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Public Health Concerns of Mice & Rats
Robbin Lindsay
Zoonotic Diseases and Special Pathogens,
National Microbiology Laboratories,
Public Health Agency of Canada,
Canadian Public Health Inspectors Meeting,
Winnipeg, Manitoba
September 16, 2011
Importance of Rodents
•Economic impact Damage to food and feed consumption
Structural damage
Other damage related to chewing/digging
•Impact on human health Stress/anxiety associated with infestation/disease potential
Direct injury from encounters (scratches or bites)
Allergic reactions to rodent by-products
Transmission of disease-causing pathogens
Pathogens transmitted by rodents
• Flea-borne infections Plague
Murine typhus (endemic)
• Louse-borne infections Epidemic typhus (R. prowazekii)
• Transmitted in excreta Cestode infections (Hymenolepiasis, Echnicoccus)
Nematode infections (Trichinosis)
Rat-bite fever (Streptobacillus moniliformis)
Salmonellosis
Toxoplasmosis
Tularemia **
Leptospirosis
Arenavirus (LCMV)
Hantaviruses (Sin Nombre virus)
Plague
Causative agent – Yersinia pestis
Member of family Enterobacteriaceae (11 species, 3 known human pathogens)
Gram negative bacteria, nonmotile, non-spore forming coccobacillus
Plague
Disease in USA typically occurs in May to September
Three primary forms of disease: bubonic*, septicemic* & pneumonic
Average case fatality rates about 14% (failure to seek early treatment)
Plague in Canada
1988 detection of plague in two dead bushy-tailed woodrats in BC,
only confirmed case of disease in wild animal
Human cases sporadic but last reported case in 1937 sparked large
surveys in BC, Alberta, & SK [1938, 1943 (RCMC) and 1948]:
Y. pestis in 6 of 817 ground squirrel tissues &
in 32 of 939 pools of fleas (SE AB)
in 2 of 61 pools of fleas from GS in SK
Serosurvey of rural dogs and cats conducted in 1995 in AB and SK
confirmed endemicity of plague [Over 4 sites in 2 provinces, 9.6% of
240 dogs and 5.4% of 242 cats with antibodies to Y. pestis]
Reasons for the rarity of human infections in Canada compared to
USA are unknown but may be linked to limited distribution of
Cynomys species (which have low resistance/high mortality) in
Canada
Plague “rediscovered” in Canada
Sask Disease Control Laboratory submitted samples from a dead prairie dog found in
Grasslands National Park to NML in early August, 2010
Isolates of Y. pestis obtained from prairie dog liver (Emerging Bacterial Diseases: NML)
Reconfirms endemicity of plague in Western Canada, minimal public health significance but
may be of concern for re-introduction of black-footed ferrets
Francisella tularensis
Tularemia: The Organism • Francisella tularensis
– small, pleomorphic, non-spore-forming, nonmotile
coccobacillus, Gram-negative
– obligate intracellular pathogen
• Macrophages
– 4 subspecies F. tularensis most in northern hemisphere
• F. tularensis tularensis (Type A; NA only, more virulent)
• F. tularensis holarctica (Type B; Old & New World, less virulent)
Ecology
• Host range
– Documented in 190 mammalian, 23 avian, 3 amphibian and 88 invertebrate species
– Primarily a disease of lagomorphs (rabbits & hares) and rodents
– In North America, most important species are:
cottontails (Sylvilagus spp.), blacktailed jack rabbits and snowshoe hare (Lepus spp.), beavers & muskrats
Key reservoirs varies by geographic locality & local ecological factors, transmission dynamics complex & poorly defined
Modes of Transmission: animals
• Vector-borne
– Ticks
• Transstadial transmission but not transovarial transmission
• 14 species in NA (different spp. in old world)
– Dermacentor andersoni *
– Dermacentor variabilis *
– Amblyomma americanum
– Haemaphysalis leporispalustris*, H. chordelis*, Ixodes dentatus
* Widespread in Canada
– Fleas, tabanid flies (mainly deer flies in Chrysops e.g., Chrysops discalis)
• Mosquito infrequent in NA but not old world
• Others: ingestion, infective bites or scratches, ingestion or direct inoculation with contaminated sources (soil, water, vegetation)
Transmission to people
• Humans can become infected by: • handling, skinning, eating or being scratched or bitten (rare) by an
infected vertebrate
• Drinking contaminated water, making skin contact with contaminated water or mud
• inhalation of infected aerosols (many potential sources: hay, grain, soil, water?)
