Emerging (and re-emerging) infectious risks to the global (and Australian)
blood supply
Albert Farrugia
University of Canberra
Faculty of Applied Science
April 2007
The Safety Tripod for blood products
• Selection of appropriate raw material• Donors• Cell lines
• Testing of raw material• Screening• Viral tests
• Processing into product• Viral inactivation
• Product integrity
The basis of blood product safetyDonor 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.
Current screening for:
•anti-HIV 1/2•anti-HCV•HBsAg•HCV RNA•HIV RNA•HTLV 1/2•Syphylis•?WNV•?Dengue•?SARS•?vCJD•?Malaria•???????
•Proven route for plasma products
•Technologies available for fresh products
•Safety/quality issues still unresolved
•Expensive!!!
•?Cost-effective
Risk of HIV per Unit (%)
2.0
1.5
1
0.5
0
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
1978 1979 1980 1981 1982 19851983 1984 1990
Risk of HIV Transmission by Blood Transfusions Before the Implementation of HIV-1 Antibody Screening
Busch et al. Transfusion 1991; 3: 4-11
HCV markers during early infection
HCV RNA
Anti-HCV EIAs1st gen 150 d2nd gen 80 d3rd gen 70 d
0 10 20 30 40 50 60 70 80 90 100
Ramp-up phase DT = 17 .7 hrs
Plateau phase viremia: 105-108 gEq/mL
Pre-ramp-up blip viremia
- HCV Ag EIA
- HCV MP-NAT
- HCV ID-NAT
ALT
Viral set-point: 102-107 gEq/mL
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 daysID-NAT WP = 3 days
MP-NAT WP = 10 days
Anti-HCV (3.0 EIA)
Safety Concerns
The things we know and love
Geographic Distribution of Chronic HBV InfectionGeographic Distribution of Chronic HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
GLOBAL PREVALENCE OF HEPATITIS C
Adults and children estimated to be living with HIV/AIDS as of end 2002
Total: 42 million
Western Europe
570 000570 000North Africa & Middle East
550 000550 000Sub-Saharan
Africa
29.4 million29.4 million
Eastern Europe & Central Asia
1.2 million1.2 million
South & South-East Asia
6 million6 million
Australia & New Zealand
15 00015 000
North America
980 000980 000Caribbean
440 000440 000
Latin America
1.5 million1.5 million
East Asia & Pacific
1.2 million1.2 million
High and low resource countries
• 83% of global population has access to only 40% of world’s blood
• Donations/1000 is 41-50 in High HDI, but 1/20th that rate in Low HDI
• High HDI 98% voluntary, Low HDI 31% voluntary
• Paid donations often masquerade as “replacement/family”
• Up to 13 of the 75 million donations were not fully tested (1998-99), mostly in low or medium HDI countries.
Risk/million repeat donations (with NAT) – High HDI
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
* NAT not included (From: Glynn et al, Transfusion 2001)
HIV incidence, prevalence and risk PHT donations (RSA)
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)
Includes impact of HIV p24 antigen testing
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
HIVHIV
HBVHBVHCVHCV
19961996199419941992199219901990198819881986198619841984
1:1001:100
1:10001:1000
1:10 0001:10 000
1:100 0001:100 000
1:1 000 0001:1 000 000
19981998 20002000
Risk, Risk, per unitper unit
20022002
BacterialBacterialContaminationContamination
(platelets)(platelets)
Septic Fatalities Septic Fatalities (platelets)(platelets)
TRALI FatalitiesTRALI Fatalities
1:2,0001:2,000
1:140,0001:140,000
1:100,0001:100,000
Evolution of Transfusion RisksEvolution of Transfusion Risks
Mistransfusion Mistransfusion FatalitiesFatalities
1:600,0001:600,000
Risks in repeat donorsHIV, HCV & HBV
Country Dates Incidence/105 person years (95% CI) Residual risk/106 repeat donationsHCV HIV HBV HCV HIV HBV
EPFA 1/97-12/97 0.9(0.7-1.2)
0.2
CentralEurope
1/97-12/00 2.3(0.3-4.7)
0.7(0.5 - 1.1)
0.4 0.2
France 1/98-12/00 0.6(0.3-1.3)
1.2(0.7 - 2.0)
1.4(0.9 - 2.2)
0.4 0.4 1.8
Italy 1/96-12/00 4.1(3.0-5.3)
3.8(2.8 - 5.0)
1.3 1.1
Spain 1/97-12/99 3.7(2.6-5.1)
3.2(2.2 - 4.5)
8.4(5.2 - 12.6)
