This document provides an overview of tularaemia, a bacterial zoonotic disease caused by Francisella tularensis. It discusses the definition, etiology, epidemiology, transmission, clinical presentation, diagnosis, treatment and prevention. F. tularensis is a highly virulent intracellular pathogen that can cause epidemics in humans and animals. Clinical forms include ulceroglandular, glandular, oculoglandular, oropharyngeal, respiratory, and typhoidal. Diagnosis involves clinical history, microscopy, culture, PCR and serology. Treatment consists of gentamicin or streptomycin for 10 days. Prevention focuses on avoiding contact with infected animals/vectors and disinfecting

1. TULARAEMİA :
RE-EMERGING DISEASES
Mehmet Doganay
Department of Infectious Diseases,
Faculty of Medicine, Erciyes University
Kayseri / Turkey
Member of Zoonoses Working Group (International
Society of Chemotherapy )
Email. mdoganay@erciyes.edu.tr
mdoganay2003@yahoo.com

2. Outline of lecture
• Definition
• Etiologic agent
• Global epidemiology
• Transmission and pathogenesis
• Clinical presentation and diagnosis
• Treatment
• Prevention and control
• Conclusions

3. TULARAEMİA
Definition
• A bacterial zoonotic disease
• The etiologic agent: Francisella tularensis
• Highly virulent for humans and animals ( such as
rodents, hares, and rabbits)
• Cause epidemics and epizootics in humans and
animals
• A potential agent for bioterrorism, classified as a
Category A agent

4. MICROBIOLOGY :Francisella tularensis
• The bacteria;
– Gram-negative coccobacillus (0.2 - 0.5 in wide
and 0.7-1.0 mm in length),
– Capsulated ( in some strain)
– Facultative
– Intracellular
– Stain weakly
– Seen single and bipolar in microscopy
– Live in a long time in pooled water, mud and
animal carcass
• Not grow in routine media
• A fastidious microorganism which requires
enriched medium for growth ( cystein hearth
agar supplemented with 9 % heated sheep red
blood cells and nonselective buffered charchoal
yeast extract agar or Thayer- Martin agar may
be used for isolation)
• Grow in cystein enriched medium in aerobic
condition at 37oC within 2-4 days
WHO Guidelines on Tularaemia,
Roger D et al. Microbiol Mol Biol Rev 2009; 73:684-711

5. MICROBIOLOGY :Francisella tularensis
Subspecies Virulence character Found place
F.tularensis subsp.
tularensis (Type A)
Highly virulent USA
F.tularensis subsp.
holarchtica (Type B)
Less virulent Throughout the
northern hemisphere
F.tularensis subsp.
mediasiatica
Moderate virulent Kazakhstan,
Turkmenistan
F.tularensis novicida Low virulence and
water born
transmission
Australia, Spain,
USA
F.philomiragia Low virulence and
found in salty water
Atlantic and
Mediterranean
WHO Guidelines on Tularaemia,
Roger D et al. Microbiol Mol Biol 2009; 73:684-711

6. • Infect and survive in the cell
types;
– Macrophages target cell
– Other cell types; dendritic
cells, neutrophils,
hepatocytes, and lung epitel
cells
• Virulence factors
– Surface structures; Capsule,
LPS, type IV pili,
– Francisella pathogenicity
island (FPI); approximately
30 kb and comprised of
roughly 17 open reading
frames
Ellis J et al. Clin Microbiol Rev 2002;
15:631-646
Pechous RD et al. Microbiol Mol Biol Rev
2009; 73:684-711
Pathogenesis and virulence factors

7. TULARAEMİA
EPİDEMİOLOGY
• Reported in many countries of the Northern
hemisphere;
– Existed for a long time in the former Russian
federation, Kazakhstan and Turkmenistan, Finland
Sweden, Eastern Europe,
– Reported outbreaks from some European
Countries; Portugal, Spain, Sweden, (Kosovo)
Serbia and Turkey
– Also reported from Japan, China
– Regularly occur in USA and Canada
WHO Guidelines on Tularaemia 2007
Ellis J et al. Clin Microbiol Rev 2002; 15:631-634

