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Emerging infectious threats to the blood supply


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Lecture to the University of Canberra April 2007

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Emerging infectious threats to the blood supply

  1. 1. Emerging (and re-emerging) infectious risks to the global (and Australian) blood supply Albert Farrugia University of Canberra Faculty of Applied Science April 2007
  2. 2. The Safety Tripod for blood products <ul><li>Selection of appropriate raw material </li></ul><ul><ul><ul><li>Donors </li></ul></ul></ul><ul><ul><ul><li>Cell lines </li></ul></ul></ul><ul><li>Testing of raw material </li></ul><ul><ul><ul><li>Screening </li></ul></ul></ul><ul><ul><ul><li>Viral tests </li></ul></ul></ul><ul><li>Processing into product </li></ul><ul><ul><ul><li>Viral inactivation </li></ul></ul></ul><ul><ul><ul><li>Product integrity </li></ul></ul></ul>
  3. 3. The basis of blood product safety Donor selection Testing Elimination/removal Have you, your sexual partner any member of your household, or any other close contact ever received human body fluids, cells, tissues or organs that came into contact outside of the body with live cells, tissues or organs from an animal? The foregoing is an example of: A) A provision in a prenuptial agreement. B) A reading comprehension test. C) A proposed donor screening question. D) A question from Ken Starr to Bill Clinton. <ul><li>Current screening for: </li></ul><ul><li>anti-HIV 1/2 </li></ul><ul><li>anti-HCV </li></ul><ul><li>HBsAg </li></ul><ul><li>HCV RNA </li></ul><ul><li>HIV RNA </li></ul><ul><li>HTLV 1/2 </li></ul><ul><li>Syphylis </li></ul><ul><li>?WNV </li></ul><ul><li>?Dengue </li></ul><ul><li>?SARS </li></ul><ul><li>?vCJD </li></ul><ul><li>?Malaria </li></ul><ul><li>??????? </li></ul><ul><li>Proven route for plasma products </li></ul><ul><li>Technologies available for fresh products </li></ul><ul><li>Safety/quality issues still unresolved </li></ul><ul><li>Expensive!!! </li></ul><ul><li>?Cost-effective </li></ul>
  4. 4. Risk of HIV per Unit (%) Year of Transfusion First AIDS cases reported First TA-AIDS cases reported; High-risk donor deferral / self-exclusion initiated. HIV discovered; Progressive impact of high-risk donor education. Anti-HIV screening impmented Risk of HIV Transmission by Blood Transfusions Before the Implementation of HIV-1 Antibody Screening Busch et al. Transfusion 1991; 3: 4-11 2.0 1.5 1 0.5 0 1978 1979 1980 1981 1982 1985 1983 1984 1990
  5. 6. Testing for Hepatitis C HCV RNA 0 10 20 30 40 50 60 70 80 90 100 - HCV MP-NAT - HCV ID-NAT Pre- MP NAT WP = 60 days ID-NAT WP = 3 days MP-NAT WP = 10 days Anti-HCV (3.0 EIA)
  6. 7. Safety Concerns The things we know and love
  7. 8. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence  8% - High 2-7% - Intermediate <2% - Low
  9. 10. Adults and children estimated to be living with HIV/AIDS as of end 2002 Total: 42 million Western Europe 570 000 North Africa & Middle East 550 000 Sub-Saharan Africa 29.4 million Eastern Europe & Central Asia 1.2 million South & South-East Asia 6 million Australia & New Zealand 15 000 North America 980 000 Caribbean 440 000 Latin America 1.5 million East Asia & Pacific 1.2 million
  10. 11. High and low resource countries <ul><li>83% of global population has access to only 40% of world’s blood </li></ul><ul><li>Donations/1000 is 41-50 in High HDI, but 1/20th that rate in Low HDI </li></ul><ul><li>High HDI 98% voluntary, Low HDI 31% voluntary </li></ul><ul><li>Paid donations often masquerade as “replacement/family” </li></ul><ul><li>Up to 13 of the 75 million donations were not fully tested (1998-99), mostly in low or medium HDI countries. </li></ul>
  11. 12. Risk/million repeat donations (with NAT) – High HDI * NAT not included (From: Glynn et al, Transfusion 2001) HIV HBV* HCV Australia 0.2 1.9 0.9 France 0.4 NA 0.1 Italy 1.1 2.1 6.6 Spain 1.0 13.5 6.0 US 0.5 4.9 0.5
  12. 13. HIV incidence, prevalence and risk PHT donations (RSA) Includes impact of HIV p24 antigen testing Prevalence Incidence Residual Risk High Prevalence 4850 512 14 (1:7100) Low Prevalence 99 12.9 0.7 (1:143000) Overall (NA) 62.8 3.4 (1:29400)
  13. 14. Range of coverage, prevalence and risk, Latin America, 2001-2 HIV HBV HCV T. cruzi Cov High Low 100% 86% 100% 93.4% 100% 49% 100% 25.1% Prev High Low 5.0/1k GUT 0.3 CHI 11.3 GUT 0.7 CHI 11.0 COL 1.3 CHI 99.1 BOL 1.5 ECU Risk High Low 11/10k 0 8.0 0 14.0 0 28.0 0
