Blood Safety: Current Risk and Emerging Infections

1
Blood Safety Current Risk and Emerging
Infections

• Harry L. Taylor, MD
• Medical Director, Mid-Atlantic Region
• ARC Blood Services
• Associate Professor of Pathology
• Eastern Virginia Medical School

2
Acknowledgments

• National ARC - Roger Dodd, PhD
• - Peter Page, MD
• Holland Labs - David Leiby, PhD

3
Components of Blood Safety

• National and local incidence/prevalence
• Criteria/Standards/
• Guide-lines
• Selection of donor population

• Donor questioning
• Laboratory testing
• Product handling
• Record keeping
• cGMP/Quality

4
Risk of Transfusion Transmitted Infection,
per million units
Now (2000) 11.15
Then (1970) 70,000
5
NIH Prospective Study of Post-Transfusion
Hepatitis
All Volunteer Donors HBsAg Assay
Non-A, Non-B
3rd Generation HBsAg
Anti HBc
PERCENT HEPATITIS
Anti HIV
Anti HCV
ALT
Hepatitis B
YEAR
6
Outline

• Current status of risks and testing
• Tests that may be eliminated
• Emerging infections
• Background
• Approach
• Examples
• Chagas
• Babesia
• WNV

7
Risk Per Unit from Schreiber (1996)
Virus Risk

• HCV 1 103,000
• HBV 1 63,000
• HTLV 1 641,000
• HIV 1 676,000

8
What is the per-unit risk today?
Conservative estimates, risk is potentially
much smaller
9
Emerging Infections
Clinically distinct conditions whose frequency
in humans has increased over the past two
decades
10
Factors Contributing to Emergence of
Infectious Disease

• Human demographics and behavior
• Technology and industry
• Economic development and land use
• International travel and commerce
• Microbial adaptation and change
• Breakdown of public health measures
• Institute of Medicine Report, 1992

11
Speed of Global Travel in Relation to World
Population Growth
From Murphy and Nathanson. Semin. Virol. 5, 87,
1994
12
Infectious Disease Mortality United States,
1980-1996
Source JAMA 1996275189-193 and unpublished CDC
data
13
Emerging Infections

• New Agent
• Expanding Range
• Imported
• Re-emergent
• Newly recognized
• Patient changes

• HIV, BSE/vCJD
• Babesia/Ehrlichia
• Chagas, WNV
• Malaria
• HHV-6, 8, TTV.
• CMV, B19?

14
Elements of a Program

• Surveillance/Intelligence
• Assessment for relevance
• Public health
• Public concern
• Measures of risk
• Investigation of intervention(s)
• Recommendations
• Implementation
• Evaluation

15
Concern High, Action Favored
(HIV)
vCJD
CJD
WNV
T.cruzi
Bacteria
Babesia
Ebola etc
HHV 8
Leishmania
B19
HAV
HHV 6
Malaria
Lyme
Ehrlichia
HGV, etc
RMSF
Chlamydia, Leptospira Bartonella, etc
Benefit High Action Favored
CTF
16
BSE and vCJD

• Large outbreak in cattle, UK, elsewhere
• Amplified through feed
• Controlled but not eliminated
• Likely causative link to vCJD
• Aberrant disease, onset early in life
• Unpredictable growth of human outbreak
• In vitro animal data under development

17
TSE Characteristics

• Difficult to detect
• Infectivity assay
• Amyloid assay
• Difficult to disinfect
• Destructive methods
• Size is disputed

• Fatal
• Central Nervous System (CNS)
• Long Subclinical Incubation
• Active (not latent)
• High CNS titers
• Present in blood

18
Transmissible Spongiform Encephalopathies

• Scrapie
• CJD
• BSE
• nv-CJD
• CWD

19
Chronic Wasting Disease of Deer and Elk

• Originated in captive herds
• No animal derived protein
• Horizontal transmission
• Does not present as a neurological disease
• Has infected white tail deer
• Is spreading
• There is a dangerous lack of knowledge

20
TSEs and Blood

• Blood-borne TSE Infectivity
• Natural Disease
• No unequivocal demonstration
• Experimental Disease
• Rodent adapted strains have infected blood
• Older Literature -Variable results
• Blood-borne PrPres
• None yet demonstrated in any system

21
Limiting Dilution Titration of Blood
Inoculate
Donor
Bleed
Whole blood, ic inoculation (³1 ml)
50 ml each
20 Recipients
22
Limiting Dilution Titration
Inoculation of 1 ml of sample
50 ml each
.
20 Recipients
Five dead out of twenty inoculated
Five dead out of 1 ml of sample inoculated
Approximately 5 ID/ml of sample
23
CJD Experiment Summary

• There is infectivity in blood.
• Present even when donor received small dose.
• Present during preclinical disease.
• Titer is 4 to 24 infectious units/ml blood.
• Blood-borne infectivity may not replicate
• Infectivity may spill into blood from other sites
  
• Infectivity correlates with PrPres not PrPc

24
CJD Transfusion Experiments

• Blood-borne infectivity
• Intact blood appears less virulent than CNS
  infectivity
• May be cell associated
• May be on a dead end pathway

25
Distribution of TSE Infectivity in Blood
Components
Plasma 25 - 30
Buffy Coat 35 - 45
RBC 20 - 25
26
Why hasnt blood transmitted TSE infections?