0.7 1.0 7.8
US 1/96-12/00 2.9(2.1-3.9)
1.6(1.0 - 2.3)
6.0(4.0 - 8.7)
0.6 0.5 8.1
1/00 -12/01
1.9(1.5 - 2.4)
1.6(1.2 - 2.0)
3.0(2.3 - 3.9)
0.5 0.5 4.0
Australia 1/00 - 6/03 3.3 0.54 0.51 0.62 0.12 0.62
HCV markers during early infection
Residual risk of TTI’s per 106 repeat donations
Glynn et al (2002) Transfusion 42:966-972
HIV
HCV
HBV
West Nile Virus, 1999West Nile Virus, 1999
Hantavirus, 1993 Hantavirus, 1993
Nipah, 1998Nipah, 1998
Diphtheria, 1993Diphtheria, 1993
Variant CJ Disease, 1996Variant CJ Disease, 1996
E. coli O 157 H7, 1998E. coli O 157 H7, 1998
V. cholerae O 139, 1992 V. cholerae O 139, 1992
Dengue, 1992Dengue, 1992
Morbillivirus, 1994Morbillivirus, 1994
Plague, 1994Plague, 1994
Rift Valley fever, 1993Rift Valley fever, 1993
Yellow fever, 1993Yellow fever, 1993
Bolivian hemorrhagic fever, 1994Bolivian hemorrhagic fever, 1994
HIV-1 subtype O, 1994HIV-1 subtype O, 1994
Lassa fever, 1992 Lassa fever, 1992
Dengue, 1994Dengue, 1994
Anthrax, 1993Anthrax, 1993
Cholera, 1991Cholera, 1991
Yellow fever/VEE, 1995 Yellow fever/VEE, 1995
Leptospirosis, 1995 Leptospirosis, 1995
Dengue, 1993 Dengue, 1993 Adenovirus type 7, 1995Adenovirus type 7, 1995
Arenavirus, 2000Arenavirus, 2000
Ebola 2000Ebola 2000
Ebola, 1995Ebola, 1995
Emerging infectious agents
Emerging Infections
• New Agent• Expanding Range• Imported• Reemergent• Newly recognized• Patient changes
• HIV, BSE/vCJD, SARS• Babesia/Ehrlichia• Chagas’, WNV• Malaria• HHV-6, 8, TTV….• CMV, B19?
Epidemiology of agents
• Prevalence– High prevalence increases impact of test failure (or absence!) – High prevalence leads to high testing loss
• Incidence– High incidence impacts window period risk
• Transmission routes– May permit risk-based intervention
• Recipient status– Susceptibility, impact of infection
Human behavior and transfusion-transmitted infections• HIV
– Bush meat, sexual behavior, travel• Malaria
– Global climate change, travel• Chagas’ disease
– Population migration• West Nile virus
– Unknown (travel?), irrigation practice• SARS
– Exotic diet? Air travel• Monkeypox
– Exotic pets• vCJD
– Intensive agricultural practice and export of feed, cattle• LCMV
– Non-exotic pets• Leishmania
– Military adventures
Malaria
Malaria: background
• Intraerythrocytic protozoan parasite, 4 species of Plasmodium
• Acute and chronic infection and disease, asymptomatic to fatal
• Transmitted by mosquitoes• Global distribution in tropics and sub-tropics• 300-500 million cases annually, 1.5-2.7 million deaths• About 1000 imported cases annually in US, plus a
handful of inexplicable cases
Malaria and transfusion
• Globally, probably most frequent TTD
• Survives in stored cellular products
• Essentially all recipients susceptible
• 2-4 transfusion cases annually in US
• Risk stable, could increase with travel and potential reemergence (Global warming)
• Travel history is current intervention– >50,000 donors/year deferred in US
Proposed reinstatement protocol for donors
traveling to malarious areas Seed et al 2005
Babesia
Babesia: background
• Intraerythrocytic protozoan parasite, one major species• Acute disease, up to 6 months subclinical infectivity,
treatable, fatal for selected recipients• Transmitted by ticks• B. microti Northeast US, upper Midwest, others
Midwest, Pacific coast• Cases not reported, seroprevalence up to 1.5%
Babesia and transfusion
• Transfusion transmission recognized in US, Japan (I case)• Survives in erythrocyte-containing components (including
platelets)• Outcomes worse in aged, splenectomized and
immunocompromised• More than 50 transfusion cases to date, demonstrable risk
1:1000 in highest incidence area of CT• Risk increasing with geographic spread of agent, host/vector
(Pseudo-rural lifestyle)• No available effective intervention
– Donor population management, hospital vigilance and recipient treatment– Potential for testing?