• handling (present in tick feces) or being bitten by infected arthropods
• working with this agent prior to the development and widespread use of biological safety cabinets/laminar flow hoods
– No person to person transmission documented
Disease in humans
• Incubation
– 3-15 days
– Varies with virulence of strain
and dose
• Typical symptoms:
– Sudden fever
– Chills
– Headache
– Myalgia
• 6 clinical syndromes
– Ulceroglandular
– Glandular
– Oculoglandular
– Oropharyngeal
– Typhoidal
– Pulmonary
• Morbidity & Mortality
– depends on strain and route of inoculation [e.g., Type A, aerosol (untreated): 30-60%]
– historically 5 –15% case-fatality rates (type A), currently reported <2% and Type B rarely fatal.
Tularemia cases in Canada
Rarely reported disease in Canada Nationwide (1940 to 1981) – 289 reported cases (12 deaths)
Sporadic cases & small number of cases more recently
e.g., MB (1994-2004) 6 cases
BC (up to 1997) 3 cases
QC (1975-2001) 26 cases
Some with obvious occupational exposure (trappers)
Unique cases of tularemia
• Martha‟s Vineyard – “Dog-borne” tularemia (shaking off water in a crowded cabin)
– “Lawnmower tularemia” (aerosolizing F. tularensis during landscaping or clearing of bush)
• Tularemia in zoological parks – Non-human primates (& handlers) in Assiniboine Park Zoo, Winnipeg, MB
– Similar outbreak in Zoological Park in Colorado
• Pet associated-tularemia – transmission of tularemia among wild-caught Prairie dogs (at pet exotic pet
distributor) to humans
– tularemia associated with the bite of a pet hamster
– recent outbreaks in hamsters/gerbils in MB pet breeder (feral rodents)
– widespread epizootic in deer mice in SK
Leptospirosis: The pathogen
Most widely distributed zoonosis in the world • Gram-negative, obligate aerobes
• Pathogenic & saprophytic strains
• Infect various animals shed in urine, persist in fresh water,
damp soil, mud and vegetation
• Taxonomically “unsettled group”, prior to 1989,
Leptospira interrogans (patho) & L. biflexa (sapro)
About 200 & 60 serovars, respectively, identified for each,
• Molecular differentiation on-going (16 genomospecies)
Leptospirosis: Modes of transmission
Maintain in nature: • Chronic infection (renal tubules) of selected hosts
• Common maintenance hosts include: rodents (rats, mice, voles)
• Select serovars associated with certain hosts (not absolute)
Rats (icterohaemorrhagiae, ballum)
Mice (ballum)
Cattle (hardjo, pomona, grippotyphosa)
Pigs (pomona, bratislava, tarassovi)
Sheep (hardjo, pomona)
Dogs (canicola)
• Incidental hosts infected by direct or indirect contact
• Human exposed via contact with hosts or contaminated water
(occupational, recreational and avocational exposures)
Leptospirosis: Disease in people
Complex manifestation: • Spectrum of symptoms extremely broad
• Two type: icteric (severe) & anicteric (less severe)
• Clinical presentation biphasic (acute & immune phase)
• Most cases sub-clinical or mild
• Recognized cases: fever of sudden onset, chills,
headache, myalgia, abdominal pain,
rash (less often) [3-10 d],
• aseptic menigitis (children), pulmonary hemorrhage
• for anicteric leptospirosis mortality near zero
• difficult differential diagnosis (tropics especially)
Leptospirosis: Disease in people 2
Icteric leptospirosis (jaundice) • 5-10% of cases, mortality 5-15%, rapid progression
• complications due to ARF, liver damage, hemorrhage,
pulmonary & cardiac involvement
• Ocular complications (uveitis in people, horses)
• Acute infestation during pregnancyabortion, fetal death
• No evidence of chronic or latent infection (Lyme?)