  14. 15. HIV HBV HCV 1996 1994 1992 1990 1988 1986 1984 1:100 1:1000 1:10 000 1:100 000 1:1 000 000 1998 2000 Risk, per unit 2002 Bacterial Contamination (platelets) Septic Fatalities (platelets) TRALI Fatalities 1:2,000 1:140,000 1:100,000 Evolution of Transfusion Risks Mistransfusion Fatalities 1:600,000
  15. 16. Risks in repeat donors HIV, HCV & HBV
  16. 19. Residual risk of TTI’s per 10 6 repeat donations Glynn et al (2002) Transfusion 42:966-972 HIV HCV HBV
  17. 20. Emerging infectious agents West Nile Virus, 1999 Hantavirus, 1993 Nipah, 1998 Diphtheria, 1993 Variant CJ Disease, 1996 E. coli O 157 H7, 1998 V. cholerae O 139, 1992 Dengue, 1992 Morbillivirus, 1994 Plague, 1994 Rift Valley fever, 1993 Yellow fever, 1993 Bolivian hemorrhagic fever, 1994 HIV-1 subtype O, 1994 Lassa fever, 1992 Dengue, 1994 Anthrax, 1993 Cholera, 1991 Yellow fever/VEE, 1995 Leptospirosis, 1995 Dengue, 1993 Adenovirus type 7, 1995 Arenavirus, 2000 Ebola 2000 Ebola, 1995
  18. 21. Emerging Infections <ul><li>New Agent </li></ul><ul><li>Expanding Range </li></ul><ul><li>Imported </li></ul><ul><li>Reemergent </li></ul><ul><li>Newly recognized </li></ul><ul><li>Patient changes </li></ul><ul><li>HIV, BSE/vCJD, SARS </li></ul><ul><li>Babesia/Ehrlichia </li></ul><ul><li>Chagas’, WNV </li></ul><ul><li>Malaria </li></ul><ul><li>HHV-6, 8, TTV…. </li></ul><ul><li>CMV, B19? </li></ul>
  19. 22. Epidemiology of agents <ul><li>Prevalence </li></ul><ul><ul><li>High prevalence increases impact of test failure (or absence!) </li></ul></ul><ul><ul><li>High prevalence leads to high testing loss </li></ul></ul><ul><li>Incidence </li></ul><ul><ul><li>High incidence impacts window period risk </li></ul></ul><ul><li>Transmission routes </li></ul><ul><ul><li>May permit risk-based intervention </li></ul></ul><ul><li>Recipient status </li></ul><ul><ul><li>Susceptibility, impact of infection </li></ul></ul>
  20. 23. Human behavior and transfusion-transmitted infections <ul><li>HIV </li></ul><ul><ul><li>Bush meat, sexual behavior, travel </li></ul></ul><ul><li>Malaria </li></ul><ul><ul><li>Global climate change, travel </li></ul></ul><ul><li>Chagas’ disease </li></ul><ul><ul><li>Population migration </li></ul></ul><ul><li>West Nile virus </li></ul><ul><ul><li>Unknown (travel?), irrigation practice </li></ul></ul><ul><li>SARS </li></ul><ul><ul><li>Exotic diet? Air travel </li></ul></ul><ul><li>Monkeypox </li></ul><ul><ul><li>Exotic pets </li></ul></ul><ul><li>vCJD </li></ul><ul><ul><li>Intensive agricultural practice and export of feed, cattle </li></ul></ul><ul><li>LCMV </li></ul><ul><ul><li>Non-exotic pets </li></ul></ul><ul><li>Leishmania </li></ul><ul><ul><li>Military adventures </li></ul></ul>
  21. 24. Concern high, Action favored Benefit High Action favored vCJD CJD Lyme HGV, etc RMSF CTF HAV Ehrlichia B19 Babesia T.cruzi Bacteria HHV 8 HHV 6 (HIV) idprio2001 Chlamydia, WNV , JC, Leptospira Bartonella etc Ebola etc Leishmania Malaria
  22. 25. Concern high, Action favored Benefit High Action favored vCJD CJD Lyme HGV, etc RMSF CTF HAV Ehrlichia B19 Babesia T.cruzi Bacteria HHV 8 HHV 6 (HIV) idprio2001 Chlamydia, JC, Leptospira Bartonella etc Ebola etc Leishmania Malaria WNV
  23. 26. Malaria
  24. 27. Malaria: background <ul><li>Intraerythrocytic protozoan parasite, 4 species of Plasmodium </li></ul><ul><li>Acute and chronic infection and disease, asymptomatic to fatal </li></ul><ul><li>Transmitted by mosquitoes </li></ul><ul><li>Global distribution in tropics and sub-tropics </li></ul><ul><li>300-500 million cases annually, 1.5-2.7 million deaths </li></ul><ul><li>About 1000 imported cases annually in US, plus a handful of inexplicable cases </li></ul>
  25. 28. Malaria and transfusion <ul><li>Globally, probably most frequent TTD </li></ul><ul><li>Survives in stored cellular products </li></ul><ul><li>Essentially all recipients susceptible </li></ul><ul><li>2-4 transfusion cases annually in US </li></ul><ul><li>Risk stable, could increase with travel and potential reemergence (Global warming) </li></ul><ul><li>Travel history is current intervention </li></ul><ul><ul><li>>50,000 donors/year deferred in US </li></ul></ul>
  26. 29. Proposed reinstatement protocol for donors traveling to malarious areas Seed et al 2005
  27. 30. Babesia
  28. 31. Babesia: background <ul><li>Intraerythrocytic protozoan parasite, one major species </li></ul><ul><li>Acute disease, up to 6 months subclinical infectivity, treatable, fatal for selected recipients </li></ul><ul><li>Transmitted by ticks </li></ul><ul><li>B. microti Northeast US, upper Midwest, others Midwest, Pacific coast </li></ul><ul><li>Cases not reported, seroprevalence up to 1.5% </li></ul>
