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From: TSS ()
Subject: Prion infections, blood and transfusions Aguzzi and Glatzel
Date: July 8, 2006 at 9:54 am PST

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Prion infections, blood and transfusions Aguzzi and Glatzel
Sat Jul 8, 2006 12:18

Prion infections, blood and transfusions

Adriano Aguzzi* and Markus Glatzel

Prion infections lead to invariably fatal diseases of the CNS, including

Creutzfeldt–Jakob disease (CJD) in humans, bovine spongiform

encephalopathy (BSE), and scrapie in sheep. There have been hundreds

of instances in which prions have been transmitted iatrogenically among

humans, usually through neurosurgical procedures or administration of

pituitary tissue extracts. Prions have not generally been regarded as bloodborne

infectious agents, and case–control studies have failed to identify

CJD in transfusion recipients. Previous understanding was, however,

questioned by reports of prion infections in three recipients of blood

donated by individuals who subsequently developed variant CJD. On

reflection, hematogenic prion transmission does not come as a surprise, as

involvement of extracerebral compartments such as lymphoid organs and

skeletal muscle is common in most prion infections, and prions have been

recovered from the blood of rodents and sheep. Novel diagnostic strategies,

which might include the use of surrogate markers of prion infection, along

with prion removal strategies, might help to control the risk of iatrogenic

prion spread through blood transfusions. ...



Prion diseases, also termed transmissible


a group of neurodegenerative conditions that

are transmissible within and between mammalian

species. A characteristic of these diseases is

the accumulation of a misfolded prion protein,

PrPSc, which is a post-translationally modified

form of the host-encoded prion protein (PrPC).

The processes underlying PrPSc formation

remain enigmatic, but there is little doubt that

a conformer of PrPC, which might exist in an

oligomeric form,1 is identical to the infectious

entity.2 Prions damage the brain by transmitting

toxic signals to cells expressing PrPC.3

Although genetic evidence has been taken

to indicate that human prion diseases have

been with us since prehistoric times,4 the first

documented cases of Creutzfeldt–Jakob disease

(CJD) date back only 85 years.5–7 Since then, it

has become obvious that human prion diseases

have three distinct etiologies: they can arise in the

absence of any documented exposure to infectious

prions as sporadic CJD (sCJD), as an autosomal

dominantly inherited disease in the case

of genetic, or familial, CJD (gCJD/fCJD), or as

an acquired condition in the case of IATROGENIC

and variant CJD (iCJD, vCJD), or kuru, which

resulted from cannibalism.8

Some prion diseases that occur in animals

might have been recognized several centuries

ago, as suggested by early descriptions of sheep

diseases that seem to correspond to scrapie.

Most prion diseases affecting animals, however,

were discovered relatively recently.6 A transmissible

spongiform encephalopathy affecting

cattle (bovine spongiform encephalopathy,

or BSE) has caused a massive epidemic in

European countries, affecting around 2 million

animals.9 Epidemiological, biochemical, neuropathological

and transmission studies have

substantiated the concern that BSE prions might

have crossed the species barrier between cattle

and humans, resulting in a novel form of human

prion disease, vCJD.10–13 During 1996–2001, the

incidence of vCJD in the UK rose year upon year,

evoking fears of a large upcoming epidemic.

Since 2001, however, the incidence of vCJD in

the UK appears to have been stabilizing, indicating

that the extent of the epidemic might be

limited.14 As might be expected for in frequent

stochastic events, the numbers of new cases of

vCJD fluctuate from year to year. For example,

data available on the web page of the National

CJD Surveillance Unit15 show that the number

of onsets of vCJD was higher in 2004 than it was

in 2003, but this is not necessarily indicative of

an upward trend.

It must be assumed that a number of asymptomatic

carriers of vCJD exist in human populations

that have been exposed to BSE. The

existence of such a chronic carrier state is a

logical and unavoidable consequence of the

long incubation time of prion diseases, which

is typically in the order of several years and—

in the case of oral exposure to prions—can

reach several decades. Consequently, anybody

who has contracted the infection but has not

developed clinical signs and symptoms might

be consider ed a carrier. Some of these carriers

are likely be ‘preclinical’, and will proceed,

in due course, to the development of disease.