8. World map showing the areas where tularemia is endemic
WHO Guidelines on Tularemia 2007, www.who.int

9. TULARAEMIA
Vectors and Reservoirs in the Environment
• Vectors
– Arthropods
• Ticks ( Ixodes spp.)
• Flies ( horse and deer flies)
• Mosquitoes (Aedes spp., Culex spp., Anopheles spp.)
• Flea ( their role is unclear)
– Mammals
• Outbreaks described in hares, prairie dogs and mink
• Mammals harbor and secrete the bacteria for a longer periods of time
• No evidence that they constitute a major natural reservoir for F.tularensis
• Voles and mice; accepting main source for the spread of F.tularensis to
humans
• Unclear the role of hares and rabbits for spreading the infection but infect
the hunters
– Reservoirs in Environment
• Field vole faeces are a source of human infection. Hay stored in barn is
contaminated with faeces and humans contract in the barns via inhalation
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

10. Water / Soil Water / Soil
Voles
Voles
Mosquitoes
Ticks
Ticks
Lagomorphs
Lagomorphs
Deer flies
Life cycles of Francisella tularensis
A. Dominant in North America
B. Dominant in Eurasia
A B

11. TULARAEMIA
Transmission to Human
• Through insect bites (ticks, flies, mosquitoes
etc)
• Contact with infected animal or contaminated
animal products, water, mud
• Inhalation of aerosol droplets
• Consumption of contaminated water and food
( Outbreaks due to drinking contaminated water
have been seen in European countries such as
Kosovo, Poland and Turkey)
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
Pechous RD. Microbiol Mol Biol Rev 2009;73:684-711
WHO Guidelines on Tularaemia 2007
Meric M et al. APMIS 2008; 116:66-73

12. Tularaemia outbreak due to stream water in Duzce / Turkey 2000

13. TULARAEMIA
RISK GROUPS
• Living in rural area
in epidemic region
• Hunters
• Butchers
• Farmers
• Gardeners
• Veterinarians
• Cookers
• Laboratory workers
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious
Diseases 2010: 1226-1230
Pechous RD. Microbiol Mol Biol Rev 2009;73:684-711
WHO Guidelines on Tularaemia 2007

14. TULARAEMİA
CINICAL PRESENTATION
• Severity of infection;
– Virulence
– Port of entry
– Systemic involvement
– Immune status of host
• An 3-5 days (1-21 days) incubation period
• Clinic pictures; asymptomatic
acute illness to sepsis
Beard and Dennis. In: Cohen, Powderly, Opal.
Infectious Diseases 2010: 1226-1230
Pechous RD. Microbiol Mol Biol Rev
2009;73:684-711
WHO Guidelines on Tularaemia 2007

15. TULARAEMIA
CLINICAL FORMS
Clinical form Rate
(%)
Transmission route
Ulceroglandular 45-85 Vectorn-borne and direct contact (touching
infected animals or material contaminated with
F.tularensis)
Glandular 10-25 Vectorn-borne and direct contact (touching
infected animals or material contaminated with
F.tularensis)
Oculoglandular < 5 Touching the eye with contaminated fingers or
possibly from infected dust
Oropharyngeal < 5 Ingestion contaminated food and water
Respiratory < 5 Inhaling contaminated dust or laboratory-
acquired infection
Typhoidal < 5 Unknown (probably oral or respiratory)
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

16. Primary ulcer in a human case of
tularaemia. WHO Guidelines on
Tularemia. Geneva, 2007
Ulceroglandular tularaemia
• Appear a local papule at the site
of inoculation, then becomes
vesiculated and pustular and then
ulcerates within a few days
•Onset of fever and generalized
symptoms
• Around one or more painful
lymphadenetis
• Ulcer heals with leaving a scar
• In some cases, an abscessed
node may suppurate, create a sinus
tract and discharge purulent
material to the outside

