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Pathogens in the Twilight Zone: Update on emerging disease issues with implications for the pork industry - Dr. Peter Davies, University of Minnesota, from the 2011 The Allen D. Leman Swine Conference, September 17-20, 2011, St Paul, MN, USA.
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Peter Davies BVSc, PhDUniversity of Minnesota
PATHOGENS in
2
Emerging diseases in intensive livestock production
Media Shoot first – ask questions later (maybe)
Blogosphere Just shoot and ask no questions Move on to next ‘crisis’
Guilty until proven innocent Habitual overstatement of public health
risks
3
Diseases in the twilight zone
BSE Model prediction up to 50,000 human deaths
from variant CJD Lower limit of 5,000 Global tally after 15 years is around 200.
H5N1 avian influenza Guesstimates up to 150 million circulated 564 Laboratory confirmed cases (August 9, 2011) 330 fatalities.
4
Discovery vs. emergence
Conventional microbiology reveals the tip of the iceberg
Today have very powerful diagnostic tools Closely related hosts (mammals,
homeotherms) likely to be colonized by ‘closely related’ organisms
Discovery involves much uncertainty Interspecies transmission Virulence in various species
5
Diseases in the twilight zone
Influenza viruses MRSA Clostridium difficile Noroviruses Sapoviruses Intestinal spirochetes ….
Recent Emerging Disease Issues in Swine
What Where When* Swine Health* Human Health*
Media hype*
Clostridium difficile (pigs) Global 1986 +/- ++(?) ++
PRRS Global 1987 +++++ - -
Salmonella typhimurium DT104 Global 1993 +/- ++ ++++
PCV2 Global 1996 +++++ - -
Hepatitis E infection USA/global 1995 - +/- +/-
Menangle virus Australia 1997 + +/- -
Nipah virus Malaysia 1998 ++ ++ ++
Bungowannah virus Australia 2003 + - -
MRSA ST398 EU/global 2004 - +/- +++++
virulent Streptococcus suis type 2 China 2005 ? ++ ++
H1N1 pandemic influenza Global 2009 + ++++(?) +++++
Recent Emerging Disease Issues in Swine
What Where When* Swine Health* Human Health*
Media hype*
Clostridium difficile (pigs) Global 1986 +/- ++(?) ++
PRRS Global 1987 +++++ - -
Salmonella typhimurium DT104 Global 1993 +/- ++ ++++
PCV2 Global 1996 +++++ - -
Hepatitis E infection USA/global 1995 - +/- +/-
Menangle virus Australia 1997 + +/- -
Nipah virus Malaysia 1998 ++ ++ ++
Bungowannah virus Australia 2003 + - -
MRSA ST398 EU/global 2004 - +/- +++++
virulent Streptococcus suis type 2 China 2005 ? ++ ++
H1N1 pandemic influenza Global 2009 + ++++(?) +++++
S. aureus and C. difficile
Common commensals found in healthy people and animals
Opportunistic pathogens increasing in incidence and clinical severity
Recognized human pathogens long before animal reservoirs thought of epidemiological significance.
Important nosocomial agents - hospital infections principal concern
Community acquired infections more important in recent years.
Animal colonization raises risk of livestock as sources of community acquired infections.
Both isolated from pork
9
MRSA in animals – publication rate
0
2
4
6
8
10
12
70s 80s 90-95
96 97 98 99 00 01 02 03 04 05 06 07
Years
Cattle
Cat, Dog
Horse
Pig, Sheep
2010: > 50 papers
PFGE with the SmaI enzymeSoge et al. J. Antimicrob. Chemother. 2009;64:1148-1155
MRSA isolated from US West Coast public marine beaches
11
Holland – an issue emerges!
Very low MRSA prevalence ‘Search and destroy’ policy Intensive screening and typing with sma1 PFGE
2004: 6mo girl screened before for surgery for a congenital heart defect
MRSA isolate not typable with Sma1 PFGE
2 other screening isolates not typable by Sma1 PFGE All 3 ‘cases’ epidemiologically linked to pigs
Studies of MRSA prevalence in pigs, farmers and pork
12
S. aureus subtyping
PFGE
MLST
SCCmec typing (I – VIII)
Spa typing Ridom
egenomics
‘Livestock associated’
Sma1 Untypable
ST398 (CC398)
III, IV, V
t034, t011, t108……...
539, ………………..…..
13
National survey of slaughter pigs in Holland 39% of 540 pigs positive (nasal swabs) 44 of 54 (81%) of farms positive
All isolates a ‘single clonal group’ Nontypable (NT) by sma1 PFGE MLST: ST 398 3 closely related spa types predominant (t011, t108, t1254,
…)
Panton-Valentine Leucocidin (PVL) toxin negative Uniformly resistant to tetracycline
Use of tetracyclines may be selecting for MRSA?
