Emerging infections involving blood transfusion

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Emerging infections involving blood transfusion

• Roger Y. Dodd, PhD.
• GCP Region, MAC
• April 29th, 2009

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Blood safety 2009

• Modern technologies have reduced the risk of
  classic TTIs to very low levels
• Although still appreciable to chronically
  transfused patients
• New infections continue to appear and old ones
  continue to spread
• The horizons of blood safety have therefore
  expanded, rather than contracted

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Emerging Infectious Diseases
those whose incidence in humans has increased
within the past two decades or threatens to
increase in the near future. Emergence may be due
to the spread of a new agent, to the recognition
of an infection that has been present in the
population but has gone undetected, or to the
realization that an established disease has an
infectious origin. Emergence may also be used to
describe the reappearance (or reemergence) of a
known infection after a decline in incidence.
(IOM)
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Some EIDs

• HIV/AIDS
• Avian influenza
• BSE/vCJD
• Chagas Disease
• Chikungunya (?)
• Cryptosporidiosis
• Dengue
• Drug resistant Strep
• Ebola
• Ehrlichia
• E. coli O157
• Hantavirus

• Hendra virus
• HHV-8
• Legionella
• Lyme disease
• Lyssa virus
• Monkeypox
• Mycobacteria
• Nipah virus
• SARS
• Drug resistant Staph
• WNV

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Why do infections emerge?

• New agent
• vCJD
• Species jump, possibly with mutation
• HIV, SARS
• Environmental change (eg global warming)
• Dengue, malaria, babesia
• Failure of control resistance and mutations
• HBV mutants, malaria, drug resistance
• Population movements migration, travel
• T. cruzi, chikungunya
• Transport of agents, reservoirs, vectors
• WNV, monkeypox
• Behavioral change among humans, including
  conflict
• HIV, leishmania
• In most cases (including those mentioned) there
  are multiple factors

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Requirements for transfusion-transmitted disease

• Asymptomatic blood-borne phase
• Chronic and/or acute
• Survival of agent in donated blood
• Infectious by IV route
• Susceptibility of recipients
• Recognized disease in recipients
• Level of concern dependent on
• Severity, incidence and/or prevalence, rate of
  emergence, (public/political perception)

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TTIs

• In the past, transfusion-transmissible infections
  were perceived to have common epidemiologic
  patterns
• Thus, it was thought that behavioral risk
  questions could have utility in reducing the risk
  of transfusion-related infection from new or
  unrecognized infectious agents
• Conversely, individuals with particular risk
  profiles might be sentinels for transfusion
  transmissibility
• Example HBV as a model for HIV

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Can we predict emerging TTIs?

• EIDs do not appear to have any overall common
  characteristics with respect to class of agent,
  transmission route or pathogenesis. Consequently,
  they cannot be considered as a homogeneous group
  
• All transfusion-transmitted infections must
  necessarily have a blood-borne phase
• This does not however, assure transmissibility by
  sexual or low-volume non-parenteral routes
• Consequently, risk behaviors associated with such
  transmission routes are not common to all TTIs

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Why the disproportionate concern about TTIs?

• Biological/medical
• New portal for introduction of infections into
  human populations
• Avoidance of adverse iatrogenic effects
• Emotional/social
• Imposed, not elective
• Specific to given unit, therefore should be
  controllable
• Dread outcome
• History

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Elements of an Emerging Infections Program

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

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vCJD
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vCJD and other TSEs

• Agent prion disease presumed to be due to
  conformational variant of a normal protein
• EID status New disease in domestic cattle (BSE)
  resulting from intensive agricultural
  technologies (MBM) and transmitted to humans via
  food-chain
• Species issues Apparently unusual species jump
  (compare kuru and scrapie of sheep?)
• Risk status Clearly transfusion transmissible,
  but future unclear, although food-chain exposure
  is largely controlled

