Recipients of plasma products manufactured from donations from
individuals who developed vCJD
Public health measures for those at risk
Not to donate bloodNot to donate tissues or organs
To tell clinicians treating them so special precautions can be
taken with instruments etc To tell family in case of emergency
treatment
This is a picture of the Surveillance Unit, and this is
Edinburgh, with rather different weather than you have here. We're
in a building called the Bryan Matthews Building, and this is a
painting of Bryan Matthews. And many of you may or may not know who
he was, because, of course, he's now, sadly, dead; but he has been
the individual who really began CJD research in the United Kingdom.
A patient of his with sporadic CJD died and the brain from this
individual was sent to Gadusek and was responsible for the first
successful transmission experiment. And he set up the first
case-control study in the UK, in the CJD, and so, we've named our
building after him. I'm going to talk briefly about prion diseases,
just to cover the background. To talk about the present position of
variant CJD; to touch upon experimental evidence for blood risk;
and then to on to the epidemiological evidence; talk about the UK
TMER Study in brief; and then, make some concluding comments. So,
an introduction: Well, first of all, this disease is now recognized
to exist in four different forms, which is very confusing to many
people, including the world media. The sporadic CJD exists in a
worldwide distribution of unknown cause, and in the United Kingdom,
we have about 50 deaths a year from this disease. Genetic CJD,
which is a familial, inherited disorder is auto-dominant, due to a
mutation on the PRNP gene, and there are about five deaths a year
in the UK from this -- Iatrogenic -- which is obviously why I'm
here talking to you at all -- is the accidental transmission of
this disease, in the past, by surgical or medical treatments, but
increasingly, the concern about blood arises; and we have about
five deaths in the UK from this a year. And variant -- used to be
called new variant; the families prefer the oxymoron of human
bovine spongiform encephalopathy, first described in '96; the
earliest symptoms ever yet identified in a human being were in '94,
and more or less confined to the U.K, although not entirely,
thought to be due to BSE in diet; and in 2003, we had 18 deaths.
This is a rare disease, and I don't know of any real precedent
where such a rare disease has led to such scientific, media,
political, and indeed, financial interest. Well, the prion protein
is essential to this disease, although I'm going to entirely avoid
the controversy of what its actual role is; and it therefore, is
not surprising that the gene on human chromosome 20, responsible
for this protein, has a profound effect, not only in the genetic
cases, but in fact, in all cases. And one particular recognized
factor is that CODON 129 of the Open Reading Frame, people may code
for either methionine or valine, and there's a common polymorphism
in the population. And everybody in this room will either be MM, MV
or VV, depending on your parents.And this has a profound
implication for the disease at a number of levels, but in
particular, it's relevant to susceptibility and these are normal
data from the UK. First of all, sporadic CJD and the normal
population, and these are five, pooled Caucasian studies. And what
you can see is about half of the UK population are heterozygotes;
just over a third MM homozygotes; and a minority valine
homozygotes. This proposition changes across the world, and there's
roughly and East/West drift; and by the time, for example, you get
to Japan, the MM column is extremely high and the MV column very
low or nonexistent.If you look at sporadic CJD in the UK over this
period of time, you'll see that there's a gross over-representation
of MM individuals and a gross under-representation of MV
individuals. And whatever the cause of sporadic CJD, methionine
heterozygosity is a risk factor and methionine/valine
heterozygosity is in some way protective. When you look at variant,
the figures are more stark, still. We have tested 130 cases of
variant CJD and all of them have been methionine homozygotes. Well,
going on to the present position with variant CJD, the cause -- I'm
not going to labor this point, it's slightly tangential, but BSE
and variant CJD have identical causative agents, bearing in mind
the slightly awkward fact that the causative agent has never been
identified or fully characterized. BSE, passed in cattle to man,
it's not proven, but it's virtually certain -- there's no other
consistent hypothesis -- and finally, it probably passed in diet.