Chagas’ disease
Chagas’: background
• Protozoan parasite, free in blood, tropism for smooth and cardiac muscle
• Acute disease and chronic (lifelong) infection, asymptomatic to fatal
• Zoonosis, transmitted by triatomine bugs• Agent, vectors found in continental Americas, 40°S - 40°N,
human cases only in Mexico, S. and Central America• 19-20 million infected individuals, incidence declining• At least 100,000 infected individuals in US as a result of
population movements
LA Seroprevalence: 1996-98
% D
onor
s P
ositi
ve
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
Chagas’ and transfusion
• 12 – 50% from infected blood in S. America• Survives in stored components, most infections from whole
blood or platelets• Severe disease in immunocompromised patients• At least 7 cases in North America, estimated seroprevalence
1:40,000 to 1:25,000 (60% parasitemia)• Risk increasing in US (population movement and focus on
Hispanic donors)• No effective intervention available: questioning neither specific
nor sensitive– Antibody testing would be effective
Leishmania
• Current and past concern relate to troop and civilian deployment in Iraq and Afghanistan
• Protozoan parasite transmitted by sandflies: widespread in tropics
• A few historical examples of bloodborne transmission: no current cases
• Intervention: deferral for returnees from middle East conflict areas
Bacterial contamination: general
• Outgrowth of bacteria in components• Acute to fatal disease• Skin or environmental contaminants or donor
bacteremia• Generalized occurrence• Frequency depends on measure
– 1:1500 platelets with reactive cultures– 1:19,000 platelets result in detectable reaction– 1:100,000 reported septic cases (BaCon)
Bacteria and transfusion
• Most frequent ID outcome in US• Platelets>rbc>plasma• All recipients susceptible, worse in
immunocompromised and fragile patients• Risk falling(?) as a result of intervention• Intervention – AABB and CAP Standard
– “Limit and detect”– Bacterial culture, surrogate measures, sample first,
skin-prep
Anaplasma phagocytophilum
• Agent of human granulocytic ehrlichiosis• Northeast, upper Midwest, occurs with Babesia
etc• Transmitted by ticks (rural/suburban exposure)• One suspect transfusion case reported• No definitive intervention (leukoreduction may
help)• Prevalence studies ongoing – up to 3.5%
Other bacteria
• Borrelia burgdorferi– Agent of Lyme disease, no transfusion cases
• Bartonella spp– Bloodborne, of concern, no cases
• Rickettsiae– RMSF, no cases, Orientia has in-vitro capability
• Chlamydia spp– Intracellular, no cases
Flavivirus• Yellow Fever
• Japanese encephalitis
• St. Louis encephalitis
• Border Disease
• Hog cholera
• Dengue
• Usutu
• Hepatitis C
• Bovine viral diarrhea
• West Nile Virus
Single-strandedRNA
Proteincapsid Lipid
envelope
LACSLEWNDEN2WEE(VEE)CTF
LACSLEPOWWNDEN2EEEHJEVE(VEE)
EEEWEEVEEMAYWNDEN2
EEEWEEVEEMAYSLEWNYFDEN2
SINCHIKWNYFDEN2TAH
SINPOW(TBE)WN(TAH,INK)
CHIKSINPOW(TBE)JEWNSSH
RRBFSINMVEDEN2
Global Distribution of Major Human Flaviviruses
WNV: background
• Flavivirus (enveloped, RNA)• Acute infection, asymptomatic to fatal disease• Transmitted by mosquitoes, usually from infected birds• S Europe, Africa, Middle East to India, arrived US
1999, endemic in essentially all of the continental US by 2004– Probably came to US by plane
• Up to 400,000 individuals infected in 2002, 2003 in US
West Nile Virus Transmission Cycle
West Nilevirus
West Nilevirus
Mosquito vector
Incidental infections
Bird reservoir hosts
Incidental infections
~80%Asymptomatic
~20%“West Nile Fever”
<1%CNS
disease
WNV Human Infection “Iceberg” in 2002WNV Human Infection “Iceberg” in 2002
284 fatalities
~ 3300 severe disease
~400,000
asymptomatic
~100,000
mild illness
Human WNV infections
WNV activity
West Nile Virus Activity: 1999-2002West Nile Virus Activity: 1999-2002
1999 2000
2001 2002
WNV and transfusion
• Transfusion transmission rare to absent outside US• Virus survives in all stored components• Most recipients susceptible• 23 documented transmissions 2002• Risk profile unknown – stable, declining?