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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 (166),
  around 39 elsewhere
• No endogenous case in US
• 2 UK exposure, 1 Saudi Arabia

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National CJD surveillance unit (UK)
http//www.cjd.ed.ac.uk/cjdq56.pdf
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Number of infected persons

• 12,674 tonsils and appendices examined
• 3 were positive for vCJD prion
• 237 (46-693) per million
• Point estimate of gt4,000 infected?
• 2 of the positives were VV homozygous at codon
  129
• (All vCJD cases were MM homozygous)
• Another tonsil study has much lower yield to date

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vCJD and transfusion transmission

• Initial concerns about vCJD justified
• To date, four cases observed, three disease, one
  infection (MV)
• 18/31 vCJD with donation history
• 66 recipients, 3 of whom developed vCJD
• 6.5 and 7.8 and 9 yrs post transfusion (2 from
  one donor)
• Donors developed vCJD 40 and 21 months after
  donation
• 29 recipients lived longer than 5 years
• 3rd recipient had vCJD prion in spleen and
  cervical lymph node at autopsy (no vCJD symptoms)
• 5 years post-transfusion from donation 18 months
  before vCJD
• Additionally, vCJD prion found in one recipient
  of a pooled plasma product
• Sheep model previously showed 17 transmission
  rate

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Comparison of transfusion transmission, CJD vs
vCJD
(P 0.0117)
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West Nile Virus Basic Transmission Cycle
Enzootic (Maintenance/Amplification)
Epidemic
Incidental hosts
Epizootic
Amplifying hosts
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West Nile fever

• Agent Flavivirus (RNA), transmitted by
  mosquitoes
• S Europe, Africa, Middle East to India, arrived
  US 1999, endemic in essentially all of the
  continental US by 2004
• EID status Explosive imported outbreak in
  Americas, but stable elsewhere
• Up to 400,000 individuals infected in 2002, 2003
  in US
• Species issues Infects many vertebrates, birds
  as amplifying hosts, not naturally transmitted
  between humans
• Risk status TTI occurs as a result of high
  incidence of acute viremia, controlled via NAT in
  US

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WNV Neuroinvasive Disease Incidence, by County,
US, 1999-2007
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Distribution of WNV-RNA-positive donations, 2007
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WNV

• 23 cases or TTI reported in 2002
• NAT implemented in 2003
• 9 subsequent cases
• Donors not detected by pooled NAT
• IDT implemented in areas/times of high incidence

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Dengue
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Dengue

• Over 2.5 billion people live in risk areas for
  dengue infection
• WHO estimates that in 2004 there were 50-100
  million cases of DF, 500,000 of DHF, and 20,000
  consequent deaths
• Epidemic is expanding due to global warming,
  expanding vectors and trafficking of subtypes.
• Dengue is the most important arboviral disease of
  humans.

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Dengue

• Flavivirus, enveloped
• 4 strains, no cross-protection
• Dengue fever, dengue hemorrhagic fever
• Transmitted by Aedes mosquitoes without need for
  animal reservoir
• Known to cause very large epidemics
• (Almost 800,000 cases in Brazil in 2002)
• In many ways, similar to WNV
• Known viremia
• Two documented transfusion transmission clusters
  (Hong Kong, Singapore)
• One possible BMT transmission
• Needlestick transmissions known

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Dengue Eastern hemisphere
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Dengue Americas
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Issues

• Good example of an infection that is under study
  as a potential transfusion risk
• Potential for infected travelers
• Competent vector present in many areas
• Donor viremia demonstrated during outbreaks in
  Puerto Rico (Caribbean), Brazil, Honduras

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Supplementary Testing of TMA-Positive Samples
LEGEND 1 Signal/Cut-Off positive, -
negative
(N 16,521)
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Chikungunya
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Chikungunya