So, you get cow sausages and ill brain. But the gradation of color
here reflects the strength of the evidence, and as you get down
towards the dietary theory, the evidence is very largely
circumstantial.Well, in the UK at present, we've identified 153
definite and probable cases. And I'm not going to discuss the
definition, except to say that "definite" means neuropathologically
confirmed, and "probable" is a use of the word "probable" that
clinical neurologists can usually only dream about -- every single
case that's been classified as probable in life, if they have come
to autopsy, has in fact had the disease. So, this is a very high
degree of probability. Mean age of onset, 28; median, 26, ranging
from the pediatric end of 12 to the geriatric end of 74. Short
duration illness, with a median of about 14 months, can be as short
as six, and be as long as 40. And an excess of males, but not one
that is statistically significant.
We've had 106 neuropathologically confirmed cases; increasingly
in the UK, even in variant CJD, it was very difficult to get
autopsies. And at any moment in time, we tend to have around about
five individuals alive with this clinical illness in the UK. Now,
this is just to show you the age at death, or the present age, if
the patients are still alive. And you can see there's a big sort of
concentration of these in the 20-to-30 age group. It does tail off,
but we have had cases in the 60- and 70-age group, and this is
perhaps something of a concern because we are a little bit worried
that we might be missing cases in the elderly, because clearly,
neurological illness in the extremes of age is not always well
investigated, at least not in the UK.
The mean age of onset, however, has not changed over time during
this small epidemic; and given the fact that there appears to have
been a point period of exposure, this is a bit odd. Could it be
that it was age-related exposure to the infection? We don't think
so, although we don't know. Could it be that there's an age-related
incubation period? It's possible, but we don't know. Could it be
that there was age-related susceptibility? And again, it's possible
and it does seem the most likely hypothesis, but we don't
know.These are the figures outside the United Kingdom: Nine cases
in France; one in Italy; one in the Republic of Ireland. And these
are in dark blue because the evidence is very strong that these
individuals contracted the illness within the country to which they
are attributed. You then have some different colors -- another
Republic of Ireland case, a USA case and a Canada case. And these
cases almost certainly contracted the illness in the United
Kingdom, while staying or living there, although, of course, we
can't be certain. And most difficult of all, is now a reported case
in Saudi Arabia. It's very unclear whether this should be publicly
discussed or not. The Saudi Arabians weren't terribly keen at one
point that this should be talked about. However, it has been all
over various websites and newspapers in the Middle East, and it is
certainly a case of variant CJD, which appears, as far as we know,
to be intrinsic to that country. And I don't know what to make of
these odd cases appearing in Sicily, Saudi Arabia, as individual
cases in their own countries -- it's very difficult to know what
that means. Well, these are the number of deaths per year in the
UK, and you can see that it apparently rises and then falls,
although the data for 2004 are incomplete. And this is, of course,
much more reliable information in terms of prediction, namely,
onset; but of course, finding the onset of a disease is in general,
a bit more difficult and unreliable than finding the date of death
of the diseased. And you can see again this profile, although the
figures for the latter years are still uncertain. So, it looks as
though this illness has appeared and is now disappearing in the UK.
Nick Andrews of the PHLS in the UK does various analyses and this
is for deaths in the UK. And these are the raw data and these are
fitted curves. And originally, an exponential rise in curve was the
best fitted curve. And now, a quadratic form is the best fit, with
a peak of deaths around about the year 2000, although a plateau
model is still statistically valid for these data; but it does look
as though this disease is not increasing in the way that some
people feared, and it may have peaked and be in decline from the
year 2000. However, you've got to be careful. First of all, all the
cases we've identified so far have been in MM individuals; and
given that MV and VV individuals may well be affected, and given
that the incubation period in those individuals may very well be
longer, there may be other peaks related to these particular
genotypes. Secondly, it seems rather likely that there are other
genetic factors determining susceptibility, and we haven't
identified those. And of course, there could be secondary,
human-to-human transmission cases, which are not taken into account
in the model that I showed you. Now, there's preclinical
involvement in this condition, which of course, is very important
because preclinical cases could have infectivity but be
symptom-free, and therefore be a risk. There are two particularly
well-established examples, two individuals who had variant CJD
beginning in '95 and '98, who were found to have had appendectomies
routinely performed for appendicitis before they developed clinical
illness. And it was possible to go back to the laboratories, get
hold of their samples and test them; and they were both positive in
these two individuals, one therefore, having appendix
lymphoreticular positivity eight months prior to illness and one
two years prior to illness. So, preclinical involvement does
exist.This, of course, led to the idea of immunocytochemical
surveillance because there are surgeons in the UK taking out bits
of the lymphoreticular system all the time -- ENT surgeons taking
out tonsils and abdominal surgeons taking out appendices. And these
anonymized specimens were identified in the UK and then analyzed,
and this was a major undertaking. And James Ironside, my new
pathological colleague, told me that he never wanted to see another
appendix in his life. They looked at over 12,000 appendices and
they found three of them were positive. Now, this was an anonymized
study, so it's not possible to go back and find out anything about
these individuals; nonetheless, this is a rather disturbing finding
for the following reason: because if you try to take these basic
data and then extrapolate to the population, you find that there
should be about 237 per million in the UK with appendix positivity.