– 1.5/10,000 RNA positive donors in 2003
• Primary intervention is NAT for WNV RNA in small pools, and singly where indicated
WN virus infection in organ donor and four organ recipients, August 2002
WNV PCR-neg
WNV IgM-neg
Organ Donor
Kidney recipientWNME (fatal)
Kidney recipientWNME
Liver recipientWNF
Heart recipientWNME
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
Model for Relative Duration of Stages of WNV Infection
101
102
103
104
105
WN
V R
NA
(gE
q pe
r m
L)
Days post infectious mosquito bite2 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-
TGA on WNVWNV 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.
MJA 6 January 2003
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.
World Distribution of Dengue 1999
Areas infested with Aedes aegyptiAreas with Aedes aegypti and recent epidemic dengue
Dengue Virus• Causes dengue and dengue hemorrhagic fever• Is an arbovirus• Transmitted by mosquitoes• Composed of single-stranded RNA• Has 4 serotypes (DEN-1, 2, 3, 4)• Each serotype provides specific lifetime immunity, and
short-term cross-immunity• All serotypes can cause severe and fatal disease• Genetic variation within serotypes• Some genetic variants within each serotype appear to
be more virulent or have greater epidemic potential
Aedes aegypti Mosquito
• Dengue transmitted by infected female mosquito
• Primarily a daytime feeder• Lives around human
habitation• Lays eggs and produces
larvae preferentially in artificial containers
Temperature, Virus Positivity and Anti-Dengue IgM , by Fever Day
Dengue IgMMean Max. Temperature Virus
Adapted from Figure 1 in Vaughn et al.,J Infect Dis, 1997; 176:322-30.
Fever Day
0
20
40
60
80
100P
erce
nt
Vir
us
Pos
itiv
e
-4 -3 -2 -1 0 1 2 3 4 5 6
39.5
39.0
38.5
38.0
37.5
37.0
Tem
per
atu
re (
deg
rees
Cel
siu
s)
Den
gue
IgM
(E
IA u
nit
s)300
150
0
75
225
Dengue viremia in blood donorsKolk et al. AABB 2005
Donations Tested 2994Initial Reactive 12Initial Reactivity Rate 0.40%Repeat Reactive 9Prevalence 0.30%
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
•One case (HK), one marrow transplant (PR)•Travel (particularly in QLD)
TGA on Dengue Fever Virus (DFV)
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.
Arboviruses in the Australianregion, 1990 to 1998
John S Mackenzie1, Annette K Broom2, Roy A Hall1, Cheryl A Johansen1, Michael D Lindsay2, Debra APhillips3, Scott A Ritchie4, Richard C Russell5, David W Smith6
AbstractArboviruses continue to be major human pathogens in the Australian region. This report provides asummary of the activities of these viruses over the past eight years, and comments on new findingsrelevant to their respective ecologies. Of particular interest and concern is the propensity of theseviruses to spread. The examples discussed include the initiation of dengue epidemics in northQueensland by virus imported in viraemic travellers; the spread of Japanese encephalitis virus to theAustralasian region and its probable enzootic establishment in the south-west of Papua New Guinea;the potential spread of Ross River virus to other countries, as demonstrated by the 1979-80 outbreakin the South Pacific, and the recent occurrence in military personnel from the United States ofAmerica after an exercise; and the recent spread of Barmah Forest virus into Western Australia,Comm Dis Intell 1998;22:93-100
HHV-8: background
• Herpesvirus (enveloped, DNA)• Chronic, persistent infection, agent of Kaposi’s
sarcoma (classic and HIV-associated)• Transmitted person-to-person (sexual, saliva, organ
transplant)• Global distribution? Africa, s Europe? MSM
– Travel, sexual behavior, aggressive therapies
• Seroprevalence is test-dependent, up to 2.4% in blood donors in US
Risk of HHV-8 infection & KS post kidney transplant
• Sero+ recipients pre-transplant are at risk of KS
• Parravicini 1997, 77% at 2 yrs
• Farge 1999, 30% at 1 yr
• Frances 2000, 28% at 3 yrs
• Sero+ kidney donors often transmit HHV-8
• Regamey 1998, 83%
• Seroconverting recipients are at risk of KS
• Parravicini 1997 25% (1/4)
• Regamey 1998, 8% (2/25)
