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Publication history
Issue online:
24 Dec 2001
Tables & Images
Table 1. Ease of transmission via
immunoglobulin therapy
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Table 2. Deaths of definite and probable
cases of Creutzfeldt–Jakob disease (CJD) in
the UK, 1985...–1...
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Volume 118 Issue s1 Page 29 -
October 1999
To cite this article: Helen M.
Chapel (1999)
Safety and availability of immunoglobulin replacement
therapy in relation to potentially transmissable agents
Clinical & Experimental Immunology 118 (s1), 29–34.
doi:10.1046/j.1365-2249.1999.00000.x
Safety and availability
of immunoglobulin replacement therapy in relation to
potentially transmissable agents
-
Helen M. Chapel FOR THE IUIS COMMITTEE ON
PRIMARY IMMUNODEFICIENCY DISEASE
Polyclonal immunoglobulin, used for
replacement therapy in immune deficiencies,
must contain the full range of protective
antibodies in order to provide prophylaxis
against infections. Unlike Factor VIII,
there is no possibility that this therapy
could be provided solely by recombinant
technology. Immunoglobulin for
immunodeficient patients will continue to be
produced from large pools of human plasma
which maximizes protection but increases the
chance that a unit of plasma contaminated
with an infectious agent will be included.
For clinicians to ensure that benefit to
an individual immunodeficient patient is
maximal, this life-long therapy must be as
safe as possible. Recently, immunoglobulin
products have been withdrawn and plasma
donors restricted in attempts to prevent
transmission of blood-borne agents. Such
measures have resulted in alarming shortages
of therapeutic immunoglobulin worldwide.
1
This balance must be redressed by a critical
look at the evidence regarding transmission
of the wide range of blood-borne diseases
potentially contaminating immunoglobulin for
replacement therapy. The safety of
replacement and high-dose therapies in
relation to infusion-related reactions is
not included here.
There are several methods by which
immunoglobulin preparations are produced
from human plasma and each product is
generically different. Although efficacy is
equivalent between these products, there are
important differences which impinge on their
long-term safety. Worldwide, there are
currently over 25 preparations of
immunoglobulin for use intravenously and
more than six preparations used
subcutaneously or intramuscularly. Almost
all are produced by initial processing of
pooled human plasma (from 1000 to 10 000
donors) by cold ethanol precipitation (Cohn–Oncley
procedure),
2
resulting in five plasma fractions. Cohn
fraction II provides a preparation
appropriate for intramuscular and
subcutaneous use and is the starting
material for purification of immunoglobulin
for intravenous use by a variety of methods.
Blood-borne agents have the potential to
contaminate immunoglobulin, and therefore
additional antiviral steps are used, before
or after the Cohn–Oncley procedure, to
reduce these risks. As the evidence for
viral transmission by immunoglobulin is
fragmentary, recommendations for a more
systemic method of data collection are made
so that real risk–benefit assessments for
immunodeficient patients can be ascertained.
The types of transmissable organisms are
discussed in order of their relevance to
safety of immunoglobulin (see
Table 1).
Although blood can be contaminated by
bacteria and protozoa, blood-borne viruses
are the major concern because bacteria and
protozoa are unlikely to survive the cold
ethanol precipitation procedure used to
produce immunoglobulin.
Hepatitis B virus was a major problem in
the 1970s but the development of appropriate
HBV screening assays has eliminated
transmission of HBV
3
in immunoglobulin, provided that standards
of production and quality assurance of
assays are maintained. In the last 15 years
there have been new concerns: human
immunodeficiency viruses (HIV) 1 and 2;
hepatitis C, with transmission via several
immunoglobulin preparations;
3
Creutzfeldt–Jakob disease (CJD); and, most
recently, variant CJD.
2.1 Human
immunodeficiency viruses 1 and 2
(HIV)
Retroviruses are inactivated by
the cold alcohol precipitation,
which is used universally in the
manufacture of immunoglobulin. This
fortuitous finding of reduced
infectivity, along with the
partitioning which takes place with
each fractionation step,
4,
5
probably explains why transmission
of HIV1 or 2 by immunoglobulin has
not been confirmed, despite
surveillance.