  29. 32. Babesia and transfusion <ul><li>Transfusion transmission recognized in US, Japan (I case) </li></ul><ul><li>Survives in erythrocyte-containing components (including platelets) </li></ul><ul><li>Outcomes worse in aged, splenectomized and immunocompromised </li></ul><ul><li>More than 50 transfusion cases to date, demonstrable risk 1:1000 in highest incidence area of CT </li></ul><ul><li>Risk increasing with geographic spread of agent, host/vector (Pseudo-rural lifestyle) </li></ul><ul><li>No available effective intervention </li></ul><ul><ul><li>Donor population management, hospital vigilance and recipient treatment </li></ul></ul><ul><ul><li>Potential for testing? </li></ul></ul>
  30. 33. Chagas’ disease
  31. 34. Chagas’: background <ul><li>Protozoan parasite, free in blood, tropism for smooth and cardiac muscle </li></ul><ul><li>Acute disease and chronic (lifelong) infection, asymptomatic to fatal </li></ul><ul><li>Zoonosis, transmitted by triatomine bugs </li></ul><ul><li>Agent, vectors found in continental Americas, 40 °S - 40°N, human cases only in Mexico, S. and Central America </li></ul><ul><li>19-20 million infected individuals, incidence declining </li></ul><ul><li>At least 100,000 infected individuals in US as a result of population movements </li></ul>
  32. 35. LA Seroprevalence: 1996-98 % Donors Positive 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 1996 1997 1998 1/9,900 1/7,200 1/5,400
  33. 36. Chagas’ and transfusion <ul><li>12 – 50% from infected blood in S. America </li></ul><ul><li>Survives in stored components, most infections from whole blood or platelets </li></ul><ul><li>Severe disease in immunocompromised patients </li></ul><ul><li>At least 7 cases in North America, estimated seroprevalence 1:40,000 to 1:25,000 (60% parasitemia) </li></ul><ul><li>Risk increasing in US (population movement and focus on Hispanic donors) </li></ul><ul><li>No effective intervention available: questioning neither specific nor sensitive </li></ul><ul><ul><li>Antibody testing would be effective </li></ul></ul>
  34. 37. Leishmania <ul><li>Current and past concern relate to troop and civilian deployment in Iraq and Afghanistan </li></ul><ul><li>Protozoan parasite transmitted by sandflies: widespread in tropics </li></ul><ul><li>A few historical examples of bloodborne transmission: no current cases </li></ul><ul><li>Intervention: deferral for returnees from middle East conflict areas </li></ul>
  35. 38. Bacterial contamination: general <ul><li>Outgrowth of bacteria in components </li></ul><ul><li>Acute to fatal disease </li></ul><ul><li>Skin or environmental contaminants or donor bacteremia </li></ul><ul><li>Generalized occurrence </li></ul><ul><li>Frequency depends on measure </li></ul><ul><ul><li>1:1500 platelets with reactive cultures </li></ul></ul><ul><ul><li>1:19,000 platelets result in detectable reaction </li></ul></ul><ul><ul><li>1:100,000 reported septic cases (BaCon) </li></ul></ul>
  36. 39. Bacteria and transfusion <ul><li>Most frequent ID outcome in US </li></ul><ul><li>Platelets>rbc>plasma </li></ul><ul><li>All recipients susceptible, worse in immunocompromised and fragile patients </li></ul><ul><li>Risk falling(?) as a result of intervention </li></ul><ul><li>Intervention – AABB and CAP Standard </li></ul><ul><ul><li>“ Limit and detect” </li></ul></ul><ul><ul><li>Bacterial culture, surrogate measures, sample first, skin-prep </li></ul></ul>
  37. 40. Anaplasma phagocytophilum <ul><li>Agent of human granulocytic ehrlichiosis </li></ul><ul><li>Northeast, upper Midwest, occurs with Babesia etc </li></ul><ul><li>Transmitted by ticks (rural/suburban exposure) </li></ul><ul><li>One suspect transfusion case reported </li></ul><ul><li>No definitive intervention (leukoreduction may help) </li></ul><ul><li>Prevalence studies ongoing – up to 3.5% </li></ul>
  38. 41. Other bacteria <ul><li>Borrelia burgdorferi </li></ul><ul><ul><li>Agent of Lyme disease, no transfusion cases </li></ul></ul><ul><li>Bartonella spp </li></ul><ul><ul><li>Bloodborne, of concern, no cases </li></ul></ul><ul><li>Rickettsiae </li></ul><ul><ul><li>RMSF, no cases, Orientia has in-vitro capability </li></ul></ul><ul><li>Chlamydia spp </li></ul><ul><ul><li>Intracellular, no cases </li></ul></ul>
  39. 42. Flavivirus <ul><li>Yellow Fever </li></ul><ul><li>Japanese encephalitis </li></ul><ul><li>St. Louis encephalitis </li></ul><ul><li>Border Disease </li></ul><ul><li>Hog cholera </li></ul><ul><li>Dengue </li></ul><ul><li>Usutu </li></ul><ul><li>Hepatitis C </li></ul><ul><li>Bovine viral diarrhea </li></ul><ul><li>West Nile Virus </li></ul>Single-stranded RNA Protein capsid Lipid envelope
