reserved.
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in blood transfusions and explore the ethical issues of disclosure and informed consent surrounding this controversial topic.
HE EMERGENCE OF bovine spongiform encephalopathy (BSE), otherwise known as “mad cow disease,” in British cattle has received significant media attention in recent years, as Europe struggles to control the spread of this fatal infection. The recent announcement of BSE in Canada and the United States has renewed fears of a worldwide epidemic. Unfortunately, the spread has not been confined to cattle, and there is now a human form of this disease called variant Creutzfeldt-Jakob disease (vCJD). The evidence of the spread from infected cattle to humans is a significant threat to public health. The extent of transmission is difficult to predict because of a long incubation time from the initial infection to the overt manifestations of this disease. Consequently, the extent of spread to humans has not been fully quantified. A further complication is that little is known about the possibility of spread between humans, especially through blood transfusions, and although there is a theoretical risk for human-to-human transmission of this disease, there have been no proven cases of spread in this way. With the lack of concrete evidence, what is the physician’s responsibility to notify patients of this theoretical risk? Given the uncertainty of spreading this disease, should it be included as one of the risks of receiving a blood transfusion, or would the mention of vCJD cause unfounded fear and scepticism of the blood supply? This article will look at the evidence for transmission of vCJD
BACKGROUND
Classic Creutzfeldt-Jakob disease (cCJD) is a rapidly progressive, untreatable, and fatal neurodegenerative disease. It is caused by an infectious protein known as a prion. Prions are the only infectious agent devoid of nucleic acid, and they reproduce by recruiting normal cellular prion protein (PrPc) and stimulating its conversion into the disease causing isoform (PrPSc). This results in a conformational change of the protein making it resistant to proteolysis, causing amyloid deposition.1 In 1996, a novel form of prion disease affecting humans was recognized in the United Kingdom, which was called vCJD.2 The epidemiologic and experimental evidence soon linked vCJD and BSE, which at that time was believed to be a cattle-specific prion disease. This raises the From the Departments of Hematology/Medical Oncology; Philosophy; and Transfusion Medicine, University of Alberta, Edmonton, Alberta, Canada. Address reprint requests to Susan Nahirniak, MD, FRCPC, 4B4.27 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada T6G 2B7. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 0887-7963/04/1803-0003$30.00/0 doi:10.1016/j.tmrv.2004.03.001
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concern of transmission between species and poses a serious threat to public health, but the extent of spread to humans is difficult to estimate because the average incubation period is 10 to 15 years.2 There is no serologic testing currently available to reliably detect prions in the preclinical stages of the disease. Little is known about their transmission between and within species, and, although there is no evidence of transmission by blood transfusion between humans, the theoretical risk is present. The threat of cCJD in the blood supply has already left its mark in North American blood banks. In 1994, the American Red Cross and United States blood manufacturers recommended voluntary withdrawals of blood donated from 3 patients that later developed cCJD.3 In the same year, a similar incident occurred in Canada, resulting in the voluntary withdrawal of all blood products from a donor recently diagnosed with cCJD. The estimated cost of the recall was $11 million. Since this time, both the United States Food and Drug Administration and Health Canada have required geographic donor exclusion criteria to minimize the possible risk of vCJD being transmitted by blood transfusion to prevent further recalls and decrease the risk of transmission to blood recipients. The implementation of more sensitive and specific laboratory-based screening programs are complicated by the lack of a “gold standard” for diagnosing vCJD in the preclinical stage of the illness.4 Consequently, there is no such screening program used by any blood banks thus far. cCJD VERSUS vCJD AND TRANSMISSION BY BLOOD
An important distinction needs to be made between cCJD and vCJD. cCJD can be acquired, inherited, or sporadic. Sporadic cCJD occurs randomly in all countries with an incidence of approximately 1 case per million people per year.2 Acquired cCJD is from exposure to human prions through medical or surgical procedures. Transmission has been documented after neurosurgical procedures, cornea transplantation, and parenteral injection of hormones derived from cadavers.5 There have been no reported cases of cCJD transmission from blood transfusions. Lookback studies of patients that have received blood from blood donors
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later diagnosed with cCJD and neuropathologic studies of hemophiliacs that have received countless transfusions have never identified a case of transmission.6,7 In addition, a recent review of case-control studies looking at the association between blood transfusion and cCJD showed no positive correlation.8 Variant CJD has many differences that distinguish it from cCJD. Geographically, cCJD is seen uniformly in all parts of the world, whereas vCJD was initially found only in the United Kingdom, with a few case reports arising in other parts of the world. Most of these cases can be related back to the possibility of exposure in the United Kingdom before the onset of the disease. As of December 2003, a total of 139 definite and probable cases have been identified in the United Kingdom,9 6 cases in France, and one each in Italy, Ireland, China, the United States, and Canada.10 Another striking difference is that, although both affect the central nervous system, vCJD has also been found in peripheral tissue, whereas cCJD appears to be confined only to the central nervous system. Abnormal prion protein (PrPSc) was found in lymphoid tissue of a patient’s appendix, which was removed 8 months before the development of symptoms of vCJD.11 Similarly, tonsil, spleen, and lymph node biopsies of deceased patients with known vCJD tested positive for abnormal prion protein. Tissue of patients infected with other forms of prion disease, as well as uninfected control subjects, had no evidence of PrPSc prions in these structures.12 Consequently, from these data there is now convincing evidence of peripheral accumulation of vCJD before the onset of symptoms in infected patients. This raises the concern of lymphocytes being possible vehicles for transmission of vCJD in the blood, as the prion protein PrPc, the native protein known to be affected by CJD, is a normal protein on the cell membrane of lymphocytes.13 Although transmission of vCJD has never been proven in humans, blood-borne transmission of BSE, the same prion as that found in vCJD, has recently been documented in sheep.14 These animals were inoculated with BSE by the ingestion of a small amount of infected cattle brain. Whole blood was transfused from asymptomatic infected animals to recipient sheep, and so far, 2 cases of
