NIAID Workshop
Development of Guillain Barre Syndrome
Following Campylobacter Infection
Natcher Conference Center, NIH
Bethesda, MD, USA
August 26-27, 1996
Guillain Barre Syndrome
(GBS) is a rare disorder, afflicting about 1
person in 100,000. Yet, since the decline in the
number of polio cases, it represents the most
common cause of acute neuromuscular paralysis. It
is more common in Japan and China than in North
America or Europe and it affects both sexes of
any age. Symptoms range from weakness and
tingling sensations in the legs to spread to the
arms and upper body. While most patients recover
with no, or minor, long term effects, total
paralysis and the need for ventilatory assist and
death can result.
In about two-thirds of
cases, GBS is preceded a few days or weeks by a
mild respiratory or intestinal infection. The
organism most commonly proven to be associated
with the development of GBS is Campylobacter
jejuni. C. jejuni has become the
leading cause of gastroenteritis in the developed
world and is often acquired by ingestion of
infected poultry products. GBS is thought to
arise as a result of the production of antibody
to bacterial sugar-containing surface antigen(s)
that, due to molecular mimicry, cross-react with
the myelin sheath and the axons of nerve cells.
The ganglioside GM1 on nerve fibers seems to be a
target for these antibodies, although other
gangliosides may also be involved. Antibody
and/or cell mediated immune reactions are
believed to produce degeneration of the nerve or
interruption of neurotransmission.
The purpose of this
workshop was to explore the relationship between
C. jejuni infection and the development of
GBS. Scientists studying this problem from around
the world were invited to present their latest
data. Represented were the disciplines of
microbiology, neurology, cell biology,
immunology, and genetics. Topics for discussion
included: the identification of the surface
antigens of C.jejuni linked to GBS, the
pathology of GBS, the identification of the
target molecules on nerves attacked by
anti-bacterial antibodies, animal models for GBS,
possible interventions to prevent the develoment
of GBS or its serious sequelae, and the
implications of these findings on the development
of a vaccine against C. jejuni.
Additional support for this
meeting was provided by the National Vaccine
Program Office (NVPO), theNational Institute for
Neurological Diseases and Stroke (NINDS), the
Food and Drug Administration (FDA), and the
Department of Defense (DOD).
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Workshop
Conclusions and Recommendations
CONCLUSIONS
- With the decrease in
polio, GBS has become the leading cause
of acute flaccid paralysis in the world.
- GBS can probably
result following a number of bacterial
and viral infections. Campylobacter
jejuni induced diarrheal disease is
most often recognized as the precedent
infection.
- The epidemiology of Campylobacter
associated with GBS is complex and not
well understood. The specific reservoirs
for GBS-related strains are not known.
There appears to be seasonality of
infection (summer) in some countries but
no seasonality of GBS. The patterns of
association seem to be different in
different parts of the world, as does the
age of individuals developing GBS.
- There is an
association of GBS with C. jejuni
O serotypes 19 and 41. The strongest
association has been with O19. For
example, in the U.S., the risk of
developing GBS following C. jejuni
infection has been estimated as 1 in
1058, but as 1 in 158 following infection
with C. jejuni O19.
- The structure of LPS
is complex and unique in Campylobacter.
These unique structures are evident in O
side chains and core oligosaccharides.
Often, portions of these structures
resemble mammalian tissue gangliosides
(molecular mimicry) and suggest a
mechanism of immune damage to nerve
fibers.
- The Department of
Defense has developed, and is testing, a
formalin-inactivated, whole cell, Campylobacter
jejuni vaccine candidate. It is
designated strain 81-176 and is a Lior
type 5 (heat labile antigen based typing
system) and O type 23/36.
- A significant amount
of antibiotic resistance has been
developing among the Campylobacter.
This could lead to an increasing problem
in treatment of human disease.
- The development of GBS
is rare in children less than 2 years of
age despite their susceptibility to Campylobacter.
This may indicate that some maturation of
the immune system is needed for GBS to
manifest itself.
- The medical costs
associated with Campylobacter
induced GBS has been estimated by the
USDA to be between $57 and $425 million
per year in the U.S. Total costs, which
include days of lost productivity, are
estimated to be between $247 million and
$1.8 billion per year.
- There is need for
better standardized case definitions of
acute motor axonal neuropathy (AMAN),
acute motor-sensory neuropathy (AMSAN),
acute inflammatory demyelinating
polyneuropathy (AIDP), and Miller Fisher
Syndrome (MFS) which are based on
clinical, electrophysiologic,
immunologic, and molecular data.