6
The ongoing screening of donor units
for HIV antibodies, combined with
donor questionnaires regarding risk
categories, remains essential.
2.2 Hepatitis C virus
(HCV)
HCV is a lipid-coated virus with
a viral core of approximately 33 nm.
It is present in high concentrations
early in the disease, prior to the
detection of HCV antibodies (the
‘window period’).
7
Contamination of donor blood is
therefore not always detected by the
antibody-based screening methods
used at present and HCV may be
present in the plasma pools from
which immunoglobulin is subsequently
purified.
Transmission of HCV by
immunoglobulin has been reported 10
times since 1984,
3
involving almost 4000 patients
worldwide although this may be an
underestimate. The new antiviral
measures of pasteurization,
nanofiltration or solvent detergent
treatment, added to the
manufacturing procedures recently,
reduce this risk because the lipid
nature of the virus coat makes it
susceptible to detergent treatment
and the size of the virus enables
removal by nanofiltration. Parallels
with factor 8 suggest that these
steps have reduced HCV transmission
in haemophiliac patients but only
continuing surveillance will show
whether these additional methods,
proven on surrogate lipid-coated
viruses, are equally effective for
immunoglobulin. Statutory
documentation of product and lot
numbers of immunoglobulin would
enable tracing of patients
retrospectively (as for HCV in blood
transfusion).
2.3 Creutzfeldt–Jakob
diseases (CJD)
Creutzfeldt–Jakob disease (CJD)
is one of the transmissible
spongiform encephalopathies (TSEs),
a group of degenerative brain
diseases that affect animals and
humans. TSE in animals includes
scrapie in sheep, bovine spongiform
encephalopathy (BSE) in cows and
kuru and CJD in humans.
Kuru was associated with
cannibalism and was transmitted
orally; how the presumed infective
particles moved from the site of
entry to the brain remains
speculative. It was transferred to
chimpanzees by intracerebral
injection of affected human brain,
but there was no evidence that kuru
was transmitted by blood.
CJD is a rare condition with an
incidence of 0.5–1 people per
million of population per year (
Table 2). There are three
well-recognized forms of CJD:
sporadic (spCJD), iatrogenic and
familial CJD. Patients with spCJD
are usually between the ages of 50
and 70 years, have a rapidly
progressive mental deterioration
with myoclonus and a typical EEG
pattern. There is a long preclinical
period but, once diagnosed, patients
die within a few months. Iatrogenic
CJD (< 1% of human cases) has
followed transplantation of cornea
or dura mater or injections of
pituitary growth hormone derived
from cadavers.
The prion protein is a normal,
protease-sensitive, component of
cells present in high concentration
in the normal central nervous system
and in many other organs including
lymphoid tissue. Little is know of
its physiological role. TSEs are
characterized by deposition within
the brain of an abnormal
protease-resistant form of the prion
protein. Inoculation of material
containing abnormal prion protein
into the brains of experimental
animals may result in the appearance
of the typical plaques of spongiform
degeneration.
Transmission, both accidental and
experimental, has been shown for
some prions. Most is known about the
agent of scrapie which has been
shown to be transmissible in rodents
from infected spleens (via
follicular dendritic cells and/or by
activated B cells), as well as from
brain, demonstrating extraneuronal
infection and a possible route of
transmission. For CJD, retrospective
studies of recipients of blood
transfusions from donors who later
died of spCJD have found no cases.
8
Case control studies have shown no
evidence of excess blood
transfusions in those with spCJD
9
and there has been no transmission
of spCJD following infusion of blood
to three monkeys over 16 years of
follow-up.
10 Autopsies on the brains
of haemophiliacs have found none of
the pathological signs of spCJD so
far: these studies are continuing in
view of the long incubation period
of spCJD.
