The Safety and Availability of Blood and Tissues — Progress and Challenges
http://www.100md.com
《新英格兰医药杂志》
The availability of a safe blood supply is critical for both medical progress and national security. Safety has been increased by nucleic acid–amplification testing, as documented by Stramer et al. in this issue of the Journal.1 As health care providers, public health officials, and providers and users of donated blood and tissues we strive to improve the safety of the blood supply and to consider future threats, including threats to the safety of the donated tissue supply.
Twenty years ago — with tragic consequences — up to 1 in 100 blood units in the United States transmitted the human immunodeficiency virus (HIV) or hepatitis C virus (HCV), as did plasma that did not undergo what is now recognized as effective viral inactivation. Careful screening of donors for risk factors and technological innovations, from immunoassays to nucleic acid–amplification testing, has since prevented thousands of transfusion-transmitted infections. As described by Stramer et al., the use of nucleic acid–amplification testing to detect HIV and HCV during the initial "window period" of seronegativity after infection has further reduced the risk of transmission and, together with the advent of modern serologic testing, has improved the safety of the blood supply by a factor of more than 1000. Although this accomplishment is remarkable, we must now consider how to prevent future potential catastrophes.
As residual risks decrease, the costs of addressing them often rise. Effective serologic testing reduced the risk of transmission of HIV and HCV to 1 in 1.5 million and 1 in 276,000, respectively. The addition of nucleic acid–amplification testing has reduced the risks of both to approximately 1 in 2 million blood units. This additional prevention of the transmission of approximately 5 HIV infections and 56 HCV infections per year costs more than $100 million annually, or about $2 million per infection prevented.2 Some costs may be offset by the discontinuation of less effective tests. Noneconomic factors must also be considered, but in some cases the cost-effectiveness of such testing may not compare favorably with that of other preventive health measures.2,3 The use of nucleic acid–amplification testing for hepatitis B virus is likely to raise similar issues, as will the potential use of nucleic acid–amplification testing for individual units of blood, as opposed to pooled units, to achieve even greater sensitivity.
Although it is likely that unknown threats to the safety of blood and tissue pose the most danger, what threats are known? Bacterial contamination, which is usually due to skin organisms and less often to occult bacteremia in the donor, occurs in approximately 1 in 2000 platelet transfusions, largely because of the need to store platelets at room temperature, and such contamination can have serious consequences.4 Recently developed, rapid culture methods offer the potential to reduce this risk, though their clinical effectiveness is not yet known. Mosquito-borne infections, including malaria and possibly dengue, both acquired during travel and, potentially, from domestic transmission, pose additional threats. As with West Nile virus infections, any epidemic will predominantly be mosquito-borne rather than blood-borne, making vector control the primary intervention. But such control may be difficult to achieve, necessitating donor testing.
Tick-borne babesial infection can, like malaria, result in an asymptomatic carrier state, as can infection with agents normally considered "tropical," including Trypanosoma cruzi, the agent of Chagas' disease, of concern among Central and South American immigrants,5 and leishmania, of special concern in returnees from the Middle East.6 Variant Creutzfeldt–Jakob disease has been transmitted by transfusion in animal models, and two cases of transfusion-transmitted disease have been reported in patients in the United Kingdom.7,8 In the absence of a useful screening test for this disease in donors, the Food and Drug Administration (FDA) has recommended deferring any potential donor with substantial risk factors for exposure.9 Although the FDA used modeling to minimize donor losses, the use of deferrals based on risk factors such as travel is inefficient and diminishes already short blood supplies. Finally, the use of biologic and other types of agents by terrorists may threaten blood and tissue safety, whether through product contamination or infection of donors. We have entered a time when both our capacity to identify and respond to new threats and the expectation and need to do so effectively have increased.
