EMERGING INFECTIOUS DISEASES
Lecture 13
Bovine Spongiform
Encephalopathy (BSE)
Objectives
§
Review the BSE epidemic
§
Investigate factors
contributing to BSE emergence
§
Discuss the appearance
of new variant Creutzfeldt-Jakob Disease
§
Highlight risk analysis
approaches to “managing” BSE
The BSE epidemic
§
First identified in 1986
§
Neurologic disease of
cattle - increased anxiety, startle easier, incoordination
§
Rapid spread throughout
UK
§
No historical evidence
of the disease
BSE epidemic in the UK
Current BSE statistics for UK
§
176,809 cases thru June 2, 2000
§
>4,325,000 cattle destroyed
BSE Basics
§
Common source, extended
epidemic
§
Feedborne, associated
with contaminated meat and bone meal
§
Long latency period, 4-5
years
§
Classified as a transmissible
spongiform encephalopathy
Transmissible Spongiform
Encephalopathies (TSE’s)
§ Bovine Spongiform
Encephalopathy (BSE)
§ Scrapie-Sheep and Goats
§ Transmissible Mink
Encephalopathy (TME)
§ Chronic Wasting Disease
(CWD)-mule deer and elk
§ Kuru
§ Creutzfeldt-Jakob Disease
(CJD)
§ (spontaneous, iatrogenic,
familial)
§ Gerstmann-Straussler
Schenker Syndrome (GSS)
§ Fatal Familial Insomnia
(FFI)
Similarities of all TSEs
§
Unconventional,
infectious agent
§
Progressive degeneration
of the brain
§
Neurological signs,
always fatal
§
No treatment
§
No immunological
response
§
Infectivity difficult to
inactivate
Transmission of TSEs vary
§
Oral transmission -
Kuru, TME, BSE, scrapie
§
Maternal transmission -
scrapie, BSE
§
Iatrogenic - CJD,
scrapie
§
Genetic predisposition -
scrapie, CJD, GSS
§
Spontaneous - CJD,
others?
Unique attributes of BSE
§
Primary means of spread
- contaminated animal feed
§
No genetic risk factors
to date
§
Limited tissue
distribution of infectivity detected to date
§
Not host specific
Potential Events Leading to a BSE-Positive
Cow
BSE:
Infectivity in bovine tissues
BSE maintenance in the UK
BSE emergence in the UK:
Two hypotheses
§
High sheep density and
scrapie incidence
§
Changes in rendering
process
§
Feeding of
animal-derived protein
ì Emergence of a new TSE strain
The ‘sporadic’ or
‘spontaneous’ BSE hypothesis
§
Proposed by Marsh to
explain transmissible mink encephalopathy
§
TME seen in mink eating
‘downer’ cows
§
‘Spontaneous’ BSE not
confirmed to date
§
Hypothesized to occur at
1/1,000,000 similar to spontaneous CJD
Expansion of the BSE epidemic
Movement
outside of the UK
Potential BSE cases
imported into some EU countries, 1985-1989
Imported
Expected Reported
Cattle Beef Dairy Cases*
Germany 6,343 30
334 6
Spain 2,769 6 74 0
Italy 1,421 6 68 2
Netherlands 1,434 5 62 0
Denmark 889 3 40 1
Benelux 572 2 24 0
* Cases occurring in imported cattle only
UK exports of
meat-and-bone meal (MBM)
Importation of
meat-and-bone meal into Switzerland from 1985 to 1989
Countries with BSE cases
in native cattle, as of Fall, 1998
UK
172,499
Ireland 314
Switzerland 281
Portugal 169
France 45
Belgium 7
Netherlands 3
Luxembourg 1
Lichtenstein 2
BSE Control
§
Identification and
destruction of BSE affected cattle
§
Import restrictions from
BSE affected countries (cattle and feed)
§
Feed bans - removing
ruminant-derived animal protein from ruminant feeds
§
Destruction of exposed
animals
Unresolved BSE issues
§
What is the pathogenesis
of BSE?