  41. 44. WNV: background <ul><li>Flavivirus (enveloped, RNA) </li></ul><ul><li>Acute infection, asymptomatic to fatal disease </li></ul><ul><li>Transmitted by mosquitoes, usually from infected birds </li></ul><ul><li>S Europe, Africa, Middle East to India, arrived US 1999, endemic in essentially all of the continental US by 2004 </li></ul><ul><ul><li>Probably came to US by plane </li></ul></ul><ul><li>Up to 400,000 individuals infected in 2002, 2003 in US </li></ul>
  42. 45. West Nile Virus Transmission Cycle West Nile virus West Nile virus Mosquito vector Incidental infections Bird reservoir hosts Incidental infections
  43. 46. ~80 % Asymptomatic ~ 20% “ West Nile Fever” <1% CNS disease WNV Human Infection “Iceberg” in 2002 284 fatalities ~ 3300 severe disease ~ 400,000 asymptomatic ~100,000 mild illness
  44. 47. Human WNV infections WNV activity West Nile Virus Activity: 1999-2002 1999 2000 2001 2002
  45. 48. WNV and transfusion <ul><li>Transfusion transmission rare to absent outside US </li></ul><ul><li>Virus survives in all stored components </li></ul><ul><li>Most recipients susceptible </li></ul><ul><li>23 documented transmissions 2002 </li></ul><ul><li>Risk profile unknown – stable, declining? </li></ul><ul><ul><li>1.5/10,000 RNA positive donors in 2003 </li></ul></ul><ul><li>Primary intervention is NAT for WNV RNA in small pools, and singly where indicated </li></ul>
  46. 49. WN virus infection in organ donor and four organ recipients, August 2002 WNV PCR-neg WNV IgM-neg Organ Donor Blood components 63 donors Organ Donor 36 hours WNV PCR-pos WNV culture-pos WNV IgM-neg F/U: 1 seroconverting donor; Retrieved, stored plasma – WNV PCR-positive Kidney recipient WNME (fatal) Kidney recipient WNME Liver recipient WNF Heart recipient WNME
  47. 50. Model for Relative Duration of Stages of WNV Infection 10 1 10 2 10 3 10 4 10 5 WNV RNA (gEq per mL) Days post infectious mosquito bite 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 RNA IgM IgG 6-7 days Stage-II IDNAT+ MPNAT- IgM- Stage-IV IDNAT+ MPNAT- IgM+ IgG+/- MP-NAT ID-NAT Stage-V IDNAT +/- MPNAT- IgM+ IgG+ Stage-I IDNAT+/-MPNAT- IgM- Stage-III MPNAT+ IgM-
  48. 51. TGA on WNV <ul><li>WNV is a virus which is transmitted through mosquito bites and is endemic in certain parts of Africa and the Middle East. As a result of international travel and commerce, this is one of many pathogens which has started to cause disease outside its original area of endemicity. WNV has caused small epidemics in Europe but has become a serious public health problem in North America where the infection has affected thousands of individuals and caused hundreds of deaths. This virus is now known to be transfusion transmissible and people infected with the virus through transfusion have suffered serious illnesses and a number have died. The TGA has therefore instituted measures to ensure the minimisation of risk from WNV in travellers to North America. These individuals' donated blood will not be used to manufacture blood components such as red cells and platelets, which are known to transmit WNV when this is present in the donor. Plasma from these donors will be fractionated as this is known to inactivate the virus. The TGA will also mandate a test for WNV for these donors who will be deferred according to their travel history, once such a test is available. </li></ul>
  49. 52. MJA 6 January 2003
  50. 55. Murray Valley encephalitis (MVE) and Kunjin virus disease are endemic in the tropical parts of the Northern Territory and Western Australia, but have been absent from Central Australia since 1974. In 2000, 5 laboratory-confirmed cases of encephalitis occurred over a short period in the normally dry inland region of Central Australia. The sudden occurrence of cases in March and April 2000 followed unusually high rainfall in the preceding months and evidence of flavivirus activity in the endemic areas in the Kimberley region of Western Australia . Further cases were reported in the following wet season, without preceding human cases in known endemic areas. These findings indicate the reintroduction of these viruses into Central Australia and establishment of local cycles of infection with an ongoing risk to the local population. This area may also act as a potential source for reintroduction of MVE into south-eastern Australia. Commun Dis Intell 2002;26:39-44.