17. Glandular tularaemia
Department of Infectious Diseases,
Erciyes University Hospital, Kayseri
Glandular tularaemia
•A similar clinical picture
as seen ulceroglandular
form
•Not having the local
cutaneous ulceration
• More likely follow
arthropod-borne
inoculation

18. Oculoglandular tularaemia
• Acquired by touching the eye
with contaminated finger or
possible by exposure to
F.tularensis containing dust
• Fever and unspecific symptoms
• Unilateral conjunctivitis,
together with swelling of eyelids,
excessive lacrimation,
photophobia, and mucopurulent
discharge
•A large , tender preauricular,
submandibular and cervical chain
lymph nodes
• Rarely leave vision loss
Oculoglandular tularaemia
Department of Infectious
Diseases, Erciyes University
Hospital, Kayseri

19. Field Guidelines for Tularaemia, Ministry of Health, Turkey, 2011
Oculoglandular tularaemia

21. Department of Infectious Diseases, Erciyes University
Hospital, Kayseri
Oropharyngeal tularaemia

22. Field Guidelines for Tularaemia, Ministry of Health, Turkey, 2011
Oropharyngeal tularaemia

23. Field Guidelines for Tularaemia, Ministry of Health, Turkey, 2011
Oropharyngeal tularaemia

24. Field Guidelines for Tularaemia, Ministry of Health, Turkey, 2011
Skin eruptions in Tularaemia

25. Typhoidal Tularaemia
• The most severe clinical form
• Seen pneumonia in 50 % of the cases
• Presents as an acute illness without localizing signs
• May be prominent a early systemic symptoms with
abdominal pain, diarrhea, vomiting and toxic
appearance
• May ensue the systemic inflammatory response
syndrome and sepsis
• May be complicated with acute respiratory distress
syndrome, disseminated intravascular coagulation and
bleeding, shock and organ failure
• Positive blood culture
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

26. Pnömonik Tularemi
• Pathogenesis
– Inhalation of the bacteria
– Spread with hemothogenic
route
• Seen in 5-10 %
• Systemic symptoms (such as
fever, toxemia)
• Respiratory symptoms (such as
coughing, side pain in the chest)
• Chest X- Ray :
– Unilateral or bilateral infiltrations,
– Hilary adenophaty,
– Pleural effusion
Extended right-sided
pulmonary consolidation
Hilar lymphadenophaty en
WHO Guidelines on Tularemia. Geneva, 2007

27. TULARAEMIA
Complications
• Frequently seen
– Abscess formation
– Sepsis
– Disseminated
intravascular coagulation
(DIC)
• Rarely seen
– Menigitis
– Osteomyelitis
– Peritonitis
– Pericarditis
– Endocarditis
– Hepatic failure
– Renal failure
– Splenic rupture
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

28. TULARAEMIA
Diagnosis
• Patient’s history ( living in endemic area,
travel to endemic area, ticks bite, hunting,
contact with any rodent etc. )
• Seen bipolar gram-negative bacilli in the
microscopic examination of samples
• Isolation of F. tularensis in the culture
• Positive PCR in the patient samples
• Positive serologic tests ( tube agglutination,
indirect hemagglutination test, ELISA etc.)
WHO Guidelines onTularaemia 2007
Ellis J et al. Clin Microbiol Rev 2002; 15:631-646

29. TULARAEMIA
DIFFERENTIAL DIAGNOSIS
CLINIC FORM CONSIDER IN DIFFERENTIAL
DIAGNOSIS
OROPHARYNGEAL FORM • Streptococcal tonsillopharygitis
• Infectious mononucleosis
• Adenovirus infection
• Diphtheria
OCULOGLANDULAR FORM • Bacterial and viral
conjunctivitis
• Syphilis
• Cat-stratch disease
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines onTularaemia 2007