§
Does BSE infectivity
exist in further tissues?
§
How large is the cattle
to mouse species barrier?
§
Has BSE transmitted to
Sheep?
§
If so, will it be
maintained by sheep?
Recognition of BSE as a Zoonotic Disease
The
appearance of new variant
Creutzfeldt-Jakob
Disease in humans - 1995
New variant of Creutzfeldt-Jakob Disease
New variant differs from Classic CJD
§
Average age 26 yrs
compared to 65
§
Presenting signs
psychiatric rather than neurologic
§
Clinical course longer
(>12 months)
§
Neuropathology different
Evidence that new variant CJD is human BSE -
#1
Place and time Will et al., 1996
§
New human TSE observed
in UK and not seen in other countries*
§
Emergence of new human
TSE follows discovery of BSE 10 years earlier
* only 1 case seen outside
UK to date
Evidence that new variant CJD is human BSE -
# 2
Molecular analysis Collinge et al., 1996
§
Glycoform analysis
creates molecular “fingerprint”
§
Unique pattern for nvCJD
(type 4), different from other forms
CJD
§
nvCJD pattern similar to
that of mice and others inoculated with BSE
Evidence that new variant CJD is human BSE -
# 3
Bioassay in mice Bruce et al., 1997
§
Inoculation of 4 inbred
mice strains creates biological “fingerprint” of incubation times and lesion
profile
§
Bioassay of nvCJD different from other forms
of
CJD and scrapie
§
Bioassay of nvCJD same
as BSE and others inoculated with BSE
Potential sources of human exposure to BSE
§
Direct contact to
affected cattle - no cases in exposed humans to date
§
Contact with specific
products containing infected materials - no common exposure to date
§
Consumption of food
contaminated with infective cattle tissues - numerous candidates
Meat product concerns
for BSE contamination
Rib
roasts, T-bone ì dorsal root
ganglion (DRG)
Bone-in
meat ì bone marrow
Mechanically-
recovered meat ì spinal
cord, DRG
Head
meat ì brain leak,
trigeminal ganglia
Sausage
casing ì distal
ileum
Ground
meats ì brain,
spinal cord
CJD Statistics from UK (through Sept 30, 1998)
Unresolved nvCJD issues
§
How many cases will
occur?
§
What is the cattle to
human species barrier for BSE?
§
What is the pathogenesis
of nvCJD?
§
Is the tissue
distribution of infectivity the same for nvCVD as for CJD?
§
Can nvCJD be transmitted
iatrogenically?
Cattle derived products are ubiquitous in
pharmaceuticals
§
Tallow - the cooked fat
derived from the ‘rendering’ of animal waste
§
Gelatin - produced from
animal hides and bones
§
Blood, serum, tissue
infusions - for bacterial and viral
culture media
§
Calcium stearate, bone
charcoal, collagen - for a variety of products
Exclusion of TSE agents is challenging
§
No immune response of
the host
§
Live animal screening
tests are not available
§
Surveillance programs in
countries vary widely
§
Hypothesis of
‘spontaneous’ BSE haunts some...
BSE (and all TSEs) are difficult to
inactivate
§
TSE agents are highly
resistant to heat, UV light, ionizing radiation and common disinfectants
§
Inactivated by sodium
hypochlorite, sodium hydroxide, very high temperatures which denature proteins
End product use questions...
§
Can BSE be transmitted
to humans through animal-derived products?
§
What is the minimum
infectious dose of BSE (and nvCJD)?
§
To what degree does
route of administration affect transmission?
§
Is there an ‘acceptable’
risk?