11 Although there are, at
present, no data on the risk of
transmission of CJD by
immunoglobulin, these postmortem
studies should be extended to all
recipients of immunoglobulin
(antibody deficient and
immunocompetent) in order to provide
this important evidence. Early
referral to surveillance units of
immunoglobulin recipients who
develop unexplained neurological or
psychiatric symptoms, especially
those on long-term therapy for
immune deficiencies, is essential.
Concerns about these diseases
have resulted, in some countries, in
the recall of those batches of
immunoglobulin containing plasma
from a donor subsequently
developing, or at risk of
developing, CJD. In 1996/7, 15% of
all IVIg produced in the USA was
withdrawn as a result of such
recall. The risk should be compared
with the high risk to
immunodeficient patients without
replacement immunoglobulin, for whom
there is no alternative therapy. It
is important that regulators consult
immunodeficient patients'
representatives and their medical
advisers in order to assess the
risks to this particular group of
patients who require life-long
immunoglobulin treatment.
2.4 Variant CJD
The possibility of transmission
of BSE from cattle to humans by
consumption of beef was raised in
1986. The BSE epidemic in cows,
which rose to a peak in 1992 when
36 682 confirmed cases were
reported, is gradually coming under
control with only approximately 3100
confirmed cases in the UK in 1998;
there have been few reported cases
in other countries. A causal link
with variant CJD was raised by the
successful cerebral transmission of
BSE into macaque monkeys, resulting
in neuropathy similar to that in
patients with vCJD.
12 Variant CJD is distinct
from spCJD, with a different
clinical presentation (depression
and abnormal sensory symptoms), the
absence of the typical EEG and a
younger age at diagnosis. Conclusive
evidence that the agents for BSE and
vCJD were identical came from two
studies in 1997.
13,
14 Disease-specific prions
(PrP vCJD) have since
been detected in lymphocytes in
tonsil and appendix, raising concern
about transmissibility in blood or
blood products.
15,
16
In view of the theoretical risk
that circulating lymphoid cells
might transmit vCJD, the UK
Government decided not to use
UK-derived plasma for production of
plasma concentrates including
immunoglobulin, thus reducing the
availability of plasma for
manufacture of immunoglobulin.
However, numbers of cases of vCJD
have remained low over 3 years (
Table 2) and there is, as yet,
no evidence of human-to-human
transmission.
17 Six of the 40 vCJD
cases were known to have given blood
prior to the development of
symptoms; the plasma was used in the
production of albumin rather than
immunoglobulin and tracing has not
been informative so far. Postmortem
brain studies (as for spCJD) of
immunoglobulin recipients would
provide data to monitor any
transmission by immunoglobulin
therapy.
2.5 Viruses not relevant
to immunoglobulin
Hepatitis A virus (HAV) is
principally transmitted orally. It
is a small nonenveloped virus with
remarkable homogeneity; antibodies
directed against one strain are
protective against more than 90% of
other strains. However, HAV has been
transmitted in solvent
detergent-treated Factor VIII, and
immunoglobulin contains relatively
high levels of neutralizing
antibodies and has not been shown to
transmit hepatitis A; some
regulators still insist on a minimum
level of HAV antibodies for
intramuscular immunoglobulins.
Parvovirus B19, which causes a
mild self-limiting illness in
children but is also associated with
transient red cell aplasia, is a
small virus, resistant to heat and
detergent. Seroconversion has been
shown after dry and steam-treated
Factor VIII therapy, but high levels
of specific antibodies in
immunoglobulin (associated with
seropositivity in at least 50% of
adults) are presumed to neutralize
any persistent virus because normal
immunoglobulin preparations have
been used to ameliorate and to
resolve B19 parvovirus infections.
Hepatitis G virus (HGV) is a
newly discovered virus detected in
patients with acute or chronic
hepatitis, especially those with
HCV. However, in a study of HCV
antibody-negative liver transplant
recipients there was no difference
in the subsequent incidence of
hepatitis between those with and
those without HGV infection.