• Treatment: oral doxycycline, hospitalized - IV penicillin
• Immunity is primarily humoral, life-long but serovar specific
• Few vaccines for people (Chinese rice workers)
Leptospirosis: Incidence in NA
US 100-200 cases per year (50% Hawaii)
Canada many fewer (most travel-related)
More activity from veterinary side • Associated with abortions in cattle, pigs, horses
• Serological surveys: activity coast to coast
• Dominant serovars: Cattle (hardjo, pomona)
Swine & horses (bratislava, pomona, ictero.)
Dogs (canicola, autumnalis, grippotyphosa)
Wildlife: skunks & red fox (pomona), wapiti
(autumnalis, bratislava, ictero.), BTD (pomona)
Emerging serovars: grippotyphosa, bratislava?
2 Vet cases: AB (86); serosurvey 92 NS vets & abbatoir
(9-16% AB+ve; bratislava, ictero.); QC (92) 5% AB+ve
ON 97 Cluster of infections (grippotyphosa), trappers
Leptospirosis: Diagnosis
Diagnostic algorithm at NML • Screen with PanBio ELISA (IgM)
• Reactor to Micro agglutination test (MAT) with serovars:
[Autumnalis, Ballum, Canicola, Hardjo,
Icterohaemorrhagiae, Grippotyphosa, Pomona & Tarassovi]
& PanBio EIA (IgM)
• other diagnostic procedures:
• Isolation (various tissues) in EMJH media [low yield]
• PCR (various tissues)
400-500 samples per year [0-8 MAT +ve/yr]
Leptospirosis: Prevention
Avoid contact with contaminated sources • swimming or wading in water especially tropical
• vaccinate dogs & farm livestock (cattle, pigs)
• use of protective clothing (occupational high risk situations)
• implementation of rodent control
• prophylactic treatment in some high risk activities
Lymphocytic Choriomeningitis Virus (LCMV)
New World Complex
Arenaviridae Paramyxoviridae
Filoviridae Bornaviridae
Old World Complex
Machupo virus
Junin virus
Sabia virus
Guanarito virus
Lymphocytic Choriomeningitis Virus (LCMV)
Lassa Virus
Reservoirs & transmission
• Chronically infected house mice (Mus musculus) are the natural reservoir of the virus (lab & field)
• LCMV in high titres in urine, feces, saliva, nasal secretions [used animal bedding a potential fomite]
• Exposure via inhalation, broken skin or into nose, eyes, or mouth and possible by bite of an infected animal
• Humans are exposed through:
– contact with infected mice or less frequently from pet rodents (infected via contact with feral infected mice),
– congenital infections (mother to offspring) and,
– organ transplant
Spectrum of disease
• Infection with LCMV is not uncommon (5% of general population), disease is relatively rare with most infections asymptomatic or only mild febrile illness
• People with weakened immune systems more severe or fatal cases (especially dangerous for those receiving organ donations)
• Infection during pregnancy can cause spontaneous abortion, and severe birth defects (hydrocephalus, chorioretinitis, blindness or mental retardation)
• Pet rodents like hamsters: asymptomatic or loss of appetite, lethargy, rough coat, inflammation of the eyes and eventually death (weeks or months later)
• Viral hepatitis caused by LCMV in non-human primates can be fatal
Callitrichid Hepatitis (CH)
• Recognized in 1980‟s - an acute viral hepatitis with a high attack
rate and fatality rate of ~ 75%