MRSA in market hogs (de Neeling et al, 2006)
14
Colonization of farm workers
ST398 also isolated from pig farmers (Voss et al 2005) 23% of farmers positive on nasal swab 760x general population prevalence
Dutch health authorities changed MRSA screening procedures People exposed to pigs and calves considered high
risk Isolated and screened before hospital admission
ST398 MRSA isolated from pork (van Loo et al., 2007)
EFSA farm prevalence study (dust samples)
*
MRSA spa types in swine barn dust (EFSA, 2010)
Predominant in North America
17
ST398 MRSANot just a pig problem!
Pigs – widespread (but not China, UK, Ireland, Japan)
ST9
Calves – Holland Horses – Austria, Belgium, France, Germany,
Holland, Canada Chickens – Belgium Dogs – Austria, Canada Lack of host specifity may indicate zoonotic risk!
18
MRSA in pigs in Ontario (Khanna et al, 2007)
Convenience sample of 20 Ontario herds 25% (71/285) of pigs positive 20% (5 of 25) farmers positive
Predominant (75%) spa types similar to ST398 Dutch isolates Spa type t034 predominant
19
Livestock associated MRSA in USA
Two farms in Iowa (Smith 2007)
One positive – 70% of pigs (ST398)
Slaughter pigs (Davies et al, 2009)
539 pigs from 45 farms 25% of pigs MRSA positive Diverse spa types - t034 predominant
20
Prevalence and characterization of MRSA in pigs and farm workers on conventional and antibiotic free swine farms in the USA
Collaborative Study – National Pork Board 54 farms across 3 centers (MN, IA-IL, OH_NC) 18 farms per state
9 conventional, 9 antibiotic free 24 pigs per farm; any human volunteers
Difficulties in finding farms 45 farms enrolled (24 conv., 21 ABF) 1084 pigs; 154 people
21
MRSA on conventional and ABF swine farms
MRSA detected in pigs on 4 farms All 4 conventional farms in IA-IL All pigs negative in ABF farms
45 (4.2%) of 1084 pigs positive 29 (18.8%) of 154 people positive
24 of 40 (60%) people positive on two farms with highest pig prevalence
MRSA on conventional and ABF swine farms
32 spa type 539/t0342 spa type 2/NT2 other ‘LA’ (t011; t571
23
MRSA in farm workers on conventional and ABF swine farms
17 spa type 539/t0345 spa type 2/NT1 other
Not LA type 539/t034
24
MSSA isolates in MN
98 isolates of MSSA characterized in MN 92 from pigs, 6 from people Pig samples clustered on 4 farms (3 conv., 1
ABF) 65 (71%) of pigs isolates were spa type
539/t034 1 isolate from human
25
Summary
MRSA detected in market hogs and occupationally exposed people
Spa type 539/t034 predominant Spa type 2/tunknown also detected in all studies
Similar to Canada
Lack of knowledge of S. aureus epidemiology in pigs Spa type 539/t034 in MN
26
Exposure assessment – ST398
High risk of exposure in groups with direct livestock contact Major concerns about occupational risk Some exposure risk to direct family members
Currently no indication of significant community exposure
27
Risk assessment
Consequences of occupational exposure Colonization vs. Infection
What is the burden of disease? Virulence Transmission
Diversity within ST398 lineage Animal vs. human isolates
28
Questions?
29
Current and future studies
Epidemiology of S. aureus in multiple site pig farms (NPB)
MRSA colonization and infection in swine veterinarians (NIOSH) 70 ‘volunteers’ Study duration of colonization over 18 months Prospective study of infection risk
30
Occupational exposure
Consistent observations that people with occupational exposure to animal species more likely to be colonized with MRSA As yet minimal data indicating increased risk of
infection Interspecies transmission of S. aureus
Frequency, Quantity, Duration Burden of disease
Primarily occupational?
31
Burden of disease from ST398 MRSA
Many reports don’t distinguish infection from colonization
Small number of serious infections Retrospective study of human isolates in
Canada 5 ST398 out of 3,687 (4 skin/soft tissue infections)
CDC has examined >12,000 isolates ST398 had not identified in a human clinical case
Current evidence suggests low pathogenicity?