  51. 56. World Distribution of Dengue 1999 Areas infested with Aedes aegypti Areas with Aedes aegypti and recent epidemic dengue
  52. 57. Dengue Virus <ul><li>Causes dengue and dengue hemorrhagic fever </li></ul><ul><li>Is an arbovirus </li></ul><ul><li>Transmitted by mosquitoes </li></ul><ul><li>Composed of single-stranded RNA </li></ul><ul><li>Has 4 serotypes (DEN-1, 2, 3, 4) </li></ul><ul><li>Each serotype provides specific lifetime immunity, and short-term cross-immunity </li></ul><ul><li>All serotypes can cause severe and fatal disease </li></ul><ul><li>Genetic variation within serotypes </li></ul><ul><li>Some genetic variants within each serotype appear to be more virulent or have greater epidemic potential </li></ul>
  53. 58. Aedes aegypti Mosquito <ul><li>Dengue transmitted by infected female mosquito </li></ul><ul><li>Primarily a daytime feeder </li></ul><ul><li>Lives around human habitation </li></ul><ul><li>Lays eggs and produces larvae preferentially in artificial containers </li></ul>
  54. 59. Temperature, Virus Positivity and Anti-Dengue IgM , by Fever Day Dengue IgM Mean Max. Temperature Virus Adapted from Figure 1 in Vaughn et al., J Infect Dis , 1997; 176:322-30. Fever Day Percent Virus Positive -4 -3 -2 -1 0 1 2 3 4 5 6 39.5 39.0 38.5 38.0 37.5 37.0 Temperature (degrees Celsius) Dengue IgM (EIA units) 0 20 40 60 80 100 300 150 0 75 225
  55. 61. Dengue viremia in blood donors Kolk et al. AABB 2005 Prevalence of dengue RNA in Honduran blood donors 7 of 9 RR cases confirmed by RT-PCR - DEN-1 (3 cases), DEN-2 (1 case), DEN-4 (3 cases) 4 cases yielded infectious virus <ul><ul><li>One case (HK), one marrow transplant (PR) </li></ul></ul><ul><ul><li>Travel (particularly in QLD) </li></ul></ul>
  56. 62. TGA on Dengue Fever Virus (DFV) <ul><li>Like WNV, DFV was thought not to be a risk as far as blood transfusion is concerned. However, the virus is transmitted through mosquitos and has been shown to be transmitted through needle stick injury. The TGA therefore considers that it is a potential hazard of blood transfusion in areas where the disease is prevalent. One such area currently is North Queensland, where outbreaks of Dengue fever have been occurring over the past thirty years. An epidemic of Dengue fever is currently causing illnesses in Cairns. The TGA has therefore directed the blood service to not use fresh blood components from people resident or visiting Cairns for a certain time period, although the plasma can still be used to manufacture derivatives. This measure will allow risk to be minimised while maintaining the blood bank in the Cairns community. The TGA will review its current requirements once evidence accrues regarding the current Dengue epidemic in North Queensland. </li></ul>
  57. 64. HHV-8: background <ul><li>Herpesvirus (enveloped, DNA) </li></ul><ul><li>Chronic, persistent infection, agent of Kaposi’s sarcoma (classic and HIV-associated) </li></ul><ul><li>Transmitted person-to-person (sexual, saliva, organ transplant) </li></ul><ul><li>Global distribution? Africa, s Europe? MSM </li></ul><ul><ul><li>Travel, sexual behavior, aggressive therapies </li></ul></ul><ul><li>Seroprevalence is test-dependent, up to 2.4% in blood donors in US </li></ul>
  58. 65. Risk of HHV-8 infection & KS post kidney transplant <ul><li>Sero+ recipients pre-transplant are at risk of KS </li></ul><ul><ul><ul><li>Parravicini 1997, 77% at 2 yrs </li></ul></ul></ul><ul><ul><ul><li>Farge 1999, 30% at 1 yr </li></ul></ul></ul><ul><ul><ul><li>Frances 2000, 28% at 3 yrs </li></ul></ul></ul><ul><li>Sero+ kidney donors often transmit HHV-8 </li></ul><ul><ul><ul><li>Regamey 1998, 83% </li></ul></ul></ul><ul><li>Seroconverting recipients are at risk of KS </li></ul><ul><ul><ul><li>Parravicini 1997 25% (1/4) </li></ul></ul></ul><ul><ul><ul><li>Regamey 1998, 8% (2/25) </li></ul></ul></ul>