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BSE have developed in the recipient animals. Although this study is preliminary, the findings are interesting and worrisome. These are the first documented cases of transmission of this prion through a blood transfusion, which occurred from a donor before overt manifestations of the infection. Although this is not entirely analogous to human blood transfusions, it may serve as a model for further assessment of the human risks. Concern of transmission of vCJD by blood transfusion between humans has recently been the topic of discussion in the British Parliament. On December 17, 2003, the British government announced the first reported case of a person dying from vCJD after receiving a blood transfusion from an infected donor. The donation was made in March 1996, when the donor had no symptoms to suggest prion disease; however, the donor subsequently developed vCJD and died of the disease in 1999. The recipient received the blood transfusion shortly after the donation was made, which was before the implementation of donor-screening programs and leukodepletion. The recipient died in autumn 2003, and portmortem examination has confirmed the recipient had vCJD. It is difficult to know or prove if this is a case of transfusiontransmitted prion disease or simply 2 people who separately acquired vCJD from eating BSE infected meat, but given the high degree of suspicion surrounding this case and the animal evidence that is now available, it is reasonable to assume that the transmission of vCJD was by blood transfusion.15 DISCLOSURE, THERAPEUTIC PRIVILEGE, AND INFORMED CONSENT
The concept of consent stems from the ethical principle of respect for patient autonomy and the need to involve patients in making decisions for their own health care. Canadian courts have determined that treating patients without their consent constitutes battery.16 If inadequate information is supplied to patients, this constitutes negligence.17 Beyond physician protection from litigation, consent improves patient satisfaction and reduces negative feelings and anxiety18 and should be obtained for any medical intervention. With a seemingly endless list of side effects or complications related to any intervention, it is impossible to include every possible side effect, reaction, or risk. In Canada, the standard of disclosure was determined by the Supreme Court of Canada in Reibl v
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Hughes.17 In this case, the physician failed to inform the patient of the risk of stroke at the time of an elective carotid endarterectomy. The Court decided, in the process of informed consent, a physician needs to disclose the material risks of a procedure, defined as the information that a reasonable person, under the same circumstances, would want to know to make an informed decision.19 Material risk encompasses the high likelihood of a minor side effect such as bruising after a blood sample is drawn, to the remote risk of a very serious outcome such as death.20 As a result, patients should be informed of the common results that are likely to occur, as well as the rare complications that are associated with significant morbidity or mortality. Included in this would be the possibility of transmitting a potentially life-threatening infectious disease through a blood transfusion. Although the risk of transmitting vCJD via blood transfusion is not known, it is an irreversible and fatal disease. Given the significant media attention to this topic, it can be assumed that a reasonable person would want to know the potential for transmission, and therefore vCJD should be considered a material risk for a blood transfusion. It should remain a material risk until sufficient evidence is collected to refute the claim that it may be transmitted via a blood transfusion. The counter-argument for disclosure of the threat of classic or variant CJD is that informing patients of the disease is causing unnecessary harm and the patient may be better off not knowing. This is the concept of therapeutic privilege.19 Because there are no proven cases of the spread of vCJD or cCJD by blood, some would argue that disclosure of the risk of contracting either form of CJD from a blood transfusion is not justified and merely causes unnecessary panic and anxiety. In 1995, the Canadian Red Cross Society recalled blood product and recommended recipient notification of possible contamination of blood with cCJD after a donor was diagnosed with this disease.21 The emotional responses of 528 transfusion recipients or guardians (if the recipient was a minor) were documented after notification. Two thirds of respondents reported feeling fearful and anxious on hearing the news; however, more than 80% of the respondents indicated that they wanted to be notified and would want to be notified again if another recall occurred. However, there still was 20% who
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did not wish to know. There are reports that notification of potential transmission of cCJD caused harm in Canadian patients that received these blood products.22,23 Some members of the Canadian CJD Society feel they are developing “early CJD” because of receiving the potentially infectious blood. Testing has not confirmed this, but recipients remain anxious. Therefore, it can be argued that mentioning cCJD or vCJD may cause unnecessary worry and patients may decline the potentially life-saving transfusion for fear of contracting “mad cow disease.” Withholding this information for these reasons would represent therapeutic privilege. There have been numerous attempts to claim therapeutic privilege as a defence in medical-legal trials. One such case is Meyer Estate v Rogers,24 in which a patient died after an intravenous injection of contrast dye for a radiologic procedure. The physician was accused of failing to warn this patient of the risks associated with intravenous contrast, and unsuccessfully used therapeutic privilege as his defence. At the end of the trial, the Judge stated, “the Supreme Court of Canada has not. . .adopted or even approved the therapeutic privilege exception . . ..”19,24 Because therapeutic privilege as an exception to informed consent has never been a successful defence and could potentially open the door for misuse, it should not be used as a rationalization for witholding information from competent patients. Implementing strategies to avoid or minimize harm may aid physicians in the informed consent process. Little has been done for transfusion recipients of blood potentially contaminated with cCJD.4 For example, no counselling programs have been offered to help recipients deal with the implications of potentially being infected with a prion disease. Similarly, there has been no second notification process to tell those with a previous transfusion exposure that cCJD is no longer believed to be transmitted by blood. This would undoubtedly help put their fears to rest. With the availability of a supportive infrastructure, a physician may be more willing to discuss the serious risks of blood transfusions, knowing that counselling is available for patients to work through their fears and concerns over the safety of the blood supply.