New forms of technology have revolutionized our response capacity. It took several years to implement nationwide nucleic acid–amplification testing of blood donors for HIV and HCV. In contrast, by building on that technique when faced with a growing epidemic of West Nile virus infection and its transmissibility through antibody-negative blood,10 prompt cooperative action by government and industry led to nationwide implementation of investigational nucleic acid–amplification testing of donors within nine months, preventing the transfusion of more than 1000 units infected with the virus in 2003. Related techniques have made it possible to identify new infectious threats rapidly; it took over three years to identify HIV but less than a month to pinpoint the viral cause of severe acute respiratory syndrome. We need further innovation. For example, the availability of mass-produced nucleic acid chips or nanoassays for proteins or nucleic acids could make possible the cost-effective detection of all known pathogens, including biologic agents used by terrorists, and even newly identified members of families of pathogens. Although these advances are promising, much work remains to develop and field-test practical, sensitive methods.
The lessons learned from blood apply to human tissues, such as skin, bone, and ligaments, particularly in view of their increasing use (in approximately 1 million medical procedures a year). These tissues can transmit the same viral infections as blood, and the products of a single tissue donation may be transplanted to as many as 100 recipients. As discussed by Zou et al. in this issue of the Journal,11 tissue donors are screened for risk factors and have lower rates of infection than the general population, though not as low as blood donors. Nucleic acid–amplification testing of tissue donors for HIV and HCV should therefore have yields similar to those for blood donors, and with similar cost–benefit issues.
In contrast to blood, transplanted tissues are commonly of cadaveric origin and undergo processing that may increase their inherent risk of bacterial or fungal contamination. Serious outcomes may result12 but have been reported uncommonly, owing in part to underrecognition but also to the good health of most recipients, the common perioperative use of antibiotics, and the adoption of voluntary standards by many in the tissue-processing industry. The FDA has stepped up its inspection and enforcement activities and is implementing a regulatory framework for tissues that includes thorough screening and testing of donors for known and emerging biologic threats, the use of validated, good tissue-manufacturing practices, and routine reporting of adverse events.13,14 These steps should enhance tissue safety but, like those for blood, will not be fail-safe.
Several actions are needed to promote the safety and availability of blood and tissue. First, we must recognize donor testing as an integral component of disease surveillance and prevention. Screening of donors for West Nile virus has helped track the epidemic in real time, finding early cases and defining geographic spread, often in advance of clinical case reporting. Donor screening also provides valuable information on disease trends in healthy populations. Better screening tools for identifying multiple pathogens may also prove useful in the early detection of emerging pathogens or bioterrorism events.
Second, we need to establish proactive and collaborative ways of communicating about emerging infectious diseases and build response capabilities into programs devised to monitor the safety of blood and tissue. We know what can be accomplished through rapid, collaborative communication and action — for example, with respect to West Nile virus. Current activities to identify and prepare for future risks to the blood supply, such as periodic scientific assessments conducted by the Public Health Service and frequent consultation with the American Association of Blood Banks task forces, have been extremely important. Similar approaches should be developed for tissues. Continuing education regarding infections that can potentially be transmitted by blood and tissues is also needed to promote the reporting of adverse events, an important frontline component of surveillance.
Third, we need to identify and prioritize an agenda of applied scientific development and related implementation activities. Market incentives for these activities are limited, and carefully targeted scientific and technical support, often collaborative, can have substantial effects. For example, the study by Stramer et al. involved academic transfusion-medicine experts and industry experts and was supported by long-term funding from the National Institutes of Health. Further scientific collaboration to identify and address public health priorities in blood and tissue safety is essential. Activities should be linked to public health preparedness needs in an anticipatory manner. An example would be the development, in advance of the need for widespread use, of assays to detect agents that represent potential threats, with phased-in formatting for and evaluation of the assays in actual screening settings. The FDA has recently described a "critical-path" initiative that seeks to identify needs and encourage scientific progress in order to facilitate the development and availability of safe and effective products.15 Such needs include the development of methods for testing for multiple pathogens; methods for better and longer-term preservation and storage of blood, blood cells, and tissues; and more effective ways of removing or inactivating pathogens or achieving sterility while maintaining function.