18 Reassurance that HGV is
not clinically relevant was shown by
a low prevalence of HGV RNA in
patients with end-stage liver
disease.
19,
20 A novel DNA virus,
transfusion transmitted virus (TTV),
which has a high incidence in blood
donors and patients with chronic
liver disease, also appears to have
no clear disease association.
21,
22
2.6 Unknown agents
Continued monitoring of the field
of emerging pathogens is required to
ensure safety against new viruses or
other agents. Storage of serum
specimens, pre-treatment and 1 month
later when commencing therapy or
changing immunoglobulin products, as
well as serially (e.g. every 6
months) for those on chronic
therapy, would enable detection of
new agents when assays become
available.
3.1 Choice of donors
The plasma donor population is
important; the choice depends on the
prevalences of the relevant
blood-borne diseases. Collection
from donors in countries where there
is a high prevalence of blood-borne
diseases is now avoided and data
from collection centres in the early
1990s showed low prevalence rates
for HIV, HBV and HCV.
23
In the early 1970s
transfusion-related hepatitis C was
less frequently associated with
volunteer blood compared with blood
from paid donors, leading to the
belief that blood was safer from
unpaid donors. The issue of relative
safety of plasma from volunteer (but
often compensated) donors vs. paid
donors has been revisited; there is
a higher incidence of blood-borne
infection markers in whole blood
donors (usually unpaid), due to a
higher level of HCV antibodies.
24
Frequency of donation has also
been controversial. Frequent
donations may have contributed to
HCV transmission by one specific lot
of immunoglobulin in the most recent
outbreak.
25 Donation frequency can
be limited in order to prevent
multiple collections of plasma
during a ‘window’ period.
Alternatively, donations can be held
in ‘quarantine’ for a few months
until the donor has been rechecked,
enabling contaminated donations to
be identified and destroyed. Studies
on the actual prevention of
transmission by quarantine is not
yet available although extrapolation
from serial testing and comparison
of first-time donors with all
donations
24 provide indirect
evidence for the success of such a
strategy. The use of previously
tested donors reduces the prevalence
of ‘positive markers’ and hence the
need to recall batches of
immunoglobulin retrospectively if a
donation is subsequently positive.
3.2 Accreditation of
blood collection centres and
manufacturing plants
In the late 1980s, concerns about
the standards of blood and plasma
collection led to rigorous
improvements, with obligatory good
manufacturing practice protocols and
quality assurance schemes.
Facilities for collection and
fractionation of plasma are
inspected and may be suspended if
the centre does not adhere to the
standards.
Failure of manufacturers to
comply with the strict application
of modern accrediting standards and
procedures, and the insistence of
regulators to repeat inspections
each time a change is made in the
processing of immunoglobulin, have
resulted in temporary closure of
manufacturing plants, contributing
to the worldwide shortages. For
example, these two factors probably
accounted for 60% of the
immunoglobulin shortages in the US
in 1998.
3.3 Individual
screening of donors and the donated
units of plasma
Questionnaires, designed to
screen out donors whose medical,
behavioural or travel histories
indicate an infection risk, are used
worldwide; questions relating to CJD
and vCJD are now included in the
questionnaire. The shortcomings of
this process were highlighted by the
finding that 1.7% of all donors were
prepared to report risk behaviour
only when asked anonymously.
24 This emphasizes the
need for in vitro screening of all
donated units of blood and plasma.
Antigen testing is probably the
screening method of choice for blood
donations because there have been no
cases of HBV transmission by
immunoglobulin since routine HBV
surface antigen screening was
introduced. There are currently no
specific antigen tests for HCV,
spCJD or vCJD, although assays are
being developed; HIV antigen
screening is now used by some blood
collection agencies.
The shortcomings of antibody
testing have been highlighted. The
sensitivity and specificity of the
assays are also important,
particularly as enzyme-linked
immunosorbent assays (ELISA) are the
standard method of detection.