• Outbreaks restricted to zoo and animal park collections of the
primate family Callitrichidae, including Marmosets and Tamarins
• Serological data implicated an arenavirus in the infection
• Stephenson et. al. (1994) identified etiologic agent as Lymphocytic
choriomeningitis virus (LCMV)
Biodôme de Montréal
• The Biodôme is the former Velodrome of the Montreal Olympics
converted into 5 different „Biospheres‟ including tropical
rainforest
• Two Tamarins and one Marmoset died
from illnesses consistent with CH
• Liver, spleen, kidney, brain and lung
samples sent to NML for testing
• Feral mice noted in some of the exhibits
Work undertaken by Special Pathogens: NML
Callitrichid Hepatitis: Case Summary
SPECIES SEX AGE ILLNESS
DURATION
CLINICAL SIGNS BLOOD WORK GROSS HISTO
Cottontop Tamarin
(Saguinus oedipus)
Female 18 yo 4 days Weakness, hind limb paresis,
terminal neurological signs
Not available Mottled liver, pulmonary
congestion, periodontal
disease
Necrotizing/lymphocy
tic hepatitis,
alveolitis/bronchiolitis,
splenic lymphoid
hyperplasia with
necrosis
Same Female 5 yo 1 day Weakness, diarrhea,
dehydration, terminal
neurological signs and bloody
diarrhea
Clinical chemistry
compatible with liver
disease, lipemic serum
Minimal gross changes Same
Goeldi‟s Marmoset
(Callimico goeldii)
Male 15 yo 2 days Weakness, appetite loss Same Hydrothorax/hydroperic
ardium, pulmonary
edema, mottled liver
with large reddish
lesions
Necrotizing/histiocytic
and neutrophilic
hepatitis, alveolitis,
ependymitis
Callitrichid Hepatitis:Gross Pathology
Biodôme de Montréal
Goeldi’s Marmoset
André Dallaire, FMV
400 x
Diagnostic Procedures
• Nucleic acid was isolated from each tissue sample using commercial extraction kits and widely reactive RT-PCR assays set up to amplify a region of LCMV S segment
• Isolation of virus attempted using Vero E6 cell lines
• LCMV RNA was found to be present in all samples – sequence analysis found all tissues to contain same unique LCMV sequence
• After second blind passage, LCMV RNA was detectable in cell culture supernatant – no cytopathic effect present on monolayer
Nucleotide Substitutions (x100)
Bootstrap Trials = 1000, seed = 111
0
30.7
51015202530
810362.seq
Armstrong 53b.seq
46.5
eu480450.seq
38.4
MX.seq
WE.seq
55.3
200504261.seq
31.4
40.3
CH-5692.seq
NA
810366.seq
MontrealCHV.seq
28.0
Y.seq
79.9
33.2
Dandenong.seq
M1.seq
65.5
LE.seq
91.7
87.4
Mopeia.seq
Phylogenetic Analysis
- 400 bp fragment of nucleoprotein used for analysis
- Sequence of this isolate most closely related to LCMV sequences from
North American sources
Biodôme de Montréal: Follow-up
• Wild mice were present in enclosure and were considered
the likely route of infection
• 7 mice were trapped, humanely killed & liver and spleens
sent for PCR-based testing
• All mice were found to be infected with the same strain
of LCMV as was found in the primates
• Rodent exclusion procedures put in place
Genus Human disease
Bunyavirus LaCrosse encephalitis, others
Phlebovirus Rift Valley fever, sandfly fever
Nairovirus Crimean-Congo hemorrhagic fever
Tospovirus Plant virus, no known human disease
Hantavirus Hemorrhagic fever with renal syndrome
Hantavirus pulmonary syndrome
5 genera, 250 species