05
1015202530354045
Holland
Denmark
Ger
man
y
Austri
aChina
Belgiu
m
Canada
Hong K
ong
Scotla
ndIta
ly
Sweden
Spain
Clinical cases = 122
Invasive = 27
32
Lethal pneumonia caused by an ST398 S. aureus strain Rasigade et al (2010)
Observations Fatal necrotizing pneumonia in a previously healthy 14yo
girl ST 398 - spa type t571 PVL positive Tetracycline susceptible Methicillin susceptible (MSSA) No livestock contact
Inference “spread of S. aureus ST398 among livestock is a matter of
increasing concern because strains of this sequence type were able to acquire PVL genes”
33
No pigsNo MRSA
34
“One Health” means more than one
inference
‘.. concern because strains ST398 strains were able to acquire PVL genes’
But…. Livestock strains almost uniformly tetracycline
resistant and PVL negative Spa type t571 uncommon in animal isolates
Could adaptation of ST398 to livestock hosts include loss of human virulence factors
35
The rest of the story
Davies et al, EID June 2011
t571 ST398 MSSA detected in 9 families from the Dominican Republic living in Manhattan
with no apparent contact with livestock (Bhat et al., 2007)
t571 the sole MSSA spa type in Dutch study of ST398 clinical isolates, including 3 independent cases of nosocomial bacteremia
with no apparent livestock contact (van Belkum et al., 2008)
t571 the predominant (11%) MSSA type at a Beijing hospital
Livestock contact unlikely (Chen et al 2010)
36
Emergence of unusual bloodstream infections associated with pig-borne-like Staphylococcus aureus ST398 in France. (van de Marquet et al., 2011)
Study of t571 MSSA strains from cases of bloodstream infections in France
The 30 isolates differed from pig-borne strains Isolates shared similarities with strains from
humans in China and virulent USA300 strains
37
Understanding LA-MRSA is embryonic Naïve perceptions of complex epidemiology
All MRSA found in livestock are ST398 Livestock are the only reservoirs of ST398
ST398 isolates of diverse genotype and geographic origin may also be epidemiologically distinct
Requires systematic investigation of S. aureus epidemiology in animals and humans.
The rest of the story……
38
Community dissemination of MRSA ST398 Cuny et al (2009)
Study of German farming community where MRSA ST398 prevalent on pig farms
Nasal swabs from Pig farmers and family members Swine vets and family members 462 pupils (10 to 16 yo) in villages in the high
density pig farming area
39
Nasal colonization with ST 398 Cuny et al (2009)
Group N Pct Pos
Pig farmers 113 86%
Farmer family members
116 4.3%
Swine Veterinarians 18 45%
Vet family members 44 9%
Schoolchildren* 462 0.007% (3)
*All 3 positive children lived on pig farms
Prevalence Ratio= 20
Prevalence Ratio= 5
40
Communities in pig dense areas in Holland (van Cleef 2010)
Mailing in 3 selected municipalities in the Netherlands where livestock MRSA prevalent
Adults complete questionnaire and nose swab (n = 583)
One of 534 persons without livestock-contact positive (0.2%)
13 of 49 of farm residents/workers positive (26.5%) Conclusions:
High prevalence of livestock-associated MRSA in people with direct contact with farm animals.
Not spread into the wider community
41
Exposure assessment – ST398
High risk of exposure in groups with direct livestock contact Major concerns about occupational risk Some exposure risk to direct family members
Currently no indication of significant community exposure
42
Risk assessment
Consequences of occupational exposure Colonization vs. Infection
What is the burden of disease? Virulence Transmission
43
Transmission of ST398 MRSA among people
Studies of transmission in Dutch hospitals (Bootsma, 2010)
ST398 is 5.9 times less transmissible than non-ST398 MRSA in Dutch hospitals’
‘Spreading capacity per admission insufficient to lead to an epidemic’
‘Nosocomial transmission of ST398 MRSA is 72% less likely than non-ST398 MRSA strains’
Wassenberg (2011)
44
Distribution of LA MRSA and other MRSA clinical isolates in Europe (van Cleef et al., 2011)
45
Diversity of genome of human and LA ST398 MRSA strains (Hallin et al., 2011)
‘LA-MRSA strains represent a homogenous lineage distinct from co-local HA- and CA-MRSA strains characterized by a lack of human-associated
virulence and adhesion determinants Absence of detectable enterotoxin gene
among ST398 LA-MRSA strains from a wide host range is reassuring regarding their foodborne pathogenic potential.’
46
Duration of colonization
Research workers (short term exposure) van Cleef et al (2011)
33 of 199 exposures led to positive culture on farm Only 3 of 33 retested positive after 24 hours
Evidence suggests most short term exposure leads to short term ‘colonization’
Veal farmers in Holland Graveland et al (2011)
Rapid decline in prevalence during absence of animal contact LA-MRSA poor persistent colonizers in most humans.