Although the currently used ELISAs
for HIV1 and HIV2 have sensitivities
and specificities of > 99%, those
for HCV caused problems when plasma
screening for HCV antibodies was
first adopted. There were concerns
that removal of these antibodies
from plasma pools would compromise
the safety of immunoglobulin
26 but immunoglobulin made
from such plasma did not transmit
HCV to chimpanzees and therefore
regular screening was introduced,
with the first lots of IVIg
available in mid-1993. Initially, an
antibody screening assay using a
single recombinant antigen was used
which gave a high proportion of
false-negative results and a product
which apparently did not transmit
HCV.
27 The introduction of ‘an
improved test’ using several
antigens, with greater efficiency of
removal of HCV antibodies, was
followed by an outbreak of hepatitis
C in over 200 immunoglobulin
recipients in late 1993–1994.
Subsequent studies showed that
several lots of immunoglobulin had
high levels of HCV-RNA by polymerase
chain reaction (PCR).
28 It was surprising that
more than half the commercial
intramuscular immunoglobulin
preparations were also HCV-RNA
positive, despite the absence of HCV
transmission by this type of
immunoglobulin. PCR methods detect
viral nucleic acid during the
viraemic stage and could be used to
overcome the ‘window’ periods in HCV
and HIV. Some manufacturers are
PCR-testing smaller plasma pools (to
prevent loss of plasma if
contamination is demonstrated) but
HCV-PCR testing of the individual
donor units might be needed.
29 Evidence is lacking at
present and serial testing of donors
and quarantining of donations may
prove to be satisfactory.
4.1 Plasma
fractionation
Plasma fractionation relies on
the varying solubility of plasma
proteins according to pH,
temperature and alcohol
concentration. At each stage the
insoluble proteins are separated by
centrifugation and viruses can
contaminate each of the insoluble
precipitates. Reductions in the
viral load have been demonstrated by
serial partitioning, for both HCV
30 and HIV.
31 However, the role of
partitioning of viruses cannot be
taken in isolation; when antibodies
to HCV were removed following the
introduction of screening, the
amount of recoverable HCV-RNA in the
various Cohn fractions changed
dramatically as a result of the
virus no longer being complexed with
antibody.
28
4.2 Downstream
processing
Fraction II provides
immunoglobulin for replacement
therapy by the intramuscular or
subcutaneous routes and only
requires further purification if it
is to be used intravenously. A
number of different methods are
used, including ion exchange
chromatography, acid pH 4 with or
without additional enzymes or
polyethylene glycol precipitation.
It was discovered, again
retrospectively, that the process of
acidification, with or without
enzymes, has the added benefit of
inactivating HCV and its surrogate
virus, bovine vesicular diarrhoea
virus (BVDV).
32
4.3 Viral inactivation
methods
As Cohn–Oncley fractionation is
not sufficient to remove
lipid-coated viruses, additional
antiviral inactivation steps are
required. Heating (steam) is used
for immunoglobulin but the molecules
tend to aggregate at 60°C unless
stabilized. Solvent detergent steps
are increasingly popular.
33 Nanofiltration, with
pore sizes of 15 or 35 nm, appears
to offer a logical (although
technically difficult) method to
remove larger viruses but is
unlikely to remove nonfibrillar
prions. The regulators have issued
guidelines for validation of these
procedures, which include proof of
viral inactivation and relevance of
surrogate viruses.
Regulators and manufacturers have paid
insufficient attention to collecting safety
data by monitoring recipients of
immunoglobulin. Given the statutory
requirements for careful documentation of
the use of blood, the failure to insist on
monitoring of the use of soluble blood
products is extraordinary. This lack of
information makes tracing of transmission
extremely difficult; for example, in the
recent 1994 outbreak of hepatitis C, usage
of specific batches of immunoglobulin was
identified in only 70% of recipients in
Europe and 50% in the USA. In contrast,
where there were full data on batch usage,
prompt detection of transmitted infection
34
and early treatment with interferon alpha
were possible; early treatment was shown to
be more effective than treatment in the
chronic phase.