HHV-8 and transfusion
• No direct evidence of transfusion transmission– Transmission by organs, epidemiologic linkage of transfusion
and elevated prevalence, IDUs
• DNA identified in seropositive donation• Recipient susceptibility unknown• Risk profile unclear• No clear intervention, although 2 higher risk groups
already excluded– Potential for Ab test, but no gold standard
SARS
SARS: general
• Novel coronavirus• Acute infection, asymptomatic to fatal disease• Transmitted person-to-person by aerosol and fecal/oral
routes, likely zoonosis• Originated in PRC, rapidly globalized by air transport,
about 8,500 cases reported– Single epidemic in 2003
• US caseload unclear, ~60, depending on case-definition
SARS and transfusion
• No transfusion cases reported
• Virus found in kidney of deceased patient, subsequently in blood of symptomatic patients by NAT
• Risk currently (apparently) absent
• Intervention by excluding patients, travelers and case-contacts
SARS• civet cat to humans, China
• rapid spread, local transmission in many countries
• cause: coronavirus
•
Dodd R 2005
SARS: general
• Novel coronavirus• Acute infection, asymptomatic to fatal disease• Transmitted person-to-person by aerosol and fecal/oral
routes, likely zoonosis• Originated in PRC, rapidly globalized by air transport,
about 8,500 cases reported– Single epidemic in 2003
• US caseload unclear, ~60, depending on case-definition
Dodd R 2005
SARS and transfusion
• No transfusion cases reported
• Virus found in kidney of deceased patient, subsequently in blood of symptomatic patients by NAT
• Risk currently (apparently) absent
• Intervention by excluding patients, travelers and case-contacts
Dodd R 2005
1st ca
se
n
otifie
d
No
tifica
tion
o
f HC
Ws
in
fec
ted
Sc
ho
ols
c
los
ed
Oth
er
ho
sp
ital
s
affe
cte
d
PP
WM
a
ffec
ted
• Drop in blood donor attendance of up to 60%:Fear of contracting
SARSCancellation of
mobile blood drives• Additional deferral of
about 4.3% of donors • Potential for adverse
donor and public perceptions and feedback
• Risk of disruption of blood supply in event of SARS infection occurring within blood agency
Effect of SARS on regional BTSs
Singapore
HK
SARS: a real concern ?
precl. incub. period• SM Poutanen et al.NEJM, May 2003
190 c/ml in plasma PCR after U/C, clinically sick patient
C Drosten et al.NEJM, May 2003
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.
vCJD: general
• Transmissible spongiform encephalopathy (prion disease)
• Degenerative, fatal disease with lengthy incubation period
• Results from consumption of tissue from BSE-infected cattle– Intensive and “unnatural” farming practices plus global
economy• Most cases in, or associated with UK (157), around 24
others• No endogenous case in US
vCJD: general
• Transmissible spongiform encephalopathy (prion disease)
• Degenerative, fatal disease with lengthy incubation period
• Results from consumption of tissue from BSE-infected cattle
• Most cases in, or associated with UK (152), 6-10 others in Europe
• No endogenous case in Australia
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)
Transmission of TSE by blood transfusion in hamsters
Rohwer 2000263 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
Transmission of BSE by blood transfusion in sheepHouston et al 2000
UK Cheviot sheep fed BSE-affected cattle brain
Transfused into NZ (scrapie-free Sheep)(Positive control transfused with BSE brain)
1/19 transfusion transmitted BSE in sheep
Tx given 310 days after oral challenge (donor asymptomatic)
Donor - TSE 629 days post oral challenge
Recipient - TSE 610 days post transfusion
vCJD and transfusion
• Concern high, occurrence infrequent• Likely present in all components (very low titer in
plasma products)• Recipient susceptibility unknown• 4 cases transfusion transmission to date, three leading
to disease (all in UK)• Risk appears to be declining, but
– Unknown number of exposed individuals– “second wave” possible
• Intervention in Australia based upon travel history
Lancet 2004; 363: 51–61
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.]