Alternatively, it is conceivable that the carrier

state can persist for an indefinite period of

time, in which case infected individuals could

be regarded as ‘permanent asymptomatic

(sub clinical) carriers’. Studies performed in

rodents indicate that the permanent subclinical

carrier state might be a common phenomenon,

such as occurs when immune deficient mice

are exposed to prions.16 Unlinked anonymous

screens for hallmarks of prion infection in

archival tissues have suggested that the prevalence

of individuals with sub clinical vCJD might

be higher than previously antici pated, and could

reach 237 cases per million individuals.17

The recent discovery of transmission of vCJD

via blood in three individuals indicates with

near certainty that blood-borne prion transmission,

in conjunction with an unknown

prevalence of vCJD-infected carriers, leads

to secondary transmission of host-adapted

prions.18 Consequently, the vCJD epidemic

might be prolonged, or, in the worst-case

scenario, vCJD be rendered endemic and selfsustained.

In this article, we review how prions

could act as blood-borne infectious agents, and

consider strategies aimed at minimizing the risk

of secondary trans mission of prion diseases.



The cause of most human prion diseases is

unknown. In the case of sCJD, the term ‘sporadic’

is used as a euphemism, meaning that we have

no idea about the origin of this form of CJD. By

contrast, gCJD always segregates within families

with mutations in the gene encoding the prion

protein (PRNP), suggesting that these mutations

are causally involved in disease pathogenesis. As

no families have been described in which gCJD

segregates with mutations in genes other than

PRNP, it has been difficult to use human genetics

to understand the pathogenesis of prion diseases.

The discovery of PRNP mutations in gCJD has

led to the proposal that at least some cases of

sCJD might be due to somatic PRNP mutations

analogous to those found in the germline of

gCJD patients. It is equally possible, however,

that some of the cases of alleged sCJD derive

from hitherto unrecognized infectious causes.

In apparent agreement with the ‘intrinsic’

origin of sCJD, which accounts for more than

90% of all human prion diseases, epidemiological

studies were not able to identify a

conclusive link between this form of CJD and

external risk factors.19 This fact is reflected in

the pathological and biochemical features of

these diseases. Although low levels of PrPSc and

prion infectivity can be demonstrated in peripheral

sites such as lymphoid organs or skeletal

muscle,20,21 the highest levels of PrPSc and prion

infectivity appear to occur in the CNS. These

facts might account, at least in part, for the lack

of evidence of sCJD transmission by labile or

stable blood products.22 Indeed, several retrospective

studies have failed to identify blood

transfusion or exposure to plasma products as

risk factors for the development of sCJD,19 and

prion diseases appear to be exceedingly rare

in hemophiliacs, a group of patients that is at

particularly high risk of contracting emerging

blood-borne infectious diseases. Although these

studies cannot exclude the possibility that transmission

of sCJD might have occurred through

blood transfusions in rare cases, and despite

the fact that the etiology of sCJD is unclear,

it would appear that transmission of sCJD by

trans fusion of blood or blood products does

not play a major role in the pathogenesis of this

disease entity.

In the case of acquired prion diseases, however,

the situation is very different. For vCJD, high

levels of prion infectivity and of PrPSc have

been detected in lymphoid organs such as the

appendix and tonsils (Figure 1).23,24 For this

reason, it has been speculated for almost a decade

that vCJD might be associated with a higher risk

of blood-borne transmission than sCJD. It is

important to be cautious, however, as the differences

in the organ tropism of sCJD and vCJD

might be quantitative rather than qualitative, and

PrPSc has been detected in the lymphoid organs

of both vCJD and sCJD patients.21 Initial studies

have failed to detect PrPSc and prion infectivity

in the blood of patients with vCJD, but these

negative data are likely to be attributable to

the lack of sensitivity of the assays available at

the time.23

The recent identification of three indiv iduals

with probable transmission of vCJD via blood

transfusion has provided tragic evidence that vCJD

prions can indeed be transmitted through blood

(Figure 2). On the basis of the epi demiological

and pathogenetic considerations discussed above,

it can only be a matter of time before further

cases of blood-transfusion-associated cases of

vCJD will ensue (Figure 3).

