# Presentation: 552202

## Tularemia

- Division of Vector-Borne Infectious Diseases
- Centers for Disease Control and Prevention
- Ft Collins, Colorado

**Notes:**
Good morning, today I’m going to present an outbreak investigation of pneumonic tularemia on Martha’s Vineyard. 

## Tularemia - Overview

- Bacterial zoonosis caused by *Francisella tularensis*
- First identified in 1911 as plague-like illness of ground squirrels in Tulare County, CA
- Multiple routes of human infection
- Clinical signs and severity of illness depend on route of transmission and strain
- Nationally notifiable (except 1994-1999)

## Microbiology

*Francisella tularensis* is a small, nonmotile, aerobic, gram-negative coccobacillus
- Hardy, non-spore forming
- Survives well in water, moist soil, straw, decaying animal carcasses
- Virulence factors poorly understood but may be enhanced through lab manipulations
- Virulent, streptomycin-resistant strains evaluated as biowarfare agents in US and USSR

## Subspecies of F. tularensis 

- Two major subspecies (biovars) by virulence testing, biochemical and epidemiology factors
*F. tularensis* biovar tularensis (type A)
- Highly virulent in humans and animals
- Most common biovar isolated in North America
- Typically associated with rabbits
*F. tularensis* biovar palaearctica (type B)
- Generally less virulent
- Most common biovar in Europe and Asia
- Typically associated with rodents or wet environments

## Ecology

- Naturally occurs in temperate and subarctic regions of North America and Eurasia
- Recovered from wide variety of small mammals and arthropods
- Two main cycles
- rabbits, hares / ticks
- voles, mice, water rats, squirrels / direct contact and contaminated aquatic environments

## Transmission

- Multiple modes of infection
- Arthropod bites (ticks, deerflies)
- Handling infected tissues or fluids
- Ingestion of contaminated water or soil
- Inhalation of infective aerosols
- agricultural dusts
- laboratory
- Person to person transmission not documented

## High Risk Occupations

- microbiologist
- farmer
- veterinarian
- sheep handler
- hunter or trapper
- cook/meat handler
- landscaper

## Tularemia in the United States

- Cases reported from every state but Hawaii
- Most cases reported from south-central and western states (MO, AR, OK, SD, MT)
- Reported cases dropped from 1000s per year prior to 1950 to <200 a year in 1990s
- Most cases occur June – September
- Arthropod transmission most common
- Winter cases commonly hunters or trappers

## Reported Tularemia Cases, United States, 1945-2002

**Notes:**
Tularemia incidence has declined significantly in the US without any noteworthy intervention.  This graph shows cases from 1931, which was the highest recorded incidence, and the present.   No cases are shown from 1932 to 1944 but that is because I could not find these numbers for this presentation.  The last ten years the average number of cases has been 109 per year.

## Geographic Distribution of Reported Tularemia Cases, United States,1990-2000

**Notes:**
Tularemia has been reported in all US states except Hawaii.  Currently, more than half of all cases are reported from 4 states: Arkansas, Missouri, Oklahoma and South Dakota.  There is an interesting focus on Cape Cod and Martha’s Vineyard, in Massachusetts.  This focus originates from the import in the ’30s of cottontail rabbits for hunting.

## Incidence of Tularemia among Ethnical Groups

**Notes:**
American Indians have by far the highest risk.  This is thought to be related to their higher exposure, especially to ticks.  Most cases however are white.

## Seasonal Distribution of Tularemia Cases 1990-98

**Notes:**
From that perspective, it is interesting to compare the current seasonal curve to the one from the ’20s to the 40’s, which is the period with the highest incidence.  The yellow bars are the curve that I showed you 2 slides ago, the pinkish bars represent the cases reported to CDC in the ’20s, ’30s, and ’40’s.  Each bar represents the proportion of the yearly total.  You can see that there has been a massive shift of cases from winter to summer.  This graph suggests that the large decrease in cases in the 20’th century is due to a decrease in rabbit-associated tularemia.  This might have to do with a decrease in the number of people hunting or the way in which meat from rabbits is handled, but there also seems to have been a significant decrease in the prevalence of tularemia in rabbits.

## Seasonal Distribution of Tularemia Cases 1928-44

**Notes:**
From that perspective, it is interesting to compare the current seasonal curve to the one from the ’20s to the 40’s, which is the period with the highest incidence.  The yellow bars are the curve that I showed you 2 slides ago, the pinkish bars represent the cases reported to CDC in the ’20s, ’30s, and ’40’s.  Each bar represents the proportion of the yearly total.  You can see that there has been a massive shift of cases from winter to summer.  This graph suggests that the large decrease in cases in the 20’th century is due to a decrease in rabbit-associated tularemia.  This might have to do with a decrease in the number of people hunting or the way in which meat from rabbits is handled, but there also seems to have been a significant decrease in the prevalence of tularemia in rabbits.

## Clinical Presentation

- Extremely variable, depends on:
- Route of inoculation
- Dose
- Virulence
- Incubation: 3-5 days (range: 1 – 21 d.)
- Febrile illness
- Chills, headache, myalgia, fatigue, sore throat, cough, shortness of breath, vomiting, diarrhea
- Prominent lymphadenopathy

**Notes:**
The clinical presentation of tularemia is extremely variable and depends on the route of inoculation, the dose of the inoculum, and the virulence of the organism.