Fourth, we must promote public discussion of the implementation of measures to enhance the safety of blood and tissue. Evidence-based public discussion, including consumer perspectives, should help set priorities. Benefits and costs should be viewed broadly. Changing procedures may have unintended effects in other areas or on product availability. Both public workshops and the Public Health Service's Advisory Committee on Blood Safety and Availability have provided useful forums for such discussions. Finally, we have to recognize and support the donation, availability, and safety of blood and tissue as part of our critical national infrastructure. Our health care system and medical progress depend on the safety and availability of blood, tissues, and organs for transplantation. We need to improve our understanding of donors' motivations and to support efforts to increase donations. The availability of blood and tissues such as skin and hematopoietic stem cells may be of special importance in wartime or after terrorist events, and in fact, their supply and integrity may be threatened during such times. The best preventive is a sound infrastructure. Industry and government are working cooperatively to anticipate and be prepared for such challenges. These efforts must be expanded and sustained.
I am indebted to Drs. Mary Chamberland and Matthew Kuehnert (Centers for Disease Control and Prevention), Dr. George Nemo (National Institutes of Health), Dr. Jerry Holmberg (Department of Health and Human Services), and Drs. Jay Epstein and Karen Midthun (FDA Center for Biologics Evaluation and Research) for their helpful comments.
Source Information
From the Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Md.
References
Stramer SL, Glynn SA, Kleinman SH, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004;351:760-768.
Jackson BR, Busch MP, Stramer SL, AuBuchon JP. The cost-effectiveness of NAT for HIV, HCV, and HBV in whole-blood donations. Transfusion 2003;43:721-729.
Marshall DA, Kleinman SH, Wong JB, et al. Cost-effectiveness of nucleic acid test screening of volunteer blood donations for hepatitis B, hepatitis C and human immunodeficiency virus in the United States. Vox Sang 2004;86:28-40.
Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: Joint ASH and AABB Educational Session in transfusion medicine. Hematology (Am Soc Hematol Educ Program) 2003;1:575-589.
Leiby DA, Herron RM Jr, Read EJ, Lenes BA, Stumpf RJ. Trypanosoma cruzi in Los Angeles and Miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission. Transfusion 2002;42:549-555. [CrossRef][ISI][Medline]
Update: cutaneous leishmaniasis in U. S. military personnel -- Southwest/Central Asia, 2002-2004. MMWR Morb Mortal Wkly Rep 2004;53:264-265.
Llewelyn CA, Hewitt PE, Knight RS, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;363:417-421.
Second case of vCJD "via blood." BBC News, UK edition. July 22, 2004. (Accessed July 30, 2004, at http://news.bbc.co.uk/1/hi/health/3916285.stm.)
Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for industry: revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jakob disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products. January 2002. (Accessed July 30, 2004, at http://www.fda.gov/cber/gdlns/cjdvcjd.pdf.)
Pealer LN, Marfin AA, Petersen LR, et al. Transmission of West Nile virus through blood transfusion in the United States in 2002. N Engl J Med 2003;349:1236-1245.
Zou S, Dodd RY, Stramer SL, Strong DM. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med 2004;351:751-759.
Kainer MA, Linden JV, Whaley DN, et al. Clostridium infections associated with musculoskeletal-tissue allografts. N Engl J Med 2004;350:2564-2571.
Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for industry: eligibility determination for donors of human cells, tissues, and cellular and tissue-based products: final rule and notice. May 25, 2004. (Accessed July 30, 2004, at http://www.fda.gov/cber/rules/suitdonor.pdf.)
Current good tissue practice for manufacturers of human cellular and tissue-based products: inspection and enforcement: proposed rule. January 8, 2001. (Accessed July 30, 2004, at http://www.fda.gov/cber/rules/gtp010801pr.pdf.)
Food and Drug Administration. Innovation or stagnation: challenge and opportunity on the critical path to new medical products. (Accessed July 30, 2004, at http://www.fda.gov/oc/initiatives/criticalpath/.)