In the first of the cases reported, a patient

received a single unit of non-leukodepleted

erythrocyte concentrate from an individual who

went on to develop vCJD 3.5 years later, and

was therefore likely to have been subclinically

prion-infected at the time of the donation. The

recipient developed vCJD 6.5 years following

the transfusion.25

In the second case, transmission of prion

disease occurred again via a single unit of nonleukodepleted

red-blood-cell concentrate.

The donor developed vCJD 2 years following

blood donation, again raising the possibility

of pre clinical infection at the time of the donation.

18 The recipient died of causes unrelated

to the prion infection 5 years after the transfusion.

Although this individual did not display

overt signs of vCJD, PrPSc could be detected

in lymphoid organs, enforcing the concept of

subclinical prion disease in this individual.

Recently, a third case of blood-borne prion

transmission has been reported.26 In this case,

the incubation time in the recipient was 8 years,

whereas the donor showed vCJD symptoms

20 months following his blood donation.

Until now, sequencing of the PRNP gene

in all individuals who succumbed to vCJD

revealed homozygosity for the sequence ‘ATG’,

which encodes methionine, at codon 129. In

the general population, only 33% of people are

homozygous for ATG at this codon of PRNP, so

this particular genetic trait, known as the MM

genotype, has been regarded as a risk factor for

vCJD.8 The second identified recipient of prioninfected

blood, however, was heterozygous for

methionine/valine at codon 129 (MV genotype).

The MV genotype is underrepresented in

sporadic and acquired CJD, and has therefore

been considered a protective genetic trait. The

fact that this individual died of a cause unrelated

to prion disease raises the question of whether

MV heterozygotes might develop a permanent

carrier status, in which the prion replicates

within their body but clinical signs are absent

for an indeterminate period of time.

Of course, it would be imprudent to draw

far-reaching conclusions on the basis of three

cases of blood-borne prion infection. We deem

it justified, however, to highlight a number of

surprising details that have become clear on

analysis of these cases.

First, vCJD prions can indeed propagate using

blood as a vector. In the past, this idea has often

been regarded as ‘worst-case scenario’, ‘highly

specula tive’, and ‘barely a theoretical possibility’.

The wishful thinking of many physicians

involved in blood transfusion has often conjured

up a sense of safety, which, as we regrettably now

know, is unwarranted.

Second, a single unit of vCJD-prion-infected

blood is sufficient to cause transmission of the

disease. This fact is particularly unsettling, as it

can only be taken to signify that the concentration

of ID50 units in blood is relatively high.

One ID50 unit is defined as the infectious

dose sufficient to establish infection in 50% of

recipients; animal experiments indicate that the

amount of prion infectivity needed to reach

one ID50 unit is much higher when prions are

administered intravenously than when they

are inoculated intracerebrally.

Third, blood from preclinically vCJD-infected

patients can be infectious. Although not

un expected, this aspect is particularly worrisome,

as it suggests that preclinical donors

might subjectively not consider themselves at

risk. Consequently, the only way to identify such

donors would be to subject the donation to a

prion screen of satisfactory sensitivity, which is

currently unavailable.

Last, despite all epidemiological evidence to

the contrary, patients who are methionine/valine

heterozygous at codon 129 of the PRNP gene are

susceptible to infection with vCJD prions, which

raises several important questions. Is the virulence

of BSE prions enhanced when passaged

from human to human, as opposed to the

original bovine to human situation? Passaging

experiments of scrapie infectivity between mice

and hamsters indicate that this scenario is highly

plausible.6 Even more importantly, can vCJD

infection of heterozygous individuals establish

a permanent subclinical carrier state? Although

this situation might constitute a best-case

scenario for the infected individuals, it could be

disastrous from an epidemiological viewpoint,

as it might lead to an unrecognized and possibly

self-sustaining epidemic. ...

snip... full text ;



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