35,
36
Post-licensing monitoring by
manufacturers is obligatory; manufacturers
are required to keep aliquots of each batch
of immunoglobulin produced so that an
individual virus can be traced
retrospectively by genotyping. This allows
good epidemiological investigation, both
within a patient population and, more
importantly, to identify a contaminated
donor or an unsafe manufacturing process.
The concerns of regulators to ensure that
transmission of all blood-borne diseases be
kept to an absolute minimum is important but
the principle of precaution on which
decisions have been based worldwide has
caused severe shortages of immunoglobulin.
1
In order to balance the safety of
immunoglobulin replacement therapy against
the morbidity of immunodeficient patients
with inadequate replacement, there needs to
be greater consistency of worldwide
regulatory agencies, more involvement of
users (physicians and patients) and
collection of more data relating to precise
risk. Issues include the size of plasma
pools, methods of testing for blood-borne
agents, continuing research on possible
transmission of pathogens and refinement of
viral inactivation methods.
Another problem relating to availability
is the ever-widening list of indications for
immunoglobulin, particularly in high doses
in autoimmune conditions and Kawasaki
disease. The expected increase in demand is
20% per year although supplies are expected
to increase by only 10% pa. Purchasers of
healthcare (governmental and private) should
be encouraged to audit the use of this
scarce resource and every effort for
alternative products, including the
development of targeted therapies for
nonimmunodeficient patients, should be
sought. Removal of regulatory restraints to
the movement of plasma and its derivatives
around the world is essential if these
life-saving therapies are to continue to be
available to all the patients who need them.
1.Statutory documentation of the
name of the product and lot numbers used in
individual patients for traceability.
2.Required monitoring by
physicians, i.e. assays for detection of
antibodies to HCV (with HCV-PCR in antibody
deficiency patients) and liver function
tests in all recipients of immunoglobulin.
This should be done pretherapy and serially,
including 6 months after the last
immunoglobulin dose.
3.Storage of serum specimens,
pre-treatment and 1 month later when
commencing therapy or changing products, and
serially (e.g. every 6 months) for chronic
therapy, to enable retrospective detection
of any new agents.
4.Early referral to surveillance
units of recipients of immunoglobulin,
especially those on long-term, repeated
therapy, if they develop unexplained
neurological or psychiatric symptoms.
5.Consideration of establishing
programmes for registration of recipients
receiving repeated doses of immunoglobulin
for eventual postmortem brain examination.
6.Establishment of national or
regional registers of those individuals
infected by immunoglobulin.
7.Greater consistency of worldwide
regulatory agencies and the wider
involvement of users including
immunodeficient patients and their
physicians.
8.Encouragement of partnership
between manufacturers, patients'
representatives and prescribers to improve
consistency of information and data/evidence
relating to risk: benefit analysis for
gaining informed consent.
9.In view of the short supply of
immunoglobulin, encouragement for
development of alternative products,
including targeted therapies for
nonimmunodeficient patients.
10.Consideration of a common
policy for deferring previous blood/blood
components/blood products recipients from
future donation of blood for use in plasma
pools from which immunoglobulin is
processed.
We are grateful to the many individuals
who made suggestions or read through the
manuscript; in particular to Philip Minor,
Tim Wallington, Lennart Hammarstrom, Turf
Martin, Martin Lee and Ed Gomperts; also to
Mrs E. Henley who processed the paper many
times. The Primary Immunodeficiencies
Committee of the International Union of
Immunological Societies discussed and
approved the following list of
recommendations.
1
Milgrom H . Shortages of intravenous
immunoglobulin.
Ann
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81: 97
9.
2
Cohn EJ , Strong LE , Hughes WL
Preparation and properties of serum
and plasma proteins IV. A system for
the separation into fractions of the
protein and lipoprotein components
of biological tissues and fluids.