Related Letters:
HIV-1 and HCV Infections among Antibody-Negative Blood Donors
Begovac J., Mihaljevic I., Perrin L., Laperche S., Pillonel J., Herve P., Prince A. M., Kainer M. A., Jarvis W. R., Stramer S. L., Dodd R. Y., Busch M. P., Goodman J. L.(Jesse L. Goodman, M.D., M)
Twenty years ago — with tragic consequences — up to 1 in 100 blood units in the United States transmitted the human immunodeficiency virus (HIV) or hepatitis C virus (HCV), as did plasma that did not undergo what is now recognized as effective viral inactivation. Careful screening of donors for risk factors and technological innovations, from immunoassays to nucleic acid–amplification testing, has since prevented thousands of transfusion-transmitted infections. As described by Stramer et al., the use of nucleic acid–amplification testing to detect HIV and HCV during the initial "window period" of seronegativity after infection has further reduced the risk of transmission and, together with the advent of modern serologic testing, has improved the safety of the blood supply by a factor of more than 1000. Although this accomplishment is remarkable, we must now consider how to prevent future potential catastrophes.
As residual risks decrease, the costs of addressing them often rise. Effective serologic testing reduced the risk of transmission of HIV and HCV to 1 in 1.5 million and 1 in 276,000, respectively. The addition of nucleic acid–amplification testing has reduced the risks of both to approximately 1 in 2 million blood units. This additional prevention of the transmission of approximately 5 HIV infections and 56 HCV infections per year costs more than $100 million annually, or about $2 million per infection prevented.2 Some costs may be offset by the discontinuation of less effective tests. Noneconomic factors must also be considered, but in some cases the cost-effectiveness of such testing may not compare favorably with that of other preventive health measures.2,3 The use of nucleic acid–amplification testing for hepatitis B virus is likely to raise similar issues, as will the potential use of nucleic acid–amplification testing for individual units of blood, as opposed to pooled units, to achieve even greater sensitivity.
Although it is likely that unknown threats to the safety of blood and tissue pose the most danger, what threats are known? Bacterial contamination, which is usually due to skin organisms and less often to occult bacteremia in the donor, occurs in approximately 1 in 2000 platelet transfusions, largely because of the need to store platelets at room temperature, and such contamination can have serious consequences.4 Recently developed, rapid culture methods offer the potential to reduce this risk, though their clinical effectiveness is not yet known. Mosquito-borne infections, including malaria and possibly dengue, both acquired during travel and, potentially, from domestic transmission, pose additional threats. As with West Nile virus infections, any epidemic will predominantly be mosquito-borne rather than blood-borne, making vector control the primary intervention. But such control may be difficult to achieve, necessitating donor testing.
Tick-borne babesial infection can, like malaria, result in an asymptomatic carrier state, as can infection with agents normally considered "tropical," including Trypanosoma cruzi, the agent of Chagas' disease, of concern among Central and South American immigrants,5 and leishmania, of special concern in returnees from the Middle East.6 Variant Creutzfeldt–Jakob disease has been transmitted by transfusion in animal models, and two cases of transfusion-transmitted disease have been reported in patients in the United Kingdom.7,8 In the absence of a useful screening test for this disease in donors, the Food and Drug Administration (FDA) has recommended deferring any potential donor with substantial risk factors for exposure.9 Although the FDA used modeling to minimize donor losses, the use of deferrals based on risk factors such as travel is inefficient and diminishes already short blood supplies. Finally, the use of biologic and other types of agents by terrorists may threaten blood and tissue safety, whether through product contamination or infection of donors. We have entered a time when both our capacity to identify and respond to new threats and the expectation and need to do so effectively have increased.
New forms of technology have revolutionized our response capacity. It took several years to implement nationwide nucleic acid–amplification testing of blood donors for HIV and HCV. In contrast, by building on that technique when faced with a growing epidemic of West Nile virus infection and its transmissibility through antibody-negative blood,10 prompt cooperative action by government and industry led to nationwide implementation of investigational nucleic acid–amplification testing of donors within nine months, preventing the transfusion of more than 1000 units infected with the virus in 2003. Related techniques have made it possible to identify new infectious threats rapidly; it took over three years to identify HIV but less than a month to pinpoint the viral cause of severe acute respiratory syndrome. We need further innovation. For example, the availability of mass-produced nucleic acid chips or nanoassays for proteins or nucleic acids could make possible the cost-effective detection of all known pathogens, including biologic agents used by terrorists, and even newly identified members of families of pathogens. Although these advances are promising, much work remains to develop and field-test practical, sensitive methods.