  59. 66. HHV-8 and transfusion <ul><li>No direct evidence of transfusion transmission </li></ul><ul><ul><li>Transmission by organs, epidemiologic linkage of transfusion and elevated prevalence, IDUs </li></ul></ul><ul><li>DNA identified in seropositive donation </li></ul><ul><li>Recipient susceptibility unknown </li></ul><ul><li>Risk profile unclear </li></ul><ul><li>No clear intervention, although 2 higher risk groups already excluded </li></ul><ul><ul><li>Potential for Ab test, but no gold standard </li></ul></ul>
  60. 67. SARS
  61. 68. SARS: general <ul><li>Novel coronavirus </li></ul><ul><li>Acute infection, asymptomatic to fatal disease </li></ul><ul><li>Transmitted person-to-person by aerosol and fecal/oral routes, likely zoonosis </li></ul><ul><li>Originated in PRC, rapidly globalized by air transport , about 8,500 cases reported </li></ul><ul><ul><li>Single epidemic in 2003 </li></ul></ul><ul><li>US caseload unclear, ~60, depending on case-definition </li></ul>
  62. 69. SARS and transfusion <ul><li>No transfusion cases reported </li></ul><ul><li>Virus found in kidney of deceased patient, subsequently in blood of symptomatic patients by NAT </li></ul><ul><li>Risk currently (apparently) absent </li></ul><ul><li>Intervention by excluding patients, travelers and case-contacts </li></ul>
  63. 70. SARS <ul><li>civet cat to humans, China </li></ul><ul><li>rapid spread, local transmission in many countries </li></ul><ul><li>cause: coronavirus </li></ul>Dodd R 2005
  64. 71. SARS: general <ul><li>Novel coronavirus </li></ul><ul><li>Acute infection, asymptomatic to fatal disease </li></ul><ul><li>Transmitted person-to-person by aerosol and fecal/oral routes, likely zoonosis </li></ul><ul><li>Originated in PRC, rapidly globalized by air transport , about 8,500 cases reported </li></ul><ul><ul><li>Single epidemic in 2003 </li></ul></ul><ul><li>US caseload unclear, ~60, depending on case-definition </li></ul>Dodd R 2005
  65. 72. SARS and transfusion <ul><li>No transfusion cases reported </li></ul><ul><li>Virus found in kidney of deceased patient, subsequently in blood of symptomatic patients by NAT </li></ul><ul><li>Risk currently (apparently) absent </li></ul><ul><li>Intervention by excluding patients, travelers and case-contacts </li></ul>Dodd R 2005
  66. 73. Effect of SARS on regional BTSs 1 st case notified Notification of HCWs infected Schools closed Other hospitals affected PPWM affected <ul><li>Drop in blood donor attendance of up to 60%: </li></ul><ul><ul><li>Fear of contracting SARS </li></ul></ul><ul><ul><li>Cancellation of mobile blood drives </li></ul></ul><ul><li>Additional deferral of about 4.3% of donors </li></ul><ul><li>Potential for adverse donor and public perceptions and feedback </li></ul><ul><li>Risk of disruption of blood supply in event of SARS infection occurring within blood agency </li></ul>Singapore HK
  67. 74. SARS: a real concern ? <ul><li>precl. incub. period </li></ul><ul><ul><ul><li>SM Poutanen et al. NEJM, May 2003 </li></ul></ul></ul><ul><li>190 c/ml in plasma </li></ul><ul><ul><li>PCR after U/C, clinically sick patient </li></ul></ul><ul><ul><ul><li>C Drosten et al. NEJM, May 2003 </li></ul></ul></ul>
  68. 75. Wei-Kung Wang, Chi-Tai Fang, Hui-Ling Chen et al. Detection of severe acute respiratory syndrome coronavirus RNA in plasma during the course of infection. J Clinical Microbiology. 2005;43(2):962-965.