But you'll note that the confidence intervals are rather wide. If
you take the ten-to-30 age group -- because most people having
appendectomies are young -- this equates to 3,808 individuals with
potential infectivity in the UK population. But again, you'll note
that the confidence intervals are wide; but still, the lower figure
is 785. So, there's sort of a discrepancy between what the
immunocytochemistry surveillance was saying, and what the
observations of individual cases of variant CJD predict. For
example, in this ten-to-30 age group, you've got about 3,800
individuals, although with wide confidence intervals; and variant
CJD cases in the same age group 90, and in decline. So, what's the
explanation for this, apart from, of course, the confidence
interval point I made already? The first is: Could these be false
positives in the lymphoreticular study? Well, they might be, but
everything has been done to assure that they are not, and
certainly, control specimens were looked at. However,
interestingly, two out of the three cases had a different pattern
of PrP staining than we are used to seeing in variant CJD.
Secondly, the clinical cases are all MM genotypes, and at present,
we don't know the genotypes of these three appendix individuals.
However, their genotype is being looked at; it is possible to
actually do this kind of genotyping on fixed material from an
appendix. I can't tell you the result of this at the moment, but a
result will be available shortly, and this could have some
implications. Subclinical cases, well, of course, these specimens
might have been from clinical cases, although we, hopefully, have
excluded that particular point. They could be from preclinical
cases; in other words, people going on to develop disease, but they
could be from subclinical cases. We don't know whether everybody
with lymphoreticular positivity will go on to develop variant CJD,
and so the discrepancy in the numbers might be that there is a sort
of carrier state in variant CJD with no neurological disease
forthcoming. That, of course, is reassuring from the neurological
illness point of view, but it's not reassuring from the issues of
public health and possible transmission. Now, this is a case report
in 2004 that I guess you will all be familiar with, which really
raises the point of subclinical illness and other genotypes. This
was an autopsy which was undertaken in a known vCJD blood
recipient. This individual had received blood from a definite case
of variant CJD, and when this individual died, a detailed autopsy
was done, simply because of that known fact. This individual had no
clinical evidence of variant CJD in life; their cause of death was
something entirely separate, they died five years after the blood
transmission, there were no neuropathological features of variant
CJD, but the spleen was clearly and distinctly positive for the
abnormal form of the prion protein. And this individual was CODON
129 MV. So, this case report is very interesting, because it
provides evidence of BSE infection in a non-MM individual, although
it's important to stress this was not in itself variant CJD, and
therefore, this was either a preclinical case or a subclinical
case. Five years is a relatively short period for the incubation of
this kind of illness. So, BSE in the UK, at least, although I don't
know about other countries, is controlled and diet, at least in the
UK, is protected. And therefore, for diet-related variant CJD, you
simply await the outcome. But could there be secondary, iatrogenic
spread, and in particular, if there's preclinical and subclinical
cases, and with lymphoreticular involvement, and that, of course,
raises the difficulty of surgery and, of course, blood. So, I'm now
going to turn to blood and briefly review the experimental
evidence, and then the epidemiological evidence. And first of all,
experimental, and I'm going to pass over this very quickly, mainly
because it's not my field as a clinician and epidemiologist, and
partly, because I think many of you will already be familiar with
it.