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RECOMMENDATIONS
- The CDC surveillance
for emerging diarrheal diseases should
include C. jejuni, and C.
upsaliensis in their plans. This
would provide a better estimate of Campylobacter
infection rates in this country.
- GBS (or more broadly
defined acute flaccid paralysis cases)
should be reportable by state health
departments to the CDC. Current estimates
are on the order of 1-4 cases of GBS per
100,000 population per year in the U.S.
When combined with increased surveillance
for Campylobacter, a much better
picture of the epidemiology of the
organism and its association with GBS
should become apparent.
- Surveillance for GBS
in targeted populations seems warranted,
particularly in China (efforts are
underway) where an increase in GBS is
seen in the summer months and is
associated with rural residence, and in
Latin America (not underway) where cases
of acute flaccid paralysis has not
declined despite the tremendous decrease
in polio cases.
- Studies should proceed
on HLA typing of clinically well defined
cases and controls in order to determine
if there is a genetic component to host
susceptibility to GBS.
- Standardized
microbiological laboratory procedures are
needed to insure isolation of Campylobacter
strains associated with GBS. In
particular C. jejuni, and C.
upsaliensis should be looked for. The
concept of viable but non-culturable Campylobacter
should be examined.
- Serologic assays for
diagnosis of C. jejuni infections
need to be standardized and validated.
- A diagnostic test
specific for various Campylobacter
species is needed. It is likely that a
large number of Campylobacter
infections go unrecognized.
- An animal model for Campylobacter
enteritis with ensuing GBS is urgently
needed. A recently described ferret model
for Campylobacter-induced
enteritis may be useful. Mouse, rat,
primate, chicken, and rabbit models for
immune neuropathies are being examined
and show promise but need to be developed
further, perhaps by examining
pathogen-free animals. The development of
transgenic mice should also be
considered.
- There should be a Campylobacter
strain bank established in which
bacterial strains isolated from patients
who develop Guillain Barre Syndrome (or
variants) can be deposited. These strains
should be available to researchers in the
field. There is a role that NIAID could
play in the storage and distribution of
strains from the NIAID repository.
- There is a need for
standardized reagents, particularly
monoclonal antibodies, that can be used
to identify bacterial epitopes and which
can be tested for their ability to react
with different neural
"targets". Well characterized
reagents could also be distributed to
researchers from an NIAID repository.
- A more complete LPS
typing system that will include more of
the strains now classified as
"un-typeable" is needed. LPS
typing should be complemented with a
molecular typing system based on DNA
restriction length polymorphisms (RFLP),
rRNA gene polymorphisms (ribotyping), or
by polymorphism of other genes.
- Continuing effort is
warranted to determine the LPS structures
associated with the development of GBS.
Identification of specific epitopes would
be helpful. Since sialylated
polysaccharides are suspect, a probe to
detect the presence of sialyl transferase
may be helpful in identifying
GBS-associated strains.
- The mechanism of
immune mediated nerve damage is poorly
understood. The nature of the initial
antigen-antibody reaction(s) which leads
to damaging immune reactions which may
involve cell mediated immunity,
complement fixation, cytokine production,
lymphocyte and macrophage infiltration,
and breech of the blood-nerve barrier
need to be better defined. Why
gangliosides on nerves are particularly
targeted or sensitive when compared to
the same molecules found on other tissues
is not known.
- Studies should be done
to try to understand the variations noted
in seasonality, or lack thereof, of GBS,
and of the basis for the differences
noted in the serotypes of C. jejuni
that have been associated with the onset
of GBS in different studies and in
different regions of the world.
- The mechanism of
intravenous immunoglobulin (IVIG)
amelioration of GBS symptoms is not
known. More research is needed with the
aim of developing improved therapies.
- A mechanism to share
preliminary information among scientists
studying Campylobacter and/or
associated GBS would be helpful in
keeping this world-wide research
community in contact. The ability to send
such information to an Internet address,
for example, that would be widely
accessible was discussed. Posting of
interesting new observations,
information, or questions would
facilitate research efforts by all
involved. Information on DNA sequences,
availability of new strains or reagents,
new techniques, reservoirs of infection,
structures of LPS or proteins, new typing
methods, antibiotic resistance patterns,
frequency of isolation of particular
serotypes associated with GBS,
epidemiology, etc. could be included in
such an exchange.
NIAID, a
component of the National Institutes of
Health, supports research on AIDS,
tuberculosis and other infectious diseases as
well as allergies and immunology.
Prepared by:
Office of Communication and Public Liaisons
National Institute of Allergy and Infectious
Diseases
National Institutes of Health
Bethesda, MD 20892
Public Health
Service
U.S. Department of Health and Human Services
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