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The Risk of No Risk From the mid-1980s to the spring of 1996, during the peak years of the so-called Mad-Cow scare, the British Government’s message to its citizens concerning the threat of contracting vCJD was one of denial. The Government, through its Ministry of Agriculture Fisheries and Food, consistently denied the possibility of BSE posing any harm to human health as a result of the consumption of beef. This denial led to a decade-long dissolution of public trust in both the Ministry of Agriculture Fisheries and Food and the British Government. The end result was a complete undermining of public confidence when in 1996 the Health Secretary officially acknowledged a link between BSE and vCJD. By 1996, the public in Britain had all but excluded Government sources of information in the process of choosing to use or serve beef products.25 In risk literature, this form of continuing denial of possible harm can be characterized as a no-risk message.26 In the British case, the no-risk approach resulted in the worst possible outcomes both in terms of the health of those individuals eventually exposed to tainted beef and in the loss of credibility of governing health bodies in the eyes of the public. Arguably, the second consequence may have greater negative impact on overall public health. An essential aspect of effective risk communication is trust. If the public does not trust the sources of information concerning risks to health, the public is less likely to follow recommendations set out by the source of that information regardless of its veridicality. In the British case, the absence of trust left a vacuum of what was believed to be reliable information. This case shows a disturbing asymmetry in the nature of the trust relationship, that is, it is much more difficult to build trust than it is to destroy it.27 This asymmetry stems from both engrained aspects of human psychology as well as the anecdotal nature of trust-destroying events. Although trust building is accomplished slowly over time through good management or policy implementation, trust-destroying events are often well-defined instances such as chemical spills, medical errors, or occasional cataclysmic events. The nature of these events make them inherently more visible, reportable, and subsequently well scrutinized by the media and the public. Also, when trust-destroying events occur,
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they are given more opinion-forming weight than trust-building events, which are often unperceivable or unnoticed.28 Thus, in the case of the British vCJD crisis, every new case of human vCJD the press exposed steadily eroded the public’s confidence in the government’s willingness or ability to tell the truth. Unlike government bureaucrats or elected officials, physicians enjoy the highest levels of public confidence and trust of all professionals.29-31 This trust allows patients to accept the risks of exposures commonly seen to be detrimental to health, such as low-dose radiation exposure (x-rays) and chemical exposure (pharmaceuticals). These common medical procedures have a much higher associated risk than similar environmental exposures, yet patients readily submit to them partially because of their foreseen benefits but also because of the inherent trust in the physician prescribing the treatment or medication.27 Stemming from this unique patient/physician trust relationship is patient autonomy, fostered by the process of informed consent. When trust is lost, it directly follows that patient autonomy is lost as well. If patients must make decisions within a vacuum of information (ie, patients do not trust the source), their subsequent decisions cannot be understood as being truly autonomous. It is for this reason that physicians cannot underestimate the role of trust in the proper functioning of the patient/physician relationship. It seems clear that the failure of a physician to articulate the potential risk of the acquisition of vCJD from transfused blood would be equivalent to communicating a no-risk message and subsequently forever assuming the potential perils of such a claim. The greatest risk of the no-risk message is the potential harm that might befall the patient/physician trust relationship. The potential acquisition of vCJD, an untreatable, uniformly fatal disease, represents the worst possible fear for an individual. Although the potential harm in mentioning a familiar and notorious illness is real, this information can be realistically qualified by a physician through a process of clear communication. If the alternative scenario is adopted in which vCJD is not included in the consent process and transmission is later documented, this could not be so easily remedied. The acquisition of vCJD through a transfusion in the context of a no-risk message would certainly undermine physician trust, espe-
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cially in light of the backward-looking scrutinization and subsequent identification of the remote risk of such an unfortunate but spectacular incident. The threat of the no-risk message to the physician/patient trust relationship is potentially far more serious than the inevitable unease caused by the raising of these issues. INFORMED CONSENT FOR BLOOD TRANSFUSIONS
There are multiple components to the informed consent process. Firstly, patients should be made aware of why the transfusion is needed. Understanding this allows them to weigh the risks and benefits of the transfusion. Secondly, patients should be informed of the alternatives that are available and the risks and benefits of each of these options. Included in this process would be the option to refuse blood products. These steps lay the groundwork necessary to discuss the risks of a blood transfusion and allow the patient to make an informed decision. When discussing the material risks of a blood transfusion, informed consent should be comprised of the common risks that are unlikely to be fatal, such as urticaria or febrile reactions, versus bacterial contamination and other risks that are rare but carry high morbidity or mortality such as human immunodeficiency virus (HIV), hemolytic reactions, and anaphylaxis. Transfusion risks can be classified into 3 broad categories: the risk of a noninfectious transfusion reaction (Table 1), infectious risk (Table 2), and theoretical or unknown risk. In addition to the risks listed in Table 1 and 2, the recipient should be aware that, although unlikely, other rare or unknown pathogens could be transmitted via blood. Similarly, if there are preexisting comorbidities present in the recipient, the consent process should be tailored to address these risks. For example, pulmonary edema may occur in patients with renal failure or congestive heart failure. Table 1. Estimated Risk of Noninfectious Transfusion Reactions Reaction
Estimated Frequency (per Unit Transfused)
Acute hemolytic32 Delayed hemolytic32 Febrile33 Urticaria34 Anaphylactic32 TRALI32
1/250,000-1/1,000,000 1/1,000 1/25-1/100 1/100-1/300 1/150,000 1/5,000
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Table 2. Estimated Risk of Transfusion-Transmissible Diseases
Infection
Human immunodeficiency virus35 Hepatitis C35 Hepatitis B35 Bacterial contamination32 Platelets Red blood cells
Estimated Rate of Transmission (per Unit)
1/1,900,000 1/1,000,000 1/137,000 1/12,000 1/500,000
Patients should also be aware that despite rigorous testing and research, there still remain some unknown risks associated with a blood transfusion, including new infectious agents that have yet to be identified, as well as known diseases which cannot be tested for. CJD fits into this latter category, and can serve as an example for the unknown risks associated with a transfusion. History lends itself to review the previously unknown risks of blood. Both HIV and hepatitis C are agents that were known to exist, but initially their risk of transmission by blood was unknown.36-38 vCJD is in a similar situation as HIV and hepatitis C was 20 to 25 years ago, and it is difficult to predict if it will follow a similar course. This abnormal prion is a potentially life-threatening agent that may be in the blood supply, and the incidence of vCJD in the general population is not known. There is no way to detect it at present and no way of testing blood donors. There is, however, a theoretical risk for blood transmission and patients are well aware of this condition because of significant media attention surrounding this disease. As a result, vCJD should be considered a material risk of a blood transfusion. Informed consent regarding vCJD provides recognition that, although our blood is as safe as we can currently make it, there are still uncertainties that remain. Instead of ignoring the possibility of transmission, physicians should use vCJD in their disclosure as a representative of the “unknown” risks of blood. CONCLUSIONS