The lessons learned from blood apply to human tissues, such as skin, bone, and ligaments, particularly in view of their increasing use (in approximately 1 million medical procedures a year). These tissues can transmit the same viral infections as blood, and the products of a single tissue donation may be transplanted to as many as 100 recipients. As discussed by Zou et al. in this issue of the Journal,11 tissue donors are screened for risk factors and have lower rates of infection than the general population, though not as low as blood donors. Nucleic acid–amplification testing of tissue donors for HIV and HCV should therefore have yields similar to those for blood donors, and with similar cost–benefit issues.
In contrast to blood, transplanted tissues are commonly of cadaveric origin and undergo processing that may increase their inherent risk of bacterial or fungal contamination. Serious outcomes may result12 but have been reported uncommonly, owing in part to underrecognition but also to the good health of most recipients, the common perioperative use of antibiotics, and the adoption of voluntary standards by many in the tissue-processing industry. The FDA has stepped up its inspection and enforcement activities and is implementing a regulatory framework for tissues that includes thorough screening and testing of donors for known and emerging biologic threats, the use of validated, good tissue-manufacturing practices, and routine reporting of adverse events.13,14 These steps should enhance tissue safety but, like those for blood, will not be fail-safe.
Several actions are needed to promote the safety and availability of blood and tissue. First, we must recognize donor testing as an integral component of disease surveillance and prevention. Screening of donors for West Nile virus has helped track the epidemic in real time, finding early cases and defining geographic spread, often in advance of clinical case reporting. Donor screening also provides valuable information on disease trends in healthy populations. Better screening tools for identifying multiple pathogens may also prove useful in the early detection of emerging pathogens or bioterrorism events.
Second, we need to establish proactive and collaborative ways of communicating about emerging infectious diseases and build response capabilities into programs devised to monitor the safety of blood and tissue. We know what can be accomplished through rapid, collaborative communication and action — for example, with respect to West Nile virus. Current activities to identify and prepare for future risks to the blood supply, such as periodic scientific assessments conducted by the Public Health Service and frequent consultation with the American Association of Blood Banks task forces, have been extremely important. Similar approaches should be developed for tissues. Continuing education regarding infections that can potentially be transmitted by blood and tissues is also needed to promote the reporting of adverse events, an important frontline component of surveillance.
Third, we need to identify and prioritize an agenda of applied scientific development and related implementation activities. Market incentives for these activities are limited, and carefully targeted scientific and technical support, often collaborative, can have substantial effects. For example, the study by Stramer et al. involved academic transfusion-medicine experts and industry experts and was supported by long-term funding from the National Institutes of Health. Further scientific collaboration to identify and address public health priorities in blood and tissue safety is essential. Activities should be linked to public health preparedness needs in an anticipatory manner. An example would be the development, in advance of the need for widespread use, of assays to detect agents that represent potential threats, with phased-in formatting for and evaluation of the assays in actual screening settings. The FDA has recently described a "critical-path" initiative that seeks to identify needs and encourage scientific progress in order to facilitate the development and availability of safe and effective products.15 Such needs include the development of methods for testing for multiple pathogens; methods for better and longer-term preservation and storage of blood, blood cells, and tissues; and more effective ways of removing or inactivating pathogens or achieving sterility while maintaining function.