Prior to 2002, largely based on work by Paul Brown and others,
it was possible to say the infectivity might be present in blood in
some models in the laboratory; certainly not always present --
these were animal models, often rodent models; they were usually
not using variant or sporadic CJD, but other forms of prion
disease; and even using variant or sporadic, there's always the
problem of the so-called "species barrier" in prion diseases and
interpreting these results. And often, this was transmitted by
intra-cerebral inoculation. So, this is a really highly artificial
situation. What came out of this was that there was certainly a
differential risk for different components and fractions, and this
is roughly a reproduction of Paul Brown's work with risky items
here and apparently unrisky items here. The fact that whole blood
in these particular experiments wasn't especially a risk is really
to do with the methodology of these experiments and problems of
dilution, if you're trying to inoculate intracerebrally a mouse.
Although I was present at one meeting where a rather naive
researcher said they didn't quite understand the problem, and why
couldn't someone inoculate a whole unit of blood into a mouse head?
Which seems slightly odd. Other factors that came out of this were
that processing steps clearly reduced infectivity; the intravenous
route was apparently less risky than the intracerebral route, and
preclinical infectivity was significantly lower or absent. And that
was, perhaps, one of the most reassuring things of all. However,
then things changed, and Nora Hunter and colleagues did some rather
more realistic experiments in terms of human practice, using sheep.
First of all, BSE in sheep -- BSE was given to sheep, blood was
taken from the infected sheep and then transfused intravenously
into other sheep; and also natural scrapie was used with blood
being taken from natural scrapie sheep and intravenously infused
into other sheep. And both of these experiments have produced
increasingly positive results. And therefore, I'm summarizing all
of this very grossly, but transmission of sheep BSE can occur by
whole blood; it can occur by intravenous transfusion of a unit of
blood; it occurs with clinical phase donations; and occurs with
preclinical phase donations. So, this immediately increased concern
amongst anyone dealing with blood risk.
Now, this is all very potentially concerning, but human disease
in humans, the usual clinical practice is rather different. And if
you really want to look at this, you might think first off -- and
indeed, many people, including, I think, Paul Brown, felt that
despite the experimental results, blood might not be a big problem.
Firstly, there was certainly a low titre of infectivity in blood,
particularly low infectivity in certain components. Plasma products
-- processing clearly reducing infectivity; a peripheral route of
administration in clinical practice, which is, of course, safer
than intracerebral inoculation; and sadly, for labile components,
which have the highest risk, there is a relatively high mortality
rate. In other words, many people might die before they had a
chance to develop variant CJD. So, this really takes us on to
observation and epidemiology in humans, because clearly, you can't
experiment on humans in these situations. And there are various
bits and pieces of information that have come from surveillance
systems, which are kind of informal, unstructured, epidemiology
studies. And in particular, CJD has never been reported in someone
that you might describe as at a high risk; and in particular, for
example, in the world, nobody with hemophilia has ever yet been
described as having a prion disease. There are many case-controlled
studies that are being done and this is a list of them. And apart
from two of them, they have included reference to blood transfusion
as a risk factor, and they've all been negative. There's no
evidence from these case-control studies that blood or blood
products have been a risk factor for sporadic CJD. And that's
really one of the difficulties -- much of the evidence around
relates to sporadic CJD and there are lots of reasons for thinking
that variant may behave differently. And of course, the trouble
with case-control studies in epidemiology is that it is reasonable
to try to prove a positive with these studies, but it's very
difficult, if not impossible, to prove a negative with them.
So, this really takes me to the final topic of the Transfusion
Medicine Epidemiological Review, the TMER study, in the United
Kingdom. And this is a study that's undertaken by our unit in
conjunction with the UK National Blood Services. And variant CJD,
we identify cases of variant CJD older than 17, because that's the
age they can donate blood, and we give these names to the relevant
Blood Service in the UK. That Service searches for records of
donations, given 1980 and beyond; they're trying to identify all
components and their fate; they give us the recipient names where
identified; and we check to see whether these recipients
subsequently turn up in our records as CJD. There's a "Reverse
Study," tracing donors of blood given to vCJD cases, and there's a
Sporadic Study undertaken concurrently on the same lines. Well, I'm
just going present some of the very general results of this and I'm
only going to concentrate on variant CJD. And the total number of
cases, 153, as I've already told you; the number in which donor
records were traced was 20; and it's actually perhaps surprising to
me, but maybe not to you, how difficult it was sometimes to trace
all of these records. The number from whom components were actually
issued was 16, and the recipients identified from these 16
components, where recipient and component information was
available, was 50. Additionally, nine vCJD individuals donated to
23 plasma pools and as far as we could ascertain, 174 products were
manufactured from these pools. This is just the 50 recipients of
components and a breakdown of the kind of material that they
actually received. And as I mentioned to you, the nine donors who
put donations into 23 plasma pools and perhaps unsurprisingly, the
greater number are up here, particularly, red cells.