30. CLINIC FORM CONSIDER IN DIFFERENTIAL
DIAGNOSIS
ULCEROGLANDULAR AND
GLANDULAR FORM
• Pyogenic bacterial skin and soft
tissue infections
• Cat-scratch disease
• Cutaneous anthrax
• Syphilis
• Chancroid
• Lymphogranuloma venereum
• Cutaneous tuberculosis
• Non-tuberculous mycobacterial
infections
•Toxoplamosis
• Sporotrichosis
• Mice bite fever
• Plague
• Lymphoma
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines onTularaemia 2007

31. RESPIRATORY FORM • Mycoplasma pneumonia pneumonia
• Legionella pneumonia
• Chlamydia pneumoniae pneumonia
• Q fever
• Psittacosis
• Tuberculosis
• Pulmonary fungal infection
• Influenza pneumonia
SYSTEMIC
(TİFOİDAL) FORM
• Salmonellosis (typhoid fever)
• Brucellosis
• Legionella infection
• Q fever
• Disseminated tuberculosis
• Fungemia
• Rickettsiosis
• Malaria
• Endocarditis
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines onTularaemia 2007

32. ANTIMICROBIAL TRETMENT IN TULARAEMIA
Antibiotic Doses in adult Doses in children Duration
(Day)
Gentamicin 5 mg/kg/day, iv,
divided into two
doses
5-6 mg/kg/day,
divided into two doses
10
Streptomycin 2x1 gr, im 15 mg/kg/day,
divided into two doses
10
Ciprofloxacin* 800 mg/day, iv
1000 mg/da oral,
divided into two
doses
15 mg/kg/day,
(maximum daily dose up to 1
gr/day)
10-14
Doxycycline* 200 mg/day,
divided into two
doses
Not suggested ≥ 15
* Not suggested for childhood period, im. Intramuscularly, iv. intravenously
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

33. Measures for preventing the spread of tularaemia
• Vaccine is unavailable for human
Oropharyngeal tularaemia
Waternborne infection
– Avoid drinking of unboiled water
– Disinfect (chlorinate) water
– Protect water sources from contact with animals such as rats, mice
Foodborne infection
– Protect food stores contact with animals ( e.g. trap mice, rats or other
rodents)
– Avoid eating food which may be contaminated animal faeces
– Wash food with care as the aerosols and dust created can be infectious
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

34. Measures for preventing the spread of tularaemia
Respiratory or Ulceroglandular Tularaemia
• Infectious aerosols, direct contact with infectious
animal, and arthropod bites:
– Avoid the hunting of hares and rabbits and consumption of
meat
– Wash hands after contact with wild and domestic animals
– Regularly inspect domestic animals for sign of disease
– Avoid dust and aerosols ( especially relevant for farmers
and landscapers)
– Avoid exposure to blood-sucking arthropods by wearing
long-sleeved clothing, and using repellents or mosquitoes
nets
Beard and Dennis. In: Cohen, Powderly, Opal. Infectious Diseases 2010: 1226-1230
WHO Guidelines on Tularaemia 2007

35. TULARAEMIA
Conclusions
• Tularaemia is a re-emerging disease
• The disease is prevalent in northern hemisphere
• Currently, some outbreaks have been occurred
• Franciesella tularensis subsp. tularensis is more virulent than others subspecies
• Franciesella tularensis subsp. tularensis is generally transmitted from animals (
rabbits, ticks and sheep) to human
• Franciesella tularensis subsp. Holarctica is often isolated in associated with
streams, ponds, lakes and riversd
• A wide range of arthropods ( ticks, mosquitoes, horse and deer flies) has been
identified in the transmission between mammalian hosts.
• Human-to-human transmission is not reported
• Varies clinical forms are seen
• Diagnose is based on history, clinical presentation, positive culture or /and serology
• The first line drugs are streptomycin, gentamicin, doxycyline and ciprofloxacin
• Vaccine is not available
• Applying to preventive measurements is very important for the control of tularemia
• We need a new vaccine for future and more researches for understanding of disease
transmission