  69. 76. vCJD: general <ul><li>Transmissible spongiform encephalopathy (prion disease) </li></ul><ul><li>Degenerative, fatal disease with lengthy incubation period </li></ul><ul><li>Results from consumption of tissue from BSE-infected cattle </li></ul><ul><ul><li>Intensive and “unnatural” farming practices plus global economy </li></ul></ul><ul><li>Most cases in, or associated with UK (157), around 24 others </li></ul><ul><li>No endogenous case in US </li></ul>
  70. 78. vCJD: general <ul><li>Transmissible spongiform encephalopathy (prion disease) </li></ul><ul><li>Degenerative, fatal disease with lengthy incubation period </li></ul><ul><li>Results from consumption of tissue from BSE-infected cattle </li></ul><ul><li>Most cases in, or associated with UK (152), 6-10 others in Europe </li></ul><ul><li>No endogenous case in Australia </li></ul>
  71. 79. Total Exports of MBM 1988 - 1993 No data 0 - < 5 5 - < 10 10 - < 20 20 - < 100 100 - < 1.000 1.000 - < 10.000 > 10.000 Legend: (in tonnes)
  72. 80. Transmission of TSE by blood transfusion in hamsters Rohwer 2000 263 K scapie adapted hamster Exchange transfusion 2 ml blood (total blood volume = 7 ml) Normal hamster 2 ml blood removed 3 out of 100 transfusions resulted in transmission
  73. 81. Transmission of BSE by blood transfusion in sheep Houston et al 2000 UK Cheviot sheep fed BSE-affected cattle brain Transfused into NZ (scrapie-free Sheep) (Positive control transfused with BSE brain) <ul><li>1/19 transfusion transmitted BSE in sheep </li></ul><ul><ul><ul><ul><li>Tx given 310 days after oral challenge (donor asymptomatic) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Donor - TSE 629 days post oral challenge </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Recipient - TSE 610 days post transfusion </li></ul></ul></ul></ul>
  74. 82. vCJD and transfusion <ul><li>Concern high, occurrence infrequent </li></ul><ul><li>Likely present in all components (very low titer in plasma products) </li></ul><ul><li>Recipient susceptibility unknown </li></ul><ul><li>4 cases transfusion transmission to date, three leading to disease (all in UK) </li></ul><ul><li>Risk appears to be declining, but </li></ul><ul><ul><li>Unknown number of exposed individuals </li></ul></ul><ul><ul><li>“ second wave” possible </li></ul></ul><ul><li>Intervention in Australia based upon travel history </li></ul>
  75. 83. Lancet 2004; 363: 51–61
  76. 85. Recipients surviving >5 yr post transfusion of blood components from vCJD/CJD Donors (using data from UK TMER and US ARC look-back studies [S Anderson, FDA; P Page, R Dodd ARC at FDA TSEAC 14 Oct 2004]) Fisher's Exact Test comparing rates of infection after transfusions from vCJD and CJD donors suggests a statistically significant difference between the two groups (  1% likelihood that the difference occurred by chance). [Conclusion: Risk of TT CJD is much less than TT vCJD.] Infection No Infection vCJD 4 14 CJD 0 >116
  77. 86. Globalisation and philosophies of risk <ul><li>Globalisation has resulted in shrinking Time and Distance </li></ul><ul><li>The Ecology of Blood Transfusion operates over global scales of Time and Distance </li></ul><ul><ul><ul><li>HIV, BSE, Chagas Disease, Malaria, WNV, Gambian Giant Rats ……… and millions of interacting events </li></ul></ul></ul><ul><ul><ul><li>Therefore management of Safety should include (at very least) a non-linear analysis </li></ul></ul></ul><ul><li>We deal in the noise as well as in the signals </li></ul><ul><li>We have to master a combination of an evidence-based approach (the future follows the past) </li></ul><ul><li>And a non-linear approach (science does not foretell the future) </li></ul>WG Murphy 2003
  78. 87. Philosophies of risk W Murphy 2003 <ul><li>Linear analysis </li></ul><ul><li>We can tell the future from the past: </li></ul><ul><ul><li>valid over small scales of time, space and matter </li></ul></ul><ul><ul><ul><li>e.g. weather here, today </li></ul></ul></ul><ul><ul><ul><li>evidence-based medicine </li></ul></ul></ul><ul><ul><li>Ignores or deliberately excludes the noise in complex systems </li></ul></ul><ul><li>Non-linear analysis </li></ul><ul><li>We can’t tell the future from the past: </li></ul><ul><ul><li>Non-deterministic/ </li></ul></ul><ul><ul><li>chaotic </li></ul></ul><ul><ul><li>Invalid over large scales of time and space </li></ul></ul><ul><ul><ul><li>e.g. weather in Cleethorpes, July 16 th 2005 </li></ul></ul></ul><ul><ul><ul><li>Global warming, etc </li></ul></ul></ul>
  79. 88. A linear process <ul><li>Introduction of measures to decrease HIV transfusion risk </li></ul>
  80. 89. A non-linear process <ul><li>The process for rendering animals for processing to meat and bone meal (MBM) for feeding cattle is changed to allow extraction of other products </li></ul><ul><li>Infectious agents from animals sick with TSEs enter the human food chain through contaminated beef products </li></ul><ul><li>The agents passaged into humans cause a new disease </li></ul><ul><li>The disease is transmitted though blood and infects other humans </li></ul>