Family Bunyaviridae
Hantaviruses - History
• Korean War, 1951-54: >3,200 cases “Korean
Hemorrhagic Fever”
• Fever, shock, ARF, pulmonary edema
• 10% case-fatality rate
• Tents “overrun with rodents”
• Rodent-association established in 1978
• Virus isolated in 1981from rodents collected
along Hantaan River in Korea (=Hantavirus)
Rodent-associated viruses
World-wide: Two lineages of hantaviruses
Old World - 9 species, 4 which cause disease
New World - 23 species, 11 which cause disease
Arvicolinae
Murinae
Sigmodontinae
Chronically infected
rodent
Virus is present in aerosolized
excreta, particularly urine
Horizontal transmission of infection
by intraspecific aggressive behavior
Virus also present in throat
swab and feces
Secondary aerosols, mucous membrane
contact, and skin breaches are also
sources of infection
General cycle of transmission of hantaviruses
Hantaviruses and disease in humans
• Hemorrhagic Fever with Renal Syndrome (HFRS)
o Old world hantaviruses
o Mortality rate ranges from <1 to 15%
o Restricted to Asia and Europe
o Annually 200,000 HFRS cases in Europe and Asia
• Hantavirus Pulmonary Syndrome (HPS)
o First described in 1993
o New world hantaviruses
o Mortality rate approx. 35%
o 1600 confirmed cases in the America‟s (PAHO website)
Sin Nombre Peromyscus maniculatus
Rio Segundo Reithrodontomys mexicanus
El Moro Canyon Reithrodontomys megalotis
Andes Oligoryzomys longicaudatus
Bayou Oryzomys palustris
Black Creek Canal Sigmodon hispidus
Rio Mamore Oligoryzomys microtis
Laguna Negra Calomys laucha
Muleshoe Sigmodon hispidus
New York Peromyscus leucopus
Juquitiba Unknown Host
Maciel Necromys benefactus
Hu39694 Unknown Host
Lechiguanas Oligoryzomys flavescens
Pergamino Akodon azarae
Orán Oligoryzomys longicaudatus
Caño Delgadito Sigmodon alstoni
Isla Vista Microtus californicus
Bloodland Lake Microtus ochrogaster
Prospect Hill Microtus pennsylvanicus
New World Hantaviruses
Bermejo Oligoryzomys chacoensis
Calabazo Zygodontomys brevicauda
Choclo Oligoryzomys fulvescens
Sin Nombre (530)
Black Creek Canal (1)
Bayou (3)
New York (2)
Virus Type
Location of North American HPS Cases by Virus Type
as of July, 2010
Total Cases: USA-545 in 34 States; Canada-74 in 5 provinces
10 41 19 3
1
HPS cases by year in Canada (n=74)
0
2
4
6
8
10
1989
1991
1993
1995
1997
1999
2001
2003
2005
2007
2009
British Columbia Alberta Saskatchew an Manitoba Quebec
3.7 (2)
R1
R6
R5
R4
R2 R3
R7
R9 R8
R10
R11
R12
R13
1.3 (1)
2.3 (1)
0.8 (2)
2.3 (1) 1.7 (5)
4.8 (2) 1.3 (2) 1.4 (1)
0.08 (1)
2.3 (7)
0.6 (6) 7.2 (8)
2.8 (5) 3.6 (5)
4.6 (1)
Incidence of HPS over 13 year period in AB & SK
HPS cases by month of exposure (n=74)
0
5
10
15
20
25
Janu
ary
Febru
ary
Mar
chApr
il
May
June
July
Aug
ust
Sep
tem
ber
Octobe
r
Nove
mbe
r
Dece
mbe
r
Month
Mean age – 39.7 yoa (range: 7-76)
Cases more frequent in males (49; 66%) than females (25; 34%)
Mortality higher in females (37.5%) than males (24.4%)
Overall case fatality rate of 29% (20/69)
Age distribution of HPS cases and percent
mortality within each age class (n=74)
0
5
10
15
20
25
0-10 11-20 21-30 31-40 41-50 51-60 61-70 70+
No
. o
f cases
0
20
40
60
80
100
Number of cases Percentage mortality
Why are there so few HPS cases?