• Agent Alphavirus, transmitted by Aedes spp.
  mosquitoes recent mutation favors A. albopictus
• EID status Appearing in new areas due to
  expansion of range of vector and travel
• Species issues sylvatic and human-to-human
  cycles
• Risk status Explosive epidemics, TTI presumed
  possible, future unclear but threatening
• Blood safety interventions in la Rèunion, Italy

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Aedes albopictus Emergence

• Albania -- 1979
• United States 1985
• Brazil 1986
• Central America 1988
• Italy -- 1991
• Africa 1991
• France --1999

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Reported distribution of Aedes albopictus in the
U.S., 2005
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HHV-8

• Agent Herpes virus, transmitted via saliva,
  sexual interactions
• EID status Recently recognized, and emerging
  among MSM, etc.
• Species issues Human infection of long standing,
  origin unclear
• Risk status TTI demonstrated, some control by
  MSM travel restrictions, perhaps leukoreduction

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HHV-8 background

• Herpesvirus (enveloped, DNA)
• Chronic, persistent infection, agent of Kaposis
  sarcoma (classic and HIV-associated)
• Transmitted person-to-person (sexual, saliva,
  organ transplant)
• Global distribution? Africa, s Europe? MSM
• Seroprevalence is test-dependent, up to 2.4 in
  blood donors in US

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HHV-8 and transfusion

• Some indirect 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

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Uganda Transfusion Study

• HHV-8 seroprevalence in blood donors is 35-40
• No leukoreduction
• 1811 transfusion recipients with linked donors
• 991 recipients HHV-8 seronegative prior to
  transfusion, followed gt 3 months
• 41 patients seroconverted (2 or more consecutive
  HHV-8 positive follow-up visits)
• No sero-reverters
• More seroconversion with units lt 5 days old
• Greatest risk _at_ 3-10 weeks (RR 4.73)
• 2.3 of seropositive units led to infection

Hladik, Dollard et al, NEJM 20063551331-1338
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Malaria
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Malaria

• Agent(s) Protozoan parasite(s) (5) of genus
  Plasmodium, transmitted by mosquitoes (Anopheles
  spp.)
• EID status Expanding in range as a result of
  climate change, travel, change in interventions
• Species issues Exclusively human (except P.
  knowlesi) presumed animal origin
• Risk status TTI well-known, controlled by
  questions (non-endemic), donation/patient
  management, potential for failure in face of
  remergence

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Malaria and transfusion

• Globally, probably most frequent TTD
• Survives in stored cellular products
• Essentially all recipients susceptible
• lt1 transfusion case annually in US
• Risk stable, could increase with travel and
  potential reemergence
• Travel history is current intervention
• gt100,000 donors/year deferred

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23,611,536 Presenting Donors

() 241,777 25,339
495 267,611 Deferred (90.3)
(9.5) (lt0.2)
Presenting Donors 1.0
0.11 0.002
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Chagas disease
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Chagas Disease

• Agent Protozoan parasite, Trypanosoma cruzi,
  transmitted by hematophagous insects (reduvid
  bugs)
• EID status Substantial vector control in
  endemic countries, emerging in US, W. Europe
  through population movement
• Species issues Widespread among numerous
  mammalian species housing location and
  construction permit interaction of hosts, vectors
  and humans
• Risk status TTI, transplant as major risk in
  non-endemic areas control by history, testing
• 7 TT cases in US, Canada, 2-3 Spain, 3 transplant
  clusters in US
• US testing program indicates 130,000 donors
  infected

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SARS
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Simian foamy virus

• Infects various monkeys
• Transmissible to humans
• Appears to be apathogenic in humans
• Exemplar of interspecies transmission
• Concern about emergence of pathogenic
  characteristics
• Canada Monkey handlers deferred from blood
  donation
• USA discussed, but no action (to date)

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Overview

• Numerous emerging and newly recognized infections
  with potential for transfusion transmission
• All classes of agents
• Many zoonoses
• No common pathogenesis, transmission route,
  infectious period or risk factor unpredictable
• Absence of effective interventions

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