cCJD and vCJD are fatal neurologic diseases that cannot be detected by screening the blood supply. The classic form of the disease is very unlikely to enter the circulation, and epidemiologic data have never shown a case of transmission through blood transfusion. However, the properties of the vCJD are quite different from cCJD, and it
should not be assumed to have the same risks of transmission. Because vCJD is a relatively new infectious agent, complete epidemiologic data are not available and the risk of blood transmission is uncertain. However, there is a growing body of evidence to suggest that transfusion transmission may be possible. Transmission via blood has been documented in sheep, and the abnormal prion has been found in lymphatic tissue of patients with vCJD before the onset of symptoms. Although not proven, there has also been one case suspicious for human-to-human transmission of vCJD in the United Kingdom. Consequently, because of the serious nature of this infection, the transmission of vCJD should be considered a material risk of a blood transfusion until such time that there is sufficient evidence disproving its transmission. Informed consent for a blood transfusion should include the risks of a transfusion reaction, the infectious risks, as well as theoretical or unproven risks recognizing that we do not know all the risks associated with receiving blood. CJD remains a good example of the theoretical risk because of its well-publicized history and the high level of public awareness. If transfusions are ordered judiciously to those who are in need, it is unlikely that a patient would refuse a life-saving blood transfusion strictly on the theoretical and unproven risk of vCJD. However, by involving the patient in the decision, autonomy is emphasized and trust is fostered in the patient/physician relationship. If vCJD is included in the informed consent and the worstcase scenario of transmissibility occurs, patients will not feel victimized. Instead, they would be part of the decision-making process and be confident that, at the time, the benefits of the transfusion outweighed the risks. The patient/physician trust relationship would be preserved. Conversely, if vCJD is subsequently found not to be transmitted in blood, then physicians would appear to be only very cautious and protective of their patients’ autonomy. Therefore, vCJD should be included in the informed consent process for blood transfusion because it promotes patient autonomy and trust resulting in improved patient satisfaction. Note in Proof. Recently, there has been a report of a possible transmission of vCJD via blood transfusion in a patient who developed symptoms of vCJD 6.5 years after receiving a transfusion of red blood cells. The blood donor was diagnosed as having vCJD 3.5 years after his blood donation.39
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REFERENCES 1. Prusiner SB: Shattuck lecture—Neurodegenerative diseases and prions. N Engl J Med 344:1516-1526, 2001 2. Coulthart MB, Cashman NR: Variant Creutzfeldt-Jakob disease: A summary of current scientific knowledge in relation to public health. Can Med Assoc J 165:51-58, 2001 3. Wilson K, Hebert PC, Laupacis A, et al: A policy analysis of major decisions relating to Creutzfeldt-Jakob disease and blood supply. Can Med Assoc J 165:59-65, 2001 4. Blajchman MA, Goldman M, Webert KE, et al: Proceedings of a consensus conference: The screening of blood donors for variant CJD. Transfus Med Rev 18:73-92, 2004 5. Brown P, Preece M, Brandel J-P, et al: Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55: 1075-1081, 2000 6. Evatt B, Austin H, Barnhart E, et al: Surveillance for Creutzfeldt-Jakob disease among persons with hemophilia. Transfusion 38:817-820, 1998 7. Holman RC, Khan AS, Belay ED, et al: Creutzfeldt-Jakob disease in the United States, 1979-1994: Using national mortality data to assess the possible occurrence of variant cases. Emerg Infect Dis 2:333-337, 1996 8. Wilson K, Code C, Ricketts MN: Risk of acquiring Creutzfeldt-Jakob disease from blood transfusions: Systemic review of case-control studies. Br Med J 321:17-19, 2000 9. UK Government Department of Health Web site on CJD/ BSE. Available at: www.doh.gov.uk/cjd. Accessed November 19, 2003 10. Jansen GH, Voll CL, Robinson CA, et al: First case of variant Creutzfeldt-Jakob disease in Canada. Can Commun Dis Rep 29:117-120, 2003 11. Hilton DA, Fathers E, Edwards P, et al: Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet 352:703-704, 1998 12. Hill AF, Butterworth RJ, Joiner S, et al: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353:183-189, 1999 13. Cashman NR, Loertscher R, Nalbantoglu J, et al: Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 61:185-192, 1990 14. Hunter N, Foster J, Chong A, et al: Transmission of prion diseases by blood transfusion. J Gen Virol 83:2897-2905, 2002 15. World Federation of Hemophilia Statement on Transmission of vCJD by Transfusion. Available at: www.wfh.org. Accessed December 19, 2003 16. Malette v Schulman [1990] 67 DLR 94th) (Ont CA) at p 338 17. Reibl v Hughes [1980] 2 SCR 880 18. Suls J, Wan CK: Effects of sensory and procedural information on coping with stressful medical procedures and pain: A meta-analysis. J Consult Clin Psychol 57:372-379, 1989 19. Etchells E, Sharpe G, Burgess MM, et al: Bioethics for clinicians: 2. Disclosure. Can Med Assoc J 155:387-391, 1996
20. Downey J, Caulfield T: Canadian Health Law and Policy. Butterworths Canada Limited, 1999, pp 117-141 21. King SM, Watson H, Heurter H, et al: Notifying patients exposed to blood products associated with Creutzfeldt-Jakob disease: Theoretical risk for real people. Can Med Assoc J 159:771-775, 1998 22. Larke B: The quandary of Creutzfeldt-Jakob disease. Can Med Assoc J 159:789-792, 1998 23. Sibbald, Barbara: Blood recipients and CJD: To notify or not to notify, that is the question. Can Med Assoc J 159:829831, 1998 24. Meyer Estate v Rogers (1991), 78 DLR (4th) 307 (Ont. Gen. Div.) 25. Powell D, Leiss W: Mad Cows or Crazy Communications? Mad Cows and Mother’s Milk: The Perils of Poor Risk Communication, McGill-Queen’s University Press, 1997, p 11 26. Powell D, Leiss W: Mad Cows or Crazy Communications? Mad Cows and Mother’s Milk: The Perils of Poor Risk Communication. McGill-Queen’s University Press, 1997, p 6 27. Slovic P: Perceived risk, trust, and democracy. Risk Analysis 13:675-682, 1993 28. Slovic P, Flynn J, Johnson S, et al: The Dynamics of Trust in Situations of Risk. Decision Research Report 93-2, Decision Research Incorporated, 1993 29. Opinion of Professions in Britain. Available at: http:// www.mori.com/polls/trends/trust.shtml. December 3, 2003 30. Davis JA, Smith TW: Annual Series. General Social Surveys, Cumulative Codebook ICPSR: Study #3764 Section D, Question d321.Annual Series. Chicago, IL, University of Chicago, National Opinion Research Center, 2002 31. How Canadians Perceive Various Professions. Available at: http://www.nwtrna.com/news/trusted_pros.pdf. Accessed February 20, 2003 32. Goodnough LT, Brecher ME, Kanter MH, et al: Blood transfusion. N Engl J Med 340:438-447, 1999 33. Petrides M: Adverse effects of transfusion, in Petrides M, Stack G (eds): Practical Guide to Transfusion Medicine Bethesda, MD, AABB Press, 2001, pp 117-150 34. Popovsky MA: Transfusion Reactions (ed). Bethesda, MD, AABB Press, 2001 35. All About Blood. Available at: http://www.aabb.org/ All_About_Blood/FAQs/aabb_faqs.htm. Accessed December 3, 2003. 36. Capen K: There’s more to Krever’s report than the blood issue—Much more. Can Med Assoc J 158:92-94, 1998 37. Fienstone SM, Kapikian AZ, Purcel RH, et al: Transfusion-associated hepatitis not due to viral hepatitis A or B. N Engl J Med 292:767-770, 1975 38. Choo Q-L, Kuo G, Weiner AJ, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359-364, 1989 39. Llewelyn CA, Hewitt PE, Knight RSG, et al: Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 363:417-421, 2004
defined as the risks that a reasonable person, under such circumstances, would want to know. Consent should, therefore, include the risks of a transfusion reaction, as well as the known infectious risks of blood. It should also include the unknown or theoretical risks of blood transfusions because full disclosure of even remote risks preserves the patient/physician trust relationship, which if breached, is very difficult to mend. Given the high level of public awareness, the potential lethality of the infection, and the theoretical risk of transmission by blood, vCJD can be considered a material risk, and consequently, it is reasonable to include it in the informed consent process. © 2004 Elsevier Inc. All rights reserved.