• Blood titers are low
• Transfusion transmission is inefficient
• Blood products are highly refined
• We have been lucky

27
nv-CJD may be different

• nv-CJD/BSE may be more virulent
• Newly emergent
• Oral route
• Jumps species barriers
• Evidence for circulatory involvement
• Tonsils
• Appendix
• BSE/bone marrow
• B-cells involved in peripheral transmission

28
BSE and vCJD

• Large outbreak in cattle, UK, elsewhere
• Amplified through feed
• Controlled but not eliminated
• Likely causative link to vCJD
• Aberrant disease, onset early in life
• Unpredictable growth of human outbreak
• In vitro animal data inconsistent
• New models under development

29
(No Transcript)
30
CJD Blood-Borne Infectivity

• Blood-borne infectivity may not replicate
• Infectivity may spill into blood from other sites
  
• Infectivity correlates with PrPres not PrPc
• If blood-borne infectivity has a significant role
  it must be due to chronic low-level exposure

31
Control of Blood-Borne Pathogens

• Deferrals
• Screening - No available test
• Inactivation/Removal - No available method

32
Are persons at risk for nv-CJD a special risk to
blood?

• Extent of BSE exposure is unknown
• Whatever its extent it is world wide
• Deferral of persons with higher exposure
• UK has ceased fractionation of domestic plasma

33
Regional Impact of CJD Deferrals--Whole Blood
34
Old FDA Recommendations
August, 1999 FDA recommends deferral of travelers
who have spend six month cumulative in the
UK January 2001 On the basis of new data, TSE
Advisory Committee recommends extending the
deferral to other BSE affected countries
35
New ARC TSE Deferral Criteria

• Anyone who has lived in the UK for a cumulative
  total to 3 months since 1980.
• Anyone who has lived in Europe countries
  (including the UK) for a cumulative total of 6
  months since 1980.
• Anyone who has received a blood transfusion in
  the UK since 1980.

36
New FDA Recommendations

• May 31, 2002
• Anyone who has lived in the UK for a cumulative
  total to 3 months from 1980 to 1996.
• Anyone who has lived in Europe for a cumulative
  total of 5 years since 1980.
• Military personnel
• Military bases in Northern Europe for 6 months or
  more from 1980 to 1990.
• Any military base elsewhere in Europe for 6
  months or more from 1980 to 1996.

37
Blood Shortages?

• FDA study - predicts new deferral policies will
  lead to a 8 reduction in eligible donors.
• 25 of blood components used in the metropolitan
  NY area are imported from Europe.
• ARC study - showed that deferrals may result in
  3 shortfall.

38
Trypanosoma cruzi

• Chagas disease
• small protozoan parasite
• chronic, asymptomatic, and
  untreatable infection
• endemic to portions of Mexico,
  Central America, and South America
• transmission vectorial, congenital, and blood
  transfusion

39
(No Transcript)
40
U.S. Residents Born in Latin America
Mexico 4,447,000 Central America 1,482,000 South
America 1,107,000Total
7,036,000
1990 Census Data
41
Hispanic Population Growth
42
Chagas Disease After Organ Transplantation ---
United States, 2001 MMWR 03/15/2002 Vol 51, No
10210  
43
Transfusion Cases
1987 California - Mexican donor 1989 New York
City - Bolivian donor Manitoba - Paraguayan
donor 1993 Houston - unknown donor 1999 Miami -
Chilean donor 2000 Manitoba - German/Paraguayan
donor
44
Seroprevalence Data
Los Angeles Miami Total no.
donations 1,104,030 181,139 Yes to risk
question 78,736 (7.1) 25,908 (14.3) Number
tested 77,967 25,352 EIA repeat
reactive 329 75 Confirmed by RIPA 147
(0.2) 20 (0.1) Seropositivity rate 1 in
7,500 1 in 9,000
45
LA Seroprevalence 1996-98
1/5,400
1/7,200
1/9,900
46
Seropositive Donors Country of Birth
2
47
T. cruzi in Blood Units

• are platelets of greatest risk?
• few platelet units in look-backs
• transfusion cases almost all involved platelets
• survival and localization studies

whole unit lt 7 days platelets lt 4 days red
cells lt 2 days plasma none
48
Nationwide Risk
12 million donors 300,000 at risk donors 480
seropositive donors 768 seropositive
donations/year 1,536 potentially infectious
components
(2.5)
1/625
(1.6)
(2.0)
49
Interventions?