Ann Am
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68: 459
75.
3
Yap PL . Viral Safety of IVIg. In:
Intravenous Immunoglobulin in
Clinical Practice (eds Lee M, Strand
V) Marcel Dekker 1997 pp 67 106.
4
Mitra G , Wong MF , Mozen MM ,
McDougal FS , Levy JA . Elimination
of infectious retroviruses during
preparation of immunoglobulin.
Transfusion 1986;
26: 394
7.
5
Wells MA , Wittek AE , Epstein JS
Inactivation and partition of human
T cell lymphotrophic virus, type
III, during ethanol fractionation of
plasma.
Transfusion 1986;
26: 210
3.
6
Center for Disease Control. Safety
of therapeutic immunoglobulin presss
with respect to transmission of
human T lymphocyte virus type
I/lymphadenopathy associated virus
infection.
MMWR
1986; 35:
231 2.
7
Vrielink H , Vander Poel CL ,
Reesink HW , Zaaijer HC , Lelie PN .
Transmission of HCV by anti-HCV
negative blood transfusion.
Vox Sang
1995; 68:
55 6.
8
Heye N , Hensen S , Muller N . spCJD
in blood transfusion.
Lancet
1994; 343:
298 9.
9
Wientjens DPWM , Davimipour Z ,
Hofman A , Kando K , Matthews WB ,
Hill RG , Van Duij CM . Risk factors
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control studies.
Neurology 1996;
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10
Brown P , Gibbs CJ , Rodgers-Johnson
P Human spongioform encephalopathy:
the NIH series of 300 cases of
experimentally transmitted disease.
Ann
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44: 513
5.
11
Lee CA , Ironside JW , Bell JE ,
Giangrande P , Ludlam C , Esiri MM ,
McLaughlin JE . Retrospective
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disease in UK haemophiliac patients.
Thromb
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11.
12
Lasmezas CI , Deslys J , Demalmay R
BSE transmission to macaques
(letter).
Nature
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743 4.
13
Bunce ME , Hill RG , Ironside JW
Transmissions to mice indicate that
‘new variant’ CJD is caused by the
BSE agent.
Nature
1997; 389:
498 501.
14
Hill AF , Destruslais M , Joiner S ,
Sidle KC , Gowland I , Collinge J ,
Doey LJ . Lantos. The same prion
strain causes vCJD and BSE.
Nature
1997; 389:
448 50.
15
Hill AF , Zeidler M , Ironside J ,
Collinge J . Diagnosis of new
variant Creutzfeldt–Jakob disease by
tonsil biopsy.
Lancet
1997; 349
(9045):
99 100.
16
Hilton DA , Fathers E , Edwards P ,
Ironside J , Zajicek J . Prion
immunoreactivity in appendix before
the clinical onset of variant
Creutzfeldt–Jakob disease.
Lancet
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703 4.
17
Will RG , Cousens SN , Farrington CP
, Smith PG , Knight RSG , Ironside
JW . Deaths from variant
Creutzfeldt–Jakob disease.
Lancet
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979 80.
18
Hoofnagle JH , Lombardero M , Wei Y
Hepatitis G virus infection before
and after liver transplantation.
Liver
Transpl Surg 1997;
3: 578
85.
19
Alter HJ , Nakatasugi Y , Mea J The
incidence of transfusion associated
hepatitis G virus infection and its
relation to liver disease.
New Eng
J Med 1997;
336: 747
54.
20
Laskus T , Wang LF , Redknowski M
Hepatitis G virus infection in
American patients with cryptogenic
cirrhosis: no evidence for liver
replication.
J Infect
Dis 1997;
176:
1491 5.
21
Simmonds P , Davidson S , Lycett C
Detection of a novel DNA virus (TTV)
in blood donors and blood products.
Lancet
1998; 352:
191 5.
22
Naoumov NV , Petrova EP , Thomas MG
, Williams R . Presence of a newly
described human DNA virus (TTV) in
patients with liver disease.
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