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in blood transfusions and explore the ethical issues of disclosure and informed consent surrounding this controversial topic.
HE EMERGENCE OF bovine spongiform encephalopathy (BSE), otherwise known as “mad cow disease,” in British cattle has received significant media attention in recent years, as Europe struggles to control the spread of this fatal infection. The recent announcement of BSE in Canada and the United States has renewed fears of a worldwide epidemic. Unfortunately, the spread has not been confined to cattle, and there is now a human form of this disease called variant Creutzfeldt-Jakob disease (vCJD). The evidence of the spread from infected cattle to humans is a significant threat to public health. The extent of transmission is difficult to predict because of a long incubation time from the initial infection to the overt manifestations of this disease. Consequently, the extent of spread to humans has not been fully quantified. A further complication is that little is known about the possibility of spread between humans, especially through blood transfusions, and although there is a theoretical risk for human-to-human transmission of this disease, there have been no proven cases of spread in this way. With the lack of concrete evidence, what is the physician’s responsibility to notify patients of this theoretical risk? Given the uncertainty of spreading this disease, should it be included as one of the risks of receiving a blood transfusion, or would the mention of vCJD cause unfounded fear and scepticism of the blood supply? This article will look at the evidence for transmission of vCJD
BACKGROUND
Classic Creutzfeldt-Jakob disease (cCJD) is a rapidly progressive, untreatable, and fatal neurodegenerative disease. It is caused by an infectious protein known as a prion. Prions are the only infectious agent devoid of nucleic acid, and they reproduce by recruiting normal cellular prion protein (PrPc) and stimulating its conversion into the disease causing isoform (PrPSc). This results in a conformational change of the protein making it resistant to proteolysis, causing amyloid deposition.1 In 1996, a novel form of prion disease affecting humans was recognized in the United Kingdom, which was called vCJD.2 The epidemiologic and experimental evidence soon linked vCJD and BSE, which at that time was believed to be a cattle-specific prion disease. This raises the From the Departments of Hematology/Medical Oncology; Philosophy; and Transfusion Medicine, University of Alberta, Edmonton, Alberta, Canada. Address reprint requests to Susan Nahirniak, MD, FRCPC, 4B4.27 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada T6G 2B7. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 0887-7963/04/1803-0003$30.00/0 doi:10.1016/j.tmrv.2004.03.001
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concern of transmission between species and poses a serious threat to public health, but the extent of spread to humans is difficult to estimate because the average incubation period is 10 to 15 years.2 There is no serologic testing currently available to reliably detect prions in the preclinical stages of the disease. Little is known about their transmission between and within species, and, although there is no evidence of transmission by blood transfusion between humans, the theoretical risk is present. The threat of cCJD in the blood supply has already left its mark in North American blood banks. In 1994, the American Red Cross and United States blood manufacturers recommended voluntary withdrawals of blood donated from 3 patients that later developed cCJD.3 In the same year, a similar incident occurred in Canada, resulting in the voluntary withdrawal of all blood products from a donor recently diagnosed with cCJD. The estimated cost of the recall was $11 million. Since this time, both the United States Food and Drug Administration and Health Canada have required geographic donor exclusion criteria to minimize the possible risk of vCJD being transmitted by blood transfusion to prevent further recalls and decrease the risk of transmission to blood recipients. The implementation of more sensitive and specific laboratory-based screening programs are complicated by the lack of a “gold standard” for diagnosing vCJD in the preclinical stage of the illness.4 Consequently, there is no such screening program used by any blood banks thus far. cCJD VERSUS vCJD AND TRANSMISSION BY BLOOD
An important distinction needs to be made between cCJD and vCJD. cCJD can be acquired, inherited, or sporadic. Sporadic cCJD occurs randomly in all countries with an incidence of approximately 1 case per million people per year.2 Acquired cCJD is from exposure to human prions through medical or surgical procedures. Transmission has been documented after neurosurgical procedures, cornea transplantation, and parenteral injection of hormones derived from cadavers.5 There have been no reported cases of cCJD transmission from blood transfusions. Lookback studies of patients that have received blood from blood donors
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later diagnosed with cCJD and neuropathologic studies of hemophiliacs that have received countless transfusions have never identified a case of transmission.6,7 In addition, a recent review of case-control studies looking at the association between blood transfusion and cCJD showed no positive correlation.8 Variant CJD has many differences that distinguish it from cCJD. Geographically, cCJD is seen uniformly in all parts of the world, whereas vCJD was initially found only in the United Kingdom, with a few case reports arising in other parts of the world. Most of these cases can be related back to the possibility of exposure in the United Kingdom before the onset of the disease. As of December 2003, a total of 139 definite and probable cases have been identified in the United Kingdom,9 6 cases in France, and one each in Italy, Ireland, China, the United States, and Canada.10 Another striking difference is that, although both affect the central nervous system, vCJD has also been found in peripheral tissue, whereas cCJD appears to be confined only to the central nervous system. Abnormal prion protein (PrPSc) was found in lymphoid tissue of a patient’s appendix, which was removed 8 months before the development of symptoms of vCJD.11 Similarly, tonsil, spleen, and lymph node biopsies of deceased patients with known vCJD tested positive for abnormal prion protein. Tissue of patients infected with other forms of prion disease, as well as uninfected control subjects, had no evidence of PrPSc prions in these structures.12 Consequently, from these data there is now convincing evidence of peripheral accumulation of vCJD before the onset of symptoms in infected patients. This raises the concern of lymphocytes being possible vehicles for transmission of vCJD in the blood, as the prion protein PrPc, the native protein known to be affected by CJD, is a normal protein on the cell membrane of lymphocytes.13 Although transmission of vCJD has never been proven in humans, blood-borne transmission of BSE, the same prion as that found in vCJD, has recently been documented in sheep.14 These animals were inoculated with BSE by the ingestion of a small amount of infected cattle brain. Whole blood was transfused from asymptomatic infected animals to recipient sheep, and so far, 2 cases of