Possibilities
Host resistance factors (children versus adults, genetic
susceptibility?)
Only recent infected deer mice (younger animals) shed
enough virus into the environment to cause illness?
Virus particles do not survive for extended period in
older droppings so illness occurs only after exposure to
fresh droppings?
Risk Factors for HPS
Infections are more common in males
Disease is rare in children
Certain occupational groups are more at
risk
High risk activities include cleaning
(creating dust) in confined spaces
(buildings, abandoned vehicles, etc.)
contaminated by rodent droppings
Different approaches used to understand
hantaviruses in Canada
• Passive surveillance
• Active surveillance/case investigations
• Field studies on transmission dynamics
Focused primarily towards deer mice
but other species collected & tested
Passive surveillance
Collaborators across Canada including: Public health inspectors, pest control personnel,
wildlife biologists, university facility, private
contractors, etc.,
Rodents collected using: Snap traps & various live traps
Whole carcasses, Nobuto strips (or
blood samples) shipped to NML Screen for AB with ELISA, lungs harvested
from selected positives for PCR
Serological survey for hantaviruses in
deer mice from across Canada
Sin Nombre virus
Seronegative rodents
Seropositive rodents
BC-627
(3) AB-2051
(7.9) SK-887
(4)
MB-1490
(3.6) ON-1898
(2.9)
QC-503
(6.2)
NF-62 (3.2)
NS-287
PE-122
NB-232
(5.6)
YT-107
(8.4) NT-184
380/7,891 (4.8%) deer mice with antibodies
Active surveillance
Intensive small mammal survey proceeding HPS cases Collaboration with local public health authorities & residents
Objectives: Define risk factors for hantavirus exposure
• Widespread & extensive rodent collection
• Field collection of relevant tissues
• Laboratory testing for AB and virus in various
tissues or fluids (RT-PCR)
Outcomes of active surveillance
Previous epidemiological investigations have revealed:
• Risk (“infected” mice) typically present throughout community
where human case (s) occur but can vary amongst them
• Distribution of “infected” animals can be highly focal
• Most human cases occur singly but multiple exposure to same
point source can occur
• Reasons for exposure of victims (relative to others in
community) difficult to establish in many instances
Quickly generate
humoral immune
response (IgG)
Detectable stages of
viremia, (now shown
to be sporadically)
Systemic infection
with no deleterious
effects SNV RNA detected
in urine and/or saliva
of a small proportion
of DM
SNV in deer mice
Study of SNV hampered by the lack
of a reliable infectious assay
Route of infection (?)
Aggression or Breeding
Environ. contaminant
Transmission dynamics remain poorly understood
Some evidence to suggest that:
Recently infected animals more likely to shed SNV than chronically
infected ones
Relatively few animals with detectable SNV RNA in excreta (few
infectious animals -> rare human cases)
Transmission among deer mice likely blood-borne
Still lack information on role of:
Distribution of SNV-infected deer mice at local spatial scale
Relationship between deer mouse abundance & probability of human
exposure (usually confounded by impact of human behaviour)
Disease prevention
Primarily through public education
Recognize rodents and/or evidence of rodent-infestation
Where possible, rodent-proof structures & reduce deer
mouse populations
Clean areas contaminated by rodent droppings using
appropriate PPE and disinfectants (avoid creating
aerosols in areas contaminated by mice)
Conclusions
• Contact with rodents can result in potential exposure to disease-causing agents in Canada
• Fortunately most rodent-associated pathogens are either rare or relatively focal in their distribution such that human disease is infrequent
• Simple preventative measures can be utilized to further reduce or minimize exposure to these rodent-borne pathogens
Questions?
Routes of exposure
Infected rodents excrete virus in urine, feces
or saliva and humans usually infected when
aerosolized virus is inhaled
Other routes of exposure theoretically
possible such as through bites but rarely
reported
Human to human transmission only reported
for Andes strains in South America