Fourth, we must promote public discussion of the implementation of measures to enhance the safety of blood and tissue. Evidence-based public discussion, including consumer perspectives, should help set priorities. Benefits and costs should be viewed broadly. Changing procedures may have unintended effects in other areas or on product availability. Both public workshops and the Public Health Service's Advisory Committee on Blood Safety and Availability have provided useful forums for such discussions. Finally, we have to recognize and support the donation, availability, and safety of blood and tissue as part of our critical national infrastructure. Our health care system and medical progress depend on the safety and availability of blood, tissues, and organs for transplantation. We need to improve our understanding of donors' motivations and to support efforts to increase donations. The availability of blood and tissues such as skin and hematopoietic stem cells may be of special importance in wartime or after terrorist events, and in fact, their supply and integrity may be threatened during such times. The best preventive is a sound infrastructure. Industry and government are working cooperatively to anticipate and be prepared for such challenges. These efforts must be expanded and sustained.
I am indebted to Drs. Mary Chamberland and Matthew Kuehnert (Centers for Disease Control and Prevention), Dr. George Nemo (National Institutes of Health), Dr. Jerry Holmberg (Department of Health and Human Services), and Drs. Jay Epstein and Karen Midthun (FDA Center for Biologics Evaluation and Research) for their helpful comments.
Source Information
From the Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Md.
References
Stramer SL, Glynn SA, Kleinman SH, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004;351:760-768.
Jackson BR, Busch MP, Stramer SL, AuBuchon JP. The cost-effectiveness of NAT for HIV, HCV, and HBV in whole-blood donations. Transfusion 2003;43:721-729.
Marshall DA, Kleinman SH, Wong JB, et al. Cost-effectiveness of nucleic acid test screening of volunteer blood donations for hepatitis B, hepatitis C and human immunodeficiency virus in the United States. Vox Sang 2004;86:28-40.
Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: Joint ASH and AABB Educational Session in transfusion medicine. Hematology (Am Soc Hematol Educ Program) 2003;1:575-589.
Leiby DA, Herron RM Jr, Read EJ, Lenes BA, Stumpf RJ. Trypanosoma cruzi in Los Angeles and Miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission. Transfusion 2002;42:549-555. [CrossRef][ISI][Medline]
Update: cutaneous leishmaniasis in U. S. military personnel -- Southwest/Central Asia, 2002-2004. MMWR Morb Mortal Wkly Rep 2004;53:264-265.
Llewelyn CA, Hewitt PE, Knight RS, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;363:417-421.
Second case of vCJD "via blood." BBC News, UK edition. July 22, 2004. (Accessed July 30, 2004, at http://news.bbc.co.uk/1/hi/health/3916285.stm.)
Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for industry: revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jakob disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products. January 2002. (Accessed July 30, 2004, at http://www.fda.gov/cber/gdlns/cjdvcjd.pdf.)
Pealer LN, Marfin AA, Petersen LR, et al. Transmission of West Nile virus through blood transfusion in the United States in 2002. N Engl J Med 2003;349:1236-1245.
Zou S, Dodd RY, Stramer SL, Strong DM. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med 2004;351:751-759.
Kainer MA, Linden JV, Whaley DN, et al. Clostridium infections associated with musculoskeletal-tissue allografts. N Engl J Med 2004;350:2564-2571.
Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for industry: eligibility determination for donors of human cells, tissues, and cellular and tissue-based products: final rule and notice. May 25, 2004. (Accessed July 30, 2004, at http://www.fda.gov/cber/rules/suitdonor.pdf.)
Current good tissue practice for manufacturers of human cellular and tissue-based products: inspection and enforcement: proposed rule. January 8, 2001. (Accessed July 30, 2004, at http://www.fda.gov/cber/rules/gtp010801pr.pdf.)
Food and Drug Administration. Innovation or stagnation: challenge and opportunity on the critical path to new medical products. (Accessed July 30, 2004, at http://www.fda.gov/oc/initiatives/criticalpath/.)
Related Letters:
HIV-1 and HCV Infections among Antibody-Negative Blood Donors
Begovac J., Mihaljevic I., Perrin L., Laperche S., Pillonel J., Herve P., Prince A. M., Kainer M. A., Jarvis W. R., Stramer S. L., Dodd R. Y., Busch M. P., Goodman J. L.(Jesse L. Goodman, M.D., M)