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BSE have developed in the recipient animals. Although this study is preliminary, the findings are interesting and worrisome. These are the first documented cases of transmission of this prion through a blood transfusion, which occurred from a donor before overt manifestations of the infection. Although this is not entirely analogous to human blood transfusions, it may serve as a model for further assessment of the human risks. Concern of transmission of vCJD by blood transfusion between humans has recently been the topic of discussion in the British Parliament. On December 17, 2003, the British government announced the first reported case of a person dying from vCJD after receiving a blood transfusion from an infected donor. The donation was made in March 1996, when the donor had no symptoms to suggest prion disease; however, the donor subsequently developed vCJD and died of the disease in 1999. The recipient received the blood transfusion shortly after the donation was made, which was before the implementation of donor-screening programs and leukodepletion. The recipient died in autumn 2003, and portmortem examination has confirmed the recipient had vCJD. It is difficult to know or prove if this is a case of transfusiontransmitted prion disease or simply 2 people who separately acquired vCJD from eating BSE infected meat, but given the high degree of suspicion surrounding this case and the animal evidence that is now available, it is reasonable to assume that the transmission of vCJD was by blood transfusion.15 DISCLOSURE, THERAPEUTIC PRIVILEGE, AND INFORMED CONSENT
The concept of consent stems from the ethical principle of respect for patient autonomy and the need to involve patients in making decisions for their own health care. Canadian courts have determined that treating patients without their consent constitutes battery.16 If inadequate information is supplied to patients, this constitutes negligence.17 Beyond physician protection from litigation, consent improves patient satisfaction and reduces negative feelings and anxiety18 and should be obtained for any medical intervention. With a seemingly endless list of side effects or complications related to any intervention, it is impossible to include every possible side effect, reaction, or risk. In Canada, the standard of disclosure was determined by the Supreme Court of Canada in Reibl v
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Hughes.17 In this case, the physician failed to inform the patient of the risk of stroke at the time of an elective carotid endarterectomy. The Court decided, in the process of informed consent, a physician needs to disclose the material risks of a procedure, defined as the information that a reasonable person, under the same circumstances, would want to know to make an informed decision.19 Material risk encompasses the high likelihood of a minor side effect such as bruising after a blood sample is drawn, to the remote risk of a very serious outcome such as death.20 As a result, patients should be informed of the common results that are likely to occur, as well as the rare complications that are associated with significant morbidity or mortality. Included in this would be the possibility of transmitting a potentially life-threatening infectious disease through a blood transfusion. Although the risk of transmitting vCJD via blood transfusion is not known, it is an irreversible and fatal disease. Given the significant media attention to this topic, it can be assumed that a reasonable person would want to know the potential for transmission, and therefore vCJD should be considered a material risk for a blood transfusion. It should remain a material risk until sufficient evidence is collected to refute the claim that it may be transmitted via a blood transfusion. The counter-argument for disclosure of the threat of classic or variant CJD is that informing patients of the disease is causing unnecessary harm and the patient may be better off not knowing. This is the concept of therapeutic privilege.19 Because there are no proven cases of the spread of vCJD or cCJD by blood, some would argue that disclosure of the risk of contracting either form of CJD from a blood transfusion is not justified and merely causes unnecessary panic and anxiety. In 1995, the Canadian Red Cross Society recalled blood product and recommended recipient notification of possible contamination of blood with cCJD after a donor was diagnosed with this disease.21 The emotional responses of 528 transfusion recipients or guardians (if the recipient was a minor) were documented after notification. Two thirds of respondents reported feeling fearful and anxious on hearing the news; however, more than 80% of the respondents indicated that they wanted to be notified and would want to be notified again if another recall occurred. However, there still was 20% who
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did not wish to know. There are reports that notification of potential transmission of cCJD caused harm in Canadian patients that received these blood products.22,23 Some members of the Canadian CJD Society feel they are developing “early CJD” because of receiving the potentially infectious blood. Testing has not confirmed this, but recipients remain anxious. Therefore, it can be argued that mentioning cCJD or vCJD may cause unnecessary worry and patients may decline the potentially life-saving transfusion for fear of contracting “mad cow disease.” Withholding this information for these reasons would represent therapeutic privilege. There have been numerous attempts to claim therapeutic privilege as a defence in medical-legal trials. One such case is Meyer Estate v Rogers,24 in which a patient died after an intravenous injection of contrast dye for a radiologic procedure. The physician was accused of failing to warn this patient of the risks associated with intravenous contrast, and unsuccessfully used therapeutic privilege as his defence. At the end of the trial, the Judge stated, “the Supreme Court of Canada has not. . .adopted or even approved the therapeutic privilege exception . . ..”19,24 Because therapeutic privilege as an exception to informed consent has never been a successful defence and could potentially open the door for misuse, it should not be used as a rationalization for witholding information from competent patients. Implementing strategies to avoid or minimize harm may aid physicians in the informed consent process. Little has been done for transfusion recipients of blood potentially contaminated with cCJD.4 For example, no counselling programs have been offered to help recipients deal with the implications of potentially being infected with a prion disease. Similarly, there has been no second notification process to tell those with a previous transfusion exposure that cCJD is no longer believed to be transmitted by blood. This would undoubtedly help put their fears to rest. With the availability of a supportive infrastructure, a physician may be more willing to discuss the serious risks of blood transfusions, knowing that counselling is available for patients to work through their fears and concerns over the safety of the blood supply.