InfectionNo
Infection
vCJD 4 14
CJD 0 >116
•Globalisation has resulted in shrinking Time and Distance
•The Ecology of Blood Transfusion operates over global scales of Time and Distance
HIV, BSE, Chagas Disease, Malaria, WNV, Gambian Giant Rats ……… and millions of interacting events
Therefore management of Safety should include (at very least) a non-linear analysis
•We deal in the noise as well as in the signals
•We have to master a combination of an evidence-based approach (the future follows the past)
•And a non-linear approach (science does not foretell the future)
WG Murphy 2003
Globalisation and philosophies of risk
Philosophies of riskW Murphy 2003
Linear analysis
We can tell the future from the past:
– valid over small scales of time, space and matter
• e.g. weather here, today
• evidence-based medicine
– Ignores or deliberately excludes the noise in complex systems
Non-linear analysis
We can’t tell the future from the past:
– Non-deterministic/
chaotic
– Invalid over large scales of time and space
• e.g. weather in Cleethorpes, July 16th 2005
• Global warming, etc
A linear process
Introduction of measures to decrease HIV transfusion risk
A non-linear process
• The process for rendering animals for processing to meat and bone meal (MBM) for feeding cattle is changed to allow extraction of other products
• Infectious agents from animals sick with TSEs enter the human food chain through contaminated beef products
• The agents passaged into humans cause a new disease
• The disease is transmitted though blood and infects other humans
Controlling Chaotic Risks - Accepting the possibility of disaster
– new infection in environment (vCJD, Parvo-like….)
– Adverse effects in donors
EID
Hb in Australian donors
Doherty 2000
Controlling Chaotic risks
• Accepting the possibility of disaster
– limiting the possibility of a disastrous event
– limiting the impact of disaster
• Limiting the impact of disaster
– Control as much as possible:
– layers of protection
–cellular environment
• Alternative engineering
Effect of globalisation on the safety-supply balance
The example of vCJD donor deferral
• In 1996 – 16% of all US business travellers visited UK
• Median US business traveller spent 96 nights in UK
between 1991-96
• Average houshold income for travellers $US98,200
• 80% come from East or West Coast
O’Neill Public Understand Sci 12 (2003) 359-380
• In Australia, donor deferral for vCJD was introduced
in September 2000
• A travel survey predicted a 6% donor loss using 6
months in the UK between 1980 and 1996 as the
criterion
• This was substantially confirmed in practice
Effect of globalisation on the safety-supply balance
The example of vCJD donor deferral
Effect of globalisation on blood safetyTravel based deferrals
• Historically, donor selection measures have excluded
the indigent and the ill
• Eg Exclusion of paid blood donors
• Modern travel-based deferrals are excluding the, mostly
middle to upper middle class repeat donor population
• These form the basis of blood safety and sufficiency in
the developed world
Infections with very long incubation periods in the modern era of trade and travel
(Kimball et al Globalization and Health 2005:1:3)1) Global forces eg market demand, GATT provisions:
– increase exports – favor consolidation, – may set the stage for streamlining processing of product
2) Streamlining of production– drives efficiency and cost savings – may contribute to emergence of new infections – when biological materials are used
3) Emerging new pathogens are disseminated through trade and travel – creates a "science gap" – where rapid research is imperative to find and implement remedies– before extensive infection occurs
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.
Trade related infections• BSE
• Vectored through contaminated meat and bone meal (MBM)• UK banned use in ruminant feeds in 1989• UK MBM exports doubled in 1989 – 15,000 to 30,000 tonnes• Value of UK beef exports doubled 1988 – 1995 – declining
domestic demand rather than increased production
• HIV/AIDS• Vectored through contaminated coagulation factors• Major source of world market US – 400 commercial aphersis
centres supplied 60% world plasma requirement• Contaminated products exported worldwide• (Domestic sources also contributed – most domestic infection
primarily acquired in US)
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)
UK Beef Exports, in 1,000 U.S. Dollars, 1970 – 1999.
FAO
Summary (1)
• Blood safety extremely variable globally• Major determinants of risk are:
– Resource availability– Medical infrastructure– Infection prevalence and incidence
• Solutions must be tailored to environment• Disproportionate focus in safest locales
Summary (2)
• Numerous emerging and newly recognized infections with potential for transfusion transmission
• All classes of agents
• No common pathogenesis, transmission route, infectious period or risk factor
• Absence of effective interventions
• Excessive public expectation