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