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The Risk of No Risk From the mid-1980s to the spring of 1996, during the peak years of the so-called Mad-Cow scare, the British Government’s message to its citizens concerning the threat of contracting vCJD was one of denial. The Government, through its Ministry of Agriculture Fisheries and Food, consistently denied the possibility of BSE posing any harm to human health as a result of the consumption of beef. This denial led to a decade-long dissolution of public trust in both the Ministry of Agriculture Fisheries and Food and the British Government. The end result was a complete undermining of public confidence when in 1996 the Health Secretary officially acknowledged a link between BSE and vCJD. By 1996, the public in Britain had all but excluded Government sources of information in the process of choosing to use or serve beef products.25 In risk literature, this form of continuing denial of possible harm can be characterized as a no-risk message.26 In the British case, the no-risk approach resulted in the worst possible outcomes both in terms of the health of those individuals eventually exposed to tainted beef and in the loss of credibility of governing health bodies in the eyes of the public. Arguably, the second consequence may have greater negative impact on overall public health. An essential aspect of effective risk communication is trust. If the public does not trust the sources of information concerning risks to health, the public is less likely to follow recommendations set out by the source of that information regardless of its veridicality. In the British case, the absence of trust left a vacuum of what was believed to be reliable information. This case shows a disturbing asymmetry in the nature of the trust relationship, that is, it is much more difficult to build trust than it is to destroy it.27 This asymmetry stems from both engrained aspects of human psychology as well as the anecdotal nature of trust-destroying events. Although trust building is accomplished slowly over time through good management or policy implementation, trust-destroying events are often well-defined instances such as chemical spills, medical errors, or occasional cataclysmic events. The nature of these events make them inherently more visible, reportable, and subsequently well scrutinized by the media and the public. Also, when trust-destroying events occur,
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they are given more opinion-forming weight than trust-building events, which are often unperceivable or unnoticed.28 Thus, in the case of the British vCJD crisis, every new case of human vCJD the press exposed steadily eroded the public’s confidence in the government’s willingness or ability to tell the truth. Unlike government bureaucrats or elected officials, physicians enjoy the highest levels of public confidence and trust of all professionals.29-31 This trust allows patients to accept the risks of exposures commonly seen to be detrimental to health, such as low-dose radiation exposure (x-rays) and chemical exposure (pharmaceuticals). These common medical procedures have a much higher associated risk than similar environmental exposures, yet patients readily submit to them partially because of their foreseen benefits but also because of the inherent trust in the physician prescribing the treatment or medication.27 Stemming from this unique patient/physician trust relationship is patient autonomy, fostered by the process of informed consent. When trust is lost, it directly follows that patient autonomy is lost as well. If patients must make decisions within a vacuum of information (ie, patients do not trust the source), their subsequent decisions cannot be understood as being truly autonomous. It is for this reason that physicians cannot underestimate the role of trust in the proper functioning of the patient/physician relationship. It seems clear that the failure of a physician to articulate the potential risk of the acquisition of vCJD from transfused blood would be equivalent to communicating a no-risk message and subsequently forever assuming the potential perils of such a claim. The greatest risk of the no-risk message is the potential harm that might befall the patient/physician trust relationship. The potential acquisition of vCJD, an untreatable, uniformly fatal disease, represents the worst possible fear for an individual. Although the potential harm in mentioning a familiar and notorious illness is real, this information can be realistically qualified by a physician through a process of clear communication. If the alternative scenario is adopted in which vCJD is not included in the consent process and transmission is later documented, this could not be so easily remedied. The acquisition of vCJD through a transfusion in the context of a no-risk message would certainly undermine physician trust, espe-
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cially in light of the backward-looking scrutinization and subsequent identification of the remote risk of such an unfortunate but spectacular incident. The threat of the no-risk message to the physician/patient trust relationship is potentially far more serious than the inevitable unease caused by the raising of these issues. INFORMED CONSENT FOR BLOOD TRANSFUSIONS
There are multiple components to the informed consent process. Firstly, patients should be made aware of why the transfusion is needed. Understanding this allows them to weigh the risks and benefits of the transfusion. Secondly, patients should be informed of the alternatives that are available and the risks and benefits of each of these options. Included in this process would be the option to refuse blood products. These steps lay the groundwork necessary to discuss the risks of a blood transfusion and allow the patient to make an informed decision. When discussing the material risks of a blood transfusion, informed consent should be comprised of the common risks that are unlikely to be fatal, such as urticaria or febrile reactions, versus bacterial contamination and other risks that are rare but carry high morbidity or mortality such as human immunodeficiency virus (HIV), hemolytic reactions, and anaphylaxis. Transfusion risks can be classified into 3 broad categories: the risk of a noninfectious transfusion reaction (Table 1), infectious risk (Table 2), and theoretical or unknown risk. In addition to the risks listed in Table 1 and 2, the recipient should be aware that, although unlikely, other rare or unknown pathogens could be transmitted via blood. Similarly, if there are preexisting comorbidities present in the recipient, the consent process should be tailored to address these risks. For example, pulmonary edema may occur in patients with renal failure or congestive heart failure. Table 1. Estimated Risk of Noninfectious Transfusion Reactions Reaction
Estimated Frequency (per Unit Transfused)
Acute hemolytic32 Delayed hemolytic32 Febrile33 Urticaria34 Anaphylactic32 TRALI32
1/250,000-1/1,000,000 1/1,000 1/25-1/100 1/100-1/300 1/150,000 1/5,000
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Table 2. Estimated Risk of Transfusion-Transmissible Diseases
Infection
Human immunodeficiency virus35 Hepatitis C35 Hepatitis B35 Bacterial contamination32 Platelets Red blood cells
Estimated Rate of Transmission (per Unit)
1/1,900,000 1/1,000,000 1/137,000 1/12,000 1/500,000
Patients should also be aware that despite rigorous testing and research, there still remain some unknown risks associated with a blood transfusion, including new infectious agents that have yet to be identified, as well as known diseases which cannot be tested for. CJD fits into this latter category, and can serve as an example for the unknown risks associated with a transfusion. History lends itself to review the previously unknown risks of blood. Both HIV and hepatitis C are agents that were known to exist, but initially their risk of transmission by blood was unknown.36-38 vCJD is in a similar situation as HIV and hepatitis C was 20 to 25 years ago, and it is difficult to predict if it will follow a similar course. This abnormal prion is a potentially life-threatening agent that may be in the blood supply, and the incidence of vCJD in the general population is not known. There is no way to detect it at present and no way of testing blood donors. There is, however, a theoretical risk for blood transmission and patients are well aware of this condition because of significant media attention surrounding this disease. As a result, vCJD should be considered a material risk of a blood transfusion. Informed consent regarding vCJD provides recognition that, although our blood is as safe as we can currently make it, there are still uncertainties that remain. Instead of ignoring the possibility of transmission, physicians should use vCJD in their disclosure as a representative of the “unknown” risks of blood. CONCLUSIONS
