Plague - CIPHI Manitoba

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Plague - CIPHI Manitoba

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


Tularemia: The Organism

• Francisella tularensis

– small, pleomorphic, non-spore-forming, nonmotile

coccobacillus, Gram-negative

– obligate intracellular pathogen

• Macrophages

Francisella tularensis

– 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


• Incubation

– 3-15 days

– Varies with virulence of strain

and dose

• Typical symptoms:

– Sudden fever

– Chills

– Headache

– Myalgia

Disease in humans

• 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


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)

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

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?


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)

Paramyxoviridae

New World Complex

Machupo virus

Junin virus

Sabia virus

Guanarito virus

Filoviridae Bornaviridae

Arenaviridae

Old World Complex

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

Cottontop Tamarin

(Saguinus oedipus)

Female 18 yo 4 days Weakness, hind limb paresis,

terminal neurological signs

Same Female 5 yo 1 day Weakness, diarrhea,

dehydration, terminal

neurological signs and bloody

diarrhea

Goeldi‟s Marmoset

(Callimico goeldii)

CLINICAL SIGNS BLOOD WORK GROSS HISTO

Not available Mottled liver, pulmonary

congestion, periodontal

disease

Clinical chemistry

compatible with liver

disease, lipemic serum

Minimal gross changes Same

Male 15 yo 2 days Weakness, appetite loss Same Hydrothorax/hydroperic

ardium, pulmonary

edema, mottled liver

with large reddish

lesions

Necrotizing/lymphocy

tic hepatitis,

alveolitis/bronchiolitis,

splenic lymphoid

hyperplasia with

necrosis

Necrotizing/histiocytic

and neutrophilic

hepatitis, alveolitis,

ependymitis


Callitrichid Hepatitis:Gross Pathology

Goeldi’s Marmoset

Biodôme de Montréal

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


30.7

30

25

87.4

Phylogenetic Analysis

20

33.2

NA

40.3

38.4

15

Nucleotide Substitutions (x100)

Bootstrap Trials = 1000, seed = 111

79.9

10

46.5

55.3

31.4

- 400 bp fragment of nucleoprotein used for analysis

- Sequence of this isolate most closely related to LCMV sequences from

North American sources

91.7

65.5

28.0

5

0

810362.seq

Armstrong 53b.seq

eu480450.seq

MX.seq

WE.seq

200504261.seq

CH-5692.seq

810366.seq

MontrealCHV.seq

Y.seq

Dandenong.seq

M1.seq

LE.seq

Mopeia.seq


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


Family Bunyaviridae

5 genera, 250 species

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


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


Sigmodontinae

Arvicolinae

Murinae


General cycle of transmission of hantaviruses

Virus is present in aerosolized

excreta, particularly urine

Chronically infected

rodent

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


Hantaviruses and disease in humans

• Hemorrhagic Fever with Renal Syndrome (HFRS)

o Old world hantaviruses

o Mortality rate ranges from


Sin Nombre

Peromyscus maniculatus

Muleshoe

Sigmodon hispidus

Isla Vista

Microtus californicus

El Moro Canyon

Reithrodontomys megalotis

Calabazo

Zygodontomys brevicauda

Caño Delgadito

Sigmodon alstoni

Choclo

Oligoryzomys fulvescens

Rio Mamore

Oligoryzomys microtis

Orán

Oligoryzomys longicaudatus

Bermejo

Oligoryzomys chacoensis

Andes

Oligoryzomys longicaudatus

New World Hantaviruses

New York

Peromyscus leucopus

Prospect Hill

Microtus pennsylvanicus

Bloodland Lake

Microtus ochrogaster

Bayou

Oryzomys palustris

Black Creek Canal

Sigmodon hispidus

Rio Segundo

Reithrodontomys mexicanus

Juquitiba

Unknown Host Laguna Negra

Calomys laucha

Maciel

Necromys benefactus

Hu39694

Unknown Host

Lechiguanas

Oligoryzomys flavescens

Pergamino

Akodon azarae


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

Virus Type

Sin Nombre (530)

New York (2)

Bayou (3)

Black Creek Canal (1)


10

8

6

4

2

0

1989

1991

1993

HPS cases by year in Canada (n=74)

1995

1997

1999

2001

2003

2005

2007

British Columbia Alberta Saskatchew an Manitoba Quebec

2009


Incidence of HPS over 13 year period in AB & SK

3.6 (5)

0.6 (6)

2.3 (7)

0.08 (1)

1.3 (1)

2.8 (5)

7.2 (8)

R10

R7

R3

R12

1.4 (1)

R13

2.3 (1)

2.3 (1)

R9

1.3 (2)

R2

R6

3.7 (2)

4.6 (1)

R11

1.7 (5)

R4

R8

4.8 (2)

R5

0.8 (2)

R1


25

20

15

10

5

0

January

February

HPS cases by month of exposure (n=74)

March

April

May

June

July

Month

August

September

October

November

December


No. of cases

25

20

15

10

5

0

Age distribution of HPS cases and percent

mortality within each age class (n=74)

0-10 11-20 21-30 31-40 41-50 51-60 61-70 70+

Number of cases Percentage mortality

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)

100

80

60

40

20

0


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

YT-107

(8.4)

BC-627

(3)

deer mice from across Canada

NT-184

AB-2051

(7.9) SK-887

(4)

Sin Nombre virus

MB-1490

(3.6) ON-1898

(2.9)

380/7,891 (4.8%) deer mice with antibodies

QC-503

(6.2)

Seronegative rodents

Seropositive rodents

PE-122

NB-232

(5.6)

NF-62 (3.2)

NS-287


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


SNV in deer mice

Quickly generate

humoral immune

Systemic infection

response (IgG)

with no deleterious

effects SNV RNA detected

in urine and/or saliva

of a small proportion

Detectable stages of

viremia, (now shown

to be sporadically)

Route of infection (?)

Aggression or Breeding

Environ. contaminant

of DM

Study of SNV hampered by the lack

of a reliable infectious assay


ansmission 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

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