Applying risk analysis to BSE: a systems approach
§
Inputs = raw materials
§
Processes = harvesting
and manufacturing
§
Outputs = end products
The underlying principles of risk analysis:
§
Every raw material,
process and use involves risks: risks
of infectivity, contamination, exposure and illness
§
Anything that can go wrong,
will go wrong at some point in time
§
Therefore, “zero risk”
is unachievable
The bright side of risk analysis:
§
Multiple safeguards
exist to reduce risks to an acceptable level
§
Supports decision making
in the absence of “perfect” data
§
Involvement of the potentially affected parties improves
the analysis
TSE risk analysis is different...
§
Combines aspects of
toxicologic and microbial risk assessments
§
In the host, the
transformation of PrP to the abnormal shape mimics microbial growth
§
However, from raw material
through the end product, handle like a toxin
TSE hazard identification
§
Hazard is BSE
§
Not all of the pathways
for BSE ‘contamination’ are clearly understood
§
Failure to identify
potential pathways will invalidate the risk analysis
Key factors in TSE risk
assessment: inputs (sourcing)
§
Origin of cattle
•
Country BSE status
•
Herd management
•
Individual animal handling
§
Tissue
•
category of infectivity
Confirmed Infectivity of
Bovine Tissues
§ INFECTIVITY FOUND IN STUDIES OF
CLINICAL BSE CASES:
•
Brain, Spinal Cord and
Eye (retina)
§ INFECTIVITY FOUND IN PATHOGENESIS
STUDIES (doses much higher than with infectivity studies):
•
Brain, Spinal Cord, Eye
(retina), Trigeminal Ganglia, Dorsal Root Ganglia, Distal Ileum and Bone Marrow
WHO Categories of
Infectivity in Bovine Tissues and Body Fluid
§
CATEGORY I: High
Infectivity
•
Brain, Spinal Cord and
(Eye)*
§
CATEGORY II: Medium
Infectivity
•
Spleen, Tonsil, Lymph
Nodes, Ileum, Proximal Colon, Cerebrospinal Fluid, Pituitary Gland, Adrenal
Gland, (Dura Mater, Pineal Gland, Placenta, Distal Colon)
WHO Categories of
Infectivity in Bovine Tissues and Body Fluid
§ CATEGORY III: Low Infectivity
•
Peripheral Nerves, Nasal
Mucosa, Thymus, Bone Marrow, Liver, Lung, Pancreas
§ CATEGORY IV: No Detectable
Infectivity
•
Skeletal muscle, Heart,
Mammary Gland, Milk, Blood Clot, Serum, Feces, Kidney, Thyroid, Salivary Gland,
Saliva, Ovary, Uterus, Testis, Seminal Testis, Fetal Tissue, (Colostrum, Bile,
Bone, Cartilaginous Tissue, Connective Tissue, Hair, Skin, Urine)
Key factors in TSE risk assessment:
Processing
§
Tissue harvesting is a
critical process - contamination concern
§
Manufacturing may
incorporate TSE partitioning, inactivation, dilution
§
Validation of the
process is a critical component
Key factors in TSE risk assessment: End
product use
§
Exposure dose - how much
TSE agent per dose
§
Age of patient at
treatment
§
Number of doses to be
expected
§
Duration of exposure -
length of treatment
§
Route of exposure - ic,
iv, ip, po, etc
Ideal TSE risk assessment
§
Know the amount of TSE
infectivity in the raw materials
§
Know the degree to which
the infectivity is inactivated
§
Know how much
infectivity is incorporated into each dose
§
Know the use pattern of
the product
§
Know the susceptibility
of humans
Conclusions
§
BSE represents a new
cattle disease, widely disseminated but coming under control
§
Mounting evidence that
BSE causes new variant CJD
§
Numerous sources of
potential human exposure to both BSE and nvCJD
Conclusions
§
Risk analysis provides a
tool to manage BSE and nvCJD risk
§
Risk analysis is a
systematic consideration of raw materials sourcing, process and end product use
§
Acceptable risk
ultimately will be decided by the consumer...
No
Sample Questions Accompany this Lecture.