cCJD and vCJD are fatal neurologic diseases that cannot be detected by screening the blood supply. The classic form of the disease is very unlikely to enter the circulation, and epidemiologic data have never shown a case of transmission through blood transfusion. However, the properties of the vCJD are quite different from cCJD, and it
should not be assumed to have the same risks of transmission. Because vCJD is a relatively new infectious agent, complete epidemiologic data are not available and the risk of blood transmission is uncertain. However, there is a growing body of evidence to suggest that transfusion transmission may be possible. Transmission via blood has been documented in sheep, and the abnormal prion has been found in lymphatic tissue of patients with vCJD before the onset of symptoms. Although not proven, there has also been one case suspicious for human-to-human transmission of vCJD in the United Kingdom. Consequently, because of the serious nature of this infection, the transmission of vCJD should be considered a material risk of a blood transfusion until such time that there is sufficient evidence disproving its transmission. Informed consent for a blood transfusion should include the risks of a transfusion reaction, the infectious risks, as well as theoretical or unproven risks recognizing that we do not know all the risks associated with receiving blood. CJD remains a good example of the theoretical risk because of its well-publicized history and the high level of public awareness. If transfusions are ordered judiciously to those who are in need, it is unlikely that a patient would refuse a life-saving blood transfusion strictly on the theoretical and unproven risk of vCJD. However, by involving the patient in the decision, autonomy is emphasized and trust is fostered in the patient/physician relationship. If vCJD is included in the informed consent and the worstcase scenario of transmissibility occurs, patients will not feel victimized. Instead, they would be part of the decision-making process and be confident that, at the time, the benefits of the transfusion outweighed the risks. The patient/physician trust relationship would be preserved. Conversely, if vCJD is subsequently found not to be transmitted in blood, then physicians would appear to be only very cautious and protective of their patients’ autonomy. Therefore, vCJD should be included in the informed consent process for blood transfusion because it promotes patient autonomy and trust resulting in improved patient satisfaction. Note in Proof. Recently, there has been a report of a possible transmission of vCJD via blood transfusion in a patient who developed symptoms of vCJD 6.5 years after receiving a transfusion of red blood cells. The blood donor was diagnosed as having vCJD 3.5 years after his blood donation.39
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REFERENCES 1. Prusiner SB: Shattuck lecture—Neurodegenerative diseases and prions. N Engl J Med 344:1516-1526, 2001 2. Coulthart MB, Cashman NR: Variant Creutzfeldt-Jakob disease: A summary of current scientific knowledge in relation to public health. Can Med Assoc J 165:51-58, 2001 3. Wilson K, Hebert PC, Laupacis A, et al: A policy analysis of major decisions relating to Creutzfeldt-Jakob disease and blood supply. Can Med Assoc J 165:59-65, 2001 4. Blajchman MA, Goldman M, Webert KE, et al: Proceedings of a consensus conference: The screening of blood donors for variant CJD. Transfus Med Rev 18:73-92, 2004 5. Brown P, Preece M, Brandel J-P, et al: Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55: 1075-1081, 2000 6. Evatt B, Austin H, Barnhart E, et al: Surveillance for Creutzfeldt-Jakob disease among persons with hemophilia. Transfusion 38:817-820, 1998 7. Holman RC, Khan AS, Belay ED, et al: Creutzfeldt-Jakob disease in the United States, 1979-1994: Using national mortality data to assess the possible occurrence of variant cases. Emerg Infect Dis 2:333-337, 1996 8. Wilson K, Code C, Ricketts MN: Risk of acquiring Creutzfeldt-Jakob disease from blood transfusions: Systemic review of case-control studies. Br Med J 321:17-19, 2000 9. UK Government Department of Health Web site on CJD/ BSE. Available at: www.doh.gov.uk/cjd. Accessed November 19, 2003 10. Jansen GH, Voll CL, Robinson CA, et al: First case of variant Creutzfeldt-Jakob disease in Canada. Can Commun Dis Rep 29:117-120, 2003 11. Hilton DA, Fathers E, Edwards P, et al: Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet 352:703-704, 1998 12. Hill AF, Butterworth RJ, Joiner S, et al: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353:183-189, 1999 13. Cashman NR, Loertscher R, Nalbantoglu J, et al: Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 61:185-192, 1990 14. Hunter N, Foster J, Chong A, et al: Transmission of prion diseases by blood transfusion. J Gen Virol 83:2897-2905, 2002 15. World Federation of Hemophilia Statement on Transmission of vCJD by Transfusion. Available at: www.wfh.org. Accessed December 19, 2003 16. Malette v Schulman [1990] 67 DLR 94th) (Ont CA) at p 338 17. Reibl v Hughes [1980] 2 SCR 880 18. Suls J, Wan CK: Effects of sensory and procedural information on coping with stressful medical procedures and pain: A meta-analysis. J Consult Clin Psychol 57:372-379, 1989 19. Etchells E, Sharpe G, Burgess MM, et al: Bioethics for clinicians: 2. Disclosure. Can Med Assoc J 155:387-391, 1996
20. Downey J, Caulfield T: Canadian Health Law and Policy. Butterworths Canada Limited, 1999, pp 117-141 21. King SM, Watson H, Heurter H, et al: Notifying patients exposed to blood products associated with Creutzfeldt-Jakob disease: Theoretical risk for real people. Can Med Assoc J 159:771-775, 1998 22. Larke B: The quandary of Creutzfeldt-Jakob disease. Can Med Assoc J 159:789-792, 1998 23. Sibbald, Barbara: Blood recipients and CJD: To notify or not to notify, that is the question. Can Med Assoc J 159:829831, 1998 24. Meyer Estate v Rogers (1991), 78 DLR (4th) 307 (Ont. Gen. Div.) 25. Powell D, Leiss W: Mad Cows or Crazy Communications? Mad Cows and Mother’s Milk: The Perils of Poor Risk Communication, McGill-Queen’s University Press, 1997, p 11 26. Powell D, Leiss W: Mad Cows or Crazy Communications? Mad Cows and Mother’s Milk: The Perils of Poor Risk Communication. McGill-Queen’s University Press, 1997, p 6 27. Slovic P: Perceived risk, trust, and democracy. Risk Analysis 13:675-682, 1993 28. Slovic P, Flynn J, Johnson S, et al: The Dynamics of Trust in Situations of Risk. Decision Research Report 93-2, Decision Research Incorporated, 1993 29. Opinion of Professions in Britain. Available at: http:// www.mori.com/polls/trends/trust.shtml. December 3, 2003 30. Davis JA, Smith TW: Annual Series. General Social Surveys, Cumulative Codebook ICPSR: Study #3764 Section D, Question d321.Annual Series. Chicago, IL, University of Chicago, National Opinion Research Center, 2002 31. How Canadians Perceive Various Professions. Available at: http://www.nwtrna.com/news/trusted_pros.pdf. Accessed February 20, 2003 32. Goodnough LT, Brecher ME, Kanter MH, et al: Blood transfusion. N Engl J Med 340:438-447, 1999 33. Petrides M: Adverse effects of transfusion, in Petrides M, Stack G (eds): Practical Guide to Transfusion Medicine Bethesda, MD, AABB Press, 2001, pp 117-150 34. Popovsky MA: Transfusion Reactions (ed). Bethesda, MD, AABB Press, 2001 35. All About Blood. Available at: http://www.aabb.org/ All_About_Blood/FAQs/aabb_faqs.htm. Accessed December 3, 2003. 36. Capen K: There’s more to Krever’s report than the blood issue—Much more. Can Med Assoc J 158:92-94, 1998 37. Fienstone SM, Kapikian AZ, Purcel RH, et al: Transfusion-associated hepatitis not due to viral hepatitis A or B. N Engl J Med 292:767-770, 1975 38. Choo Q-L, Kuo G, Weiner AJ, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359-364, 1989 39. Llewelyn CA, Hewitt PE, Knight RSG, et al: Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 363:417-421, 2004