So, what about labile components? Well, this is just a graph
showing the recipients of labile blood components donated by
variant CJD cases; and of the 50, 17 are still alive. The mean age
of the alive recipients is 65; median 70, with a range here. Four
out of the 17 are below 50. And I've put an arrow here because this
is an arrow demonstrating the one suggested case of actual
transfusion-related transmission, and this occurred at about 6.5
years. So, you can see that quite a number of individuals who are
alive have survived beyond that point, some to ten or ten years and
beyond, and yet, haven't so far developed variant CJD. These are
the cases who died; 33 of the 50 died and you can see this is 6.5
years. The majority of these individuals, as you might expect, died
withinrelatively short time of receiving the labile components, and
certainly, within a period before you might expect variant CJD to
develop, if indeed, they were going to develop it. And I'm just
going to close on two specific cases. This is clinical variant CJD
in a recipient. Onset was 6.5 years after transfusion, as I just
told you; and also, the reticular endothelial system abnormality,
not variant CJD in a recipients who died from another illness after
transfusion. And these are two cases identified, partly through the
TMER Study, and these are the only two cases of suggested BSE or
variant CJD-related transmission to date.
Just to look at the first case: 1996, a 62-year-old underwent
surgery, received five units of red blood cells; one unit came from
a 24-year-old donor who had onset of variant CJD three years and
four months later. The donor had definite variant CJD. 2002, 6.5
years later, relatively typical illness of variant CJD died after
the typical duration of illness; neuropathologically confirmed
variant CJD, which had typical appearances -- there was nothing
unusual about the neuropathology, and there were CODON 129 MM. And
the importance of this was that if this was related to the blood
transfusion, this was from a preclinical donor. Now, of course,
this individual also lived in the UK, and ate the same food that we
all ate; and therefore, could they have had dietary-related variant
CJD. Well, Simon Cousins, in the London School of Hygiene and
Tropical Medicine, did a careful analysis of this and tried to find
out what the probability was of recording a case of variant CJD in
this recipient population, given the background figures and
prevalence and incidence of variant CJD, in the absence of a
transfusion-related infection. And the answer was that the chances
of just finding variant CJD through diet by coincidence in this
individual was somewhere between one in 15,000 and one in 30,000 --
which is a difficult sort of figure, because it's clearly an
unlikely event, but it's not impossible. And therefore, at the
moment, we regard this as a possible case of transfusion
transmission. The second case, as I've said, was not a case of
variant CJD, but either a preclinical or a subclinical case. Died
five years after transfusion; no clinical evidence of variant CJD
in life; another cause of death; no neuropathology; spleen was
positive for the abnormal variant CJD-related prion protein; and
they were CODON 129 MV.
And just a footnote about fractionated blood products, 9 donors
contributed to 23 pools, 174 products as I've mentioned to you, and
there is in the United Kingdom something called the Health
Protection Agency and one part of this, the CJD Incidents Panel
developed a model of risk assessment for the people who have
received these products. And this allows some sort of calculation
of dose of product as a threshold beyond which certain measures are
taking informing the individual and precautions to reduce further
risk. This is a highly complex area and one that's not really
directly related to the national CJD unit nor the TMER, but as I
say part of public health protection in the UK. And this is an
ongoing process and anybody interested in this rather complex
process could, if they wish, visit this particular website and they
can learn all about it there. And therefore, just to conclude
variant CJD in the UK is decline apparently, but concerns remain.
They're appearing in different countries, variant cases. Over time,
there's increasing risk that blood is a potential problem. There
are two possible instances of actual transmission. Increasing
concern over preclinical or subclinical cases, the UK TMER study
continues to collect data. And we and other countries of course,
have taken many precautionary measures which hopefully will limit
the effects of any of these risks and these precautionary measures
continue to be revised in the light of accumulating knowledge.
Thank you.