Following an incubation period of 3-5 days, patients with tularemia typically present with a high fever that is often accompanied by other nonspecific signs such as chills, headache, myalgias, fatigue, sore throat, cough, shortness of breath, vomiting or diarrhea.  A common feature of tularemia is a  prominent local lymphadenopathy.  

## Clinical Syndromes of Tularemia

## Clinical Syndromes of Tularemia

- Cervical lymphadenitis
- in patient with
- pharyngeal tularemia

- Patient with ulceroglandular tularemia

- Chest radiograph of patient with pulmonary tularemia
- (Radiograph shows bilateral pneumonitis and left pleural effusion)

## Laboratory Diagnosis 

**Suspect:**
- Poorly-stained, tiny gram-negative rods from patient with compatible exposure and clinical symptoms
- Organism is slow growing (up to 72 hours) and difficult to recover in automated culture systems

## Laboratory Diagnosis (cont)

**Presumptive**:
- Positive direct fluorescent antibody
- Positive immunohistochemical staining
- Fatty acid profile consistent
- AND/OR
- Single serum specimen with a titer _>_ 1:160 (tube agglutination) or 1:128 (microagglutination)

## Laboratory Confirmation (BSL III)

- Culture and/or isolate grown on cysteine heart agar
- grows well  at 37° C, but poorly at 25° C
- characteristic colonial morphology
- direct fluorescent antibody positive
- biochemical pattern consistent with *Francisella tularensis* profile
- Four-fold or greater change in titer
- two specimens taken at least 2 weeks apart
- at least one titer _>_ 1:160 (tube agglutination) or 1:128 (microagglutination)

## Fluorescent Antibody for F. tularensis 

**Magnification x 400**

## Treatment

- Aminoglycosides are bactericidal
- Streptomycin 7.5-15 mg/kg IM q12 hrs for 7 to 14 days
- Gentamicin 3-5mg/kg/day IV for 7-14 days with peak levels of at least 5.0 g/ml
- Doxycycline and ciprofloxacin also effective
- Tetracycline and chloramphenicol  are bacteriostatic

## Prophylaxis

- A live attenuated vaccine is available as an investigational agent
- Antibiotic prophylaxis following exposure is not generally recommended
- Exposed persons should be watched for fever (>37°C).  Antibiotic therapy should be initiated promptly if fever develops

## Infection Control for Patients 

- No human-to-human transmission of tularemia
- Standard precautions are appropriate
- Isolation of patients is not recommended
- Bodies of patients should be handled using standard precautions
- Autopsy procedures likely to produce aerosols should be avoided
- Clothing and linens contaminated with body fluids should be disinfected per standard hospital protocols

## Infection Control Measures for Tularemia in the Laboratory (I)

- Alert microbiology laboratory personnel when *F. tularensis* is suspected
- Routine diagnostic procedures can be performed under BSL-2 conditions
- BSL-3 conditions necessary during activities involving high potential for aerosol or droplet production
- Centrifuging, grinding, vigorous shaking, growing cultures in volume, and animal studies

## Infection Control Measures for Tularemia in the Laboratory (II)

- Specimens presumptively identified in routine BSL-2 clinical lab (Level A) should be immediately forwarded to BSL-3 (Level B) laboratory
- State public health laboratory or CDC laboratory
- Provide confirmation of agent and antimicrobial susceptibility testing

## Prevention

- Avoid tick- infested areas
- Protective clothing, repellents, tick checks
- Use gloves, masks, protective eye-cover when handling wild animals
- Cook wild game thoroughly
- Standard precautions for handling drainage from a wound or the eyes in patients with tularemia

## Threat of Biological Warfare

*Francisella tularensis* was weaponized by U.S. in the 1950s and 1960s.  Other countries suspected to have weaponized it as well.
- Estimated that 50 kilograms of aerosolized *F. tularensis* dispensed 2 kilometers upwind of a population center of 500,000 unprotected people under ideal weather conditions would kill up to 155,000 people. (World Health Organization, 1970)
- Local disease cycles could occur involving other mammals, ticks and biting flies.
- Contamination of the water supply also a concern.

## Tularemia 

**	*****I know of no other infection of animals communicable to man that can be acquired from sources so numerous and so diverse.  In short, one can but feel the status of tularemia, both as a disease in nature and of man, is one of potentiality. ***
**	****	****	****	****	****R.R. Parker (1934)**

**Notes:**
To determine if there were other unreported cases of pneumonic tularemia, we performed systematic case finding by reviewing medical records with a discharge diagnosis of unspecified pneumonia from the MVH, and three hospitals on Cape Cod and Nantucket.

We contacted health care practitioners on the island to establish an active surveillance system in which the infection control nurse at the MVH served as a liaison between practitioners and public health authorities.  

To test the hypothesis that lawn-mowing and brush-cutting aerosolized F. tularensis resulting in primary pneumonic tularemia, we conducted a case-control study and an environmental investigation.