• question strategies
• designed to identify at-risk donors for deferral
  or testing
• lack sensitivity
• blood screening
• lack of licensed tests
• potential strategies
• added value of NAT testing minimal
• one-time testing
• logistically difficult, not cost effective?
• universal testing

50
Chagas/T. cruzi Summary

• seropositive donors nationwide
• levels vary based on at-risk population
• no reliable risk factors
• infections are
• asymptomatic, chronic untreatable
• congenitally transmitted
• infectious donors demonstrable
• universal screening likely
• ongoing blood safety issue

51
RecommendationsChagas Blue Ribbon Panel

• intervention needed for increased blood safety
• universal blood screening best approach
• role of risk-factor questions to be re-examined
• potential implications of pathogen inactivation
  should be considered
• decisions/directions toward testing strategy
  within one year

52
Babesia microti

• agent of babesiosis
• intracellular pathogen of red cells
• tick-borne zoonosis - Ixodid ticks
• flu/malaria-like symptoms
• infection generally asymptomatic or
  self-limiting
• can be severe or fatal in elderly,
  immunocompromised, or asplenic hosts

53
Known Geographical Distribution

• focal distribution of B. microti
• sporadic distribution of Babesia-like organisms
• (e.g., WA-1, CA-1, MO-1)
• expanding endemic ranges
• limited seroprevalence data

54
Vectors and Reservoirs-
55
Life Cycle -
56
Post-transfusion Babesiosis

• gt 40 known cases (1979 - present)
• includes 2 WA-1 cases
• recipients
• age - neonates to 79 years
• most immunocompromised
• platelets RBCs (lt 35 days) implicated
• incubation period 2-8 weeks
• infections identified by serology, PCR, and/or
  animal inoculations

57
Babesia microti Seroprevalence
non-endemic
endemic
n ELISA () IFA () Endemic
1,745 116 (6.6) 24 (1.4)
Non-endemic 1,745 76 (4.4)
6 (0.3) Totals 3,490 192 (5.5)
30 (0.9) significant at P lt 0.002, c2 9.7
58
Babesia Summary

• expanding distribution
• no reliable risk factors
• chronic carriers not seasonal
• infectious donors demonstrable
• redouble education efforts
• blood screening?
• lack of available tests
• universal testing
• testing for at-risk recipients
• BRP May 25, 2000

59
West Nile Virus
60
West Nile Fever Human Disease

• Febrile, influenza-like illness with abrupt onset
• Moderate to high fever
• Headache, sore throat, backache, myalgia,
  arthralgia, fatigue
• Rash, lymphadenopathy
• Acute aseptic meningitis or encephalitis
• Most fatal cases gt50 years old.

61
Distribution -
62
Life Cycle -
63
West Nile Fever
64
(No Transcript)
65
Queens Serosurvey Preliminary Conclusions

• In the study area, approximately 1,256 persons
  were infected with WN virus during the epidemic
• Approximately 239 persons or 19 may have had a
  mild clinical illness associated with their
  infection
• This suggests a subclinical to clinical infection
  ration of 4 to 1
• The age specific seroprevalence data suggest
  novel introduction

66
WNV surveillance, 2000

• Human cases 149, 18 deaths
• Conn, NJ, NY
• Infected birds 4323
• 28 States, all east of Mississippi
• 483 infected mosquito pools
• 60 horses
• (Infected area larger than 2000)

67
MMWR - USA, 2001
68
MMWR - USA, 2001

• Total of 64 human cases
• ages 9 - 90
• median age 68
• 9 Fatalities (14)
• ages 44 - 90
• median age 70
• Total of 149 cases with 19 fatalities

69
MMWR - USA, 10/2002
70
Virginia 10/2002
71
Transplant Related Cases

• Aug. 1, 2002 Atlanta, GA
• Four organs from WNV organ donor to 4
  recipients
• Three recipients tested for WNV
• One recipient with clinical disease
• Donor had received blood products from 63 blood
  donors
• 41 retention segments
• 31 have tested negative
• Other blood recipients under investigation

72
Transplant Related Cases

• Six cases of post-transfusion WNV are under
  investigation
• Two cases has been associated with WNV blood
  components.
• A blood component implicated in one of these
  cases as been linked to another, newly WNV case
  (10/04/02).

73
WNV Other Developments

• WNV mother transmitted virus by breast feeding
  new-born infant.
• CDC, FDA, AABB, and ARC have issued guideline for
  WNV associated donor call-back

74
West Nile Fever

• Viremia before and during clinical disease
• 1-6 days incubation, 3-6 days disease
• Many infections mild or asymptomatic
• Localized outbreaks
• Testing IgG and IgM RIA methods
• Consider emphasis on call-back for fever
• High public concern

75
Re-emerging Malaria
76
Note As of 1999, annual cases averaged 20,000
77
Presumed mosquito-borne malaria, US, 1957-94
From Zucker JR, EID 199621-10
78
Summary Malaria

• Expansion of endemic areas
• Re-emergence
• Unexplained autochthonous cases
• Travel and relocations lead to increasing
  incidence of imported cases
• Increasing risk to blood supply
• Drug resistance, partial immunity
• New strategies for transfusion safety?

79
Summary

• Emerging infections may impact blood safety
• Continuing, structured review of field needed
• Risk assessment is performed as required
• Selected agents are further evaluated in the
  field and the laboratory
• Interventions testing, interview, call-back
• Partnerships with industry, public health agencies

80
Blood Safety Current Risk and Emerging
Infections

• Questions?
• Discussion!