  81. 90. Controlling Chaotic Risks - Accepting the possibility of disaster <ul><ul><li>new infection in environment (vCJD, Parvo-like….) </li></ul></ul><ul><ul><li>Adverse effects in donors </li></ul></ul>EID Hb in Australian donors Doherty 2000
  82. 91. Controlling Chaotic risks <ul><li>Accepting the possibility of disaster </li></ul><ul><ul><li>limiting the possibility of a disastrous event </li></ul></ul><ul><ul><li>limiting the impact of disaster </li></ul></ul><ul><li>Limiting the impact of disaster </li></ul><ul><ul><li>Control as much as possible: </li></ul></ul><ul><ul><ul><ul><li>layers of protection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>cellular environment </li></ul></ul></ul></ul><ul><li>Alternative engineering </li></ul>
  83. 92. Effect of globalisation on the safety-supply balance The example of vCJD donor deferral <ul><li>In 1996 – 16% of all US business travellers visited UK </li></ul><ul><li>Median US business traveller spent 96 nights in UK between 1991-96 </li></ul><ul><li>Average houshold income for travellers $US98,200 </li></ul><ul><li>80% come from East or West Coast </li></ul>O’Neill Public Understand Sci 12 (2003) 359-380
  84. 93. <ul><li>In Australia, donor deferral for vCJD was introduced in September 2000 </li></ul><ul><li>A travel survey predicted a 6% donor loss using 6 months in the UK between 1980 and 1996 as the criterion </li></ul><ul><li>This was substantially confirmed in practice </li></ul>Effect of globalisation on the safety-supply balance The example of vCJD donor deferral
  85. 94. Effect of globalisation on blood safety Travel based deferrals <ul><li>Historically, donor selection measures have excluded the indigent and the ill </li></ul><ul><ul><ul><li>Eg Exclusion of paid blood donors </li></ul></ul></ul><ul><li>Modern travel-based deferrals are excluding the, mostly middle to upper middle class repeat donor population </li></ul><ul><li>These form the basis of blood safety and sufficiency in the developed world </li></ul>
  86. 96. Infections with very long incubation periods in the modern era of trade and travel (Kimball et al Globalization and Health 2005:1:3) <ul><li>Global forces eg market demand, GATT provisions: </li></ul><ul><ul><li>increase exports </li></ul></ul><ul><ul><li>favor consolidation, </li></ul></ul><ul><ul><li>may set the stage for streamlining processing of product </li></ul></ul><ul><li>2) Streamlining of production </li></ul><ul><ul><li>drives efficiency and cost savings </li></ul></ul><ul><ul><li>may contribute to emergence of new infections </li></ul></ul><ul><ul><li>when biological materials are used </li></ul></ul><ul><li>3) Emerging new pathogens are disseminated through trade and travel </li></ul><ul><ul><li>creates a &quot;science gap&quot; </li></ul></ul><ul><ul><li>where rapid research is imperative to find and implement remedies </li></ul></ul><ul><ul><li>before extensive infection occurs </li></ul></ul><ul><li>4) Once clinical disease is manifest widespread dissemination of infection has occurred and risk can be mapped using product specific trade data. This mapping may allow timely institution of surveillance. </li></ul>
  87. 97. Trade related infections <ul><li>BSE </li></ul><ul><ul><ul><li>Vectored through contaminated meat and bone meal (MBM) </li></ul></ul></ul><ul><ul><ul><li>UK banned use in ruminant feeds in 1989 </li></ul></ul></ul><ul><ul><ul><li>UK MBM exports doubled in 1989 – 15,000 to 30,000 tonnes </li></ul></ul></ul><ul><ul><ul><li>Value of UK beef exports doubled 1988 – 1995 – declining domestic demand rather than increased production </li></ul></ul></ul><ul><li>HIV/AIDS </li></ul><ul><ul><ul><li>Vectored through contaminated coagulation factors </li></ul></ul></ul><ul><ul><ul><li>Major source of world market US – 400 commercial aphersis centres supplied 60% world plasma requirement </li></ul></ul></ul><ul><ul><ul><li>Contaminated products exported worldwide </li></ul></ul></ul><ul><ul><ul><li>(Domestic sources also contributed – most domestic infection primarily acquired in US) </li></ul></ul></ul>
  88. 98. Total Exports of MBM 1988 - 1993 No data 0 - < 5 5 - < 10 10 - < 20 20 - < 100 100 - < 1.000 1.000 - < 10.000 > 10.000 Legend: (in tonnes)
  89. 99. UK Beef Exports, in 1,000 U.S. Dollars, 1970 – 1999. FAO
  90. 100. Summary (1) <ul><li>Blood safety extremely variable globally </li></ul><ul><li>Major determinants of risk are: </li></ul><ul><ul><li>Resource availability </li></ul></ul><ul><ul><li>Medical infrastructure </li></ul></ul><ul><ul><li>Infection prevalence and incidence </li></ul></ul><ul><li>Solutions must be tailored to environment </li></ul><ul><li>Disproportionate focus in safest locales </li></ul>
  91. 101. Summary (2) <ul><li>Numerous emerging and newly recognized infections with potential for transfusion transmission </li></ul><ul><li>All classes of agents </li></ul><ul><li>No common pathogenesis, transmission route, infectious period or risk factor </li></ul><ul><li>Absence of effective interventions </li></ul><ul><li>Excessive public expectation </li></ul>