Tularemia (also referred to as Deerfly Fever or Rabbit Fever) is a zoonosis caused by Francisella tularensis, a small gram negative, facultative, intracellular bacterium. The bacterium is first isolated by Mc Coy and Chapin in Tulare country, California in 1911. The causative agent isolated from rodents named as Bacterium tularensis. The genus was named as Francisella tularensis in honor of American bacteriologist Edward Francis, who defined and characterized the organism, and the disease associated with it.
Etiology and Pathogenesis
F. tularensis is a relatively small (0.2 to 0.7-1 μm), nonmotile, non-sporeforming, aerobic, gram negative coccobacillus. Four subspecies of the bacteria identified according to virulence testing, biochemical characteristics (citrulline ureidase activity, acid production from glycerol) and epidemiological features: subsp. tularensis (also known as biovar type A), subsp. palaearctica (also known as biovar type B or holarctica), mediasiatica and novicida. Type A and Type B biovars are particularly associated with human disease.
The main portal of entry for human infection is through the skin or mucous membrane in ulceroglandular form of infection. This may occur through the bite of a contaminated arthropod or by way of unapparent abrasions. Within 48-72 hr after cutaneous inoculation, F.tularensis multiplies locally, producing an erythematous, tender, or pruritic papule appearing at the portal of entry. This papule may enlarge and form an ulcer with a black base. Macrophages and circulating mononuclear phagocytes ingest and harbor the organism and carry from the local lesion to the regional lymph nodes. Once F. tularensis reaches the lymph nodes, the organism may multiply, form granulomas and cause enlarged, tender nodes that may suppurate. Abscess formation is typical for involved lymph nodes. Bacteremia may also be present, and although any organ of the body may be involved, the reticuloendothelial system is the most commonly affected.
Approximately 2 weeks after infection, specific T lymphocytes are activated, and macrophages ingest and kill the organism. From the lymph nodes, the organisms can spread via the lymphatic system to other organs and tissues, including lungs, liver, spleen, kidneys, and the central nerve system. As few as 10-50 organisms may cause disease if inhaled or injected into the skin, whereas more than 108 organisms are required when introduced orally.
Tularemia is usually a disease of animals. The bacteria are commonly found in various terrestrial and aquatic mammals (rabbits, hares, muskrats, beavers and voles), some domesticated animals (dogs, cats, hamsters) and exotic animals (monkeys, prairie dogs)
Infection can be acquired by humans by various modes: i) bites by infected arthropods, ii) handling of infected animal tissues or fluids, direct contact with or ingestion of contaminated water, food, or soil, iii) inhalation of infected aerosols (including laboratory exposure). Person-to-person transmission is rare or nonexistent. In addition, humans could be exposed as a result of bioterrorism.
F. tularensis is a hardy bacterium capable of surviving for weeks at low temperatures in water, moist soil, hay, straw, or decaying animal carcasses. F. tularensis (Type A) is found in lagomorphs (rabbits and similar animals) in North America and it is highly virulent in humans. Type A is usually transmitted to humans by contact with infected animals or is bitten by insects that have fed on an infected animal. Ticks (Dermacentor variabilis, Amblyomma americana), deer flies (Chrysops discalis), and mosquitoes have been shown to transmit tularemia between animals and humans.
Two primary disease manifestations, ulceroglandular and glandular, can arise from the bite of an infected vector. Conjunctival inoculation may result in infection of the eye with preauricular lymphadenopathy (oculoglandular form). Inhalation or ingestion of F. tularensis can also result in infection. F. tularensis is an aerosolizable intracellular bacterium and one of the most infectious pathogens known. It is considered to be a serious potential biological threat agent capable of causing a debilitating or fatal disease with low doses.
Who is at risk?
Anyone who comes into contact with the bacteria are at risk of infection. Tularaemia occurs in parts of North America, Europe, Russia, China and Japan. People who are bitten by tick or deer flies, drink untreated water or hunt or skin animals in affected areas may be at risk.
What are the symptoms?
Symptoms usually appear suddenly and include high fever, chills, fatigue, general body aches, headache and nausea. Other symptoms depend on where the bacteria entered the body. The infection can cause the following:
• A skin ulcer at the site of the bite or skin exposure, and swelling of the nearby lymph glands (armpit or groin)
• Irritation and swelling of the eye and swelling of the lymph glands in front of the ear
• Sore throat, mouth ulcers, tonsillitis and swelling of the lymph glands in the neck
• cough, chest pain and difficulty breathing.
Symptoms usually develop between 3 and 5 days after being infected but can be delayed up to 14 days. Most infected people recover fully with the appropriate treatment.
Clinical manifestations of Tularemia
Ulceroglandular: This form is usually caused by inoculation of the skin and is associated with ulcer at the site of infection and then spreads lymphatically, causing swollen, painful regional lymph nodes. Ulceroglandular form is contracted to humans through the bite of an infected tick.
Glandular: F tularensis is considered to enter through an inapparent abrasion and then to spread lymphatically. This form has the same signs and symptoms of ulceroglandular tularemia, with no visible skin ulcers.
Oculoglandular: F tularensis enters through the conjunctivae, humans contracted from either splashing of blood or rubbing of eyes after contact with contaminated tissue fluids. Patients with oculoglandular tularemia usually present with acute conjunctivitis, itching, lacrimation and pain. Clinical manifestations are usually unilateral and preauricular or cervical lymphadenitis may accompany with. Chemosis, periorbital edema, and small nodular or ulcerative lesions of the palpebral conjunctivae are also reported. If untreated, corneal ulceration may occur.
Oropharyngeal: After consumption of contaminated food or water oropharyngeal or gastrointestinal tularemia may occur depending on the site of colonization. Patients with oropharyngeal tularemia usually report a fever, painful sore throat and swelling on the neck. Clinical presentation is typically enlargement of tonsils, formation of yellow-white pseudo membrane accompanied by swollen cervical lymph nodes.
Due to a considerable delay in the start of effective treatment, lymph nodes continue to enlarge; an abscess formation followed by spontaneous suppuration may develop during the course of oropharyngeal tularemia. Suppurating lymph nodes were present in almost 20-40% of the cases in outbreaks in Turkey.
Depending on the infecting dose, gastrointestinal tularemia ranges from mild to severe disease. Abdominal pain (due to mesenteric lymphadenopathy), nausea, vomiting, diarrhea, and, occasionally, frank gastrointestinal bleeding (caused by intestinal ulcerations) may be observed.
Pneumonic: Disease involving the lungs is termed pneumonic disease. Primary tularemia pneumonia is uncommon and occurs after inhalation of the F tularensis. Rarely acquired naturally, pneumonic tularemia may develop in laboratory workers. Pneumonia develops after hematogenous spread in patients with ulceroglandular tularemia and typhoidal tularemia.
Patients usually report a dry cough, dyspnea, and pleuritic-type chest pain. Chest radiography may reveal patchy ill-defined infiltrates in one or more lobes. Frank lobar pneumonia may also develop. Bilateral hilar adenopathy may be present. Bloody pleural effusions are characteristic and demonstrate a mononuclear cellular response. Adult respiratory distress syndrome (ARDS) develops in some patients.
Typhoidal: Tularemia that predominately affects the bloodstream and body organs is referred to as typhoidal tularemia. It is more severe and probably represents F tularensis bacteremia. Patients usually present with fever, chills, myalgias, malaise, and weight loss. They often have pneumonia. Diagnosis is difficult because ulcers and lymphadenopathy are usually absent.
The choice of specimen for diagnostic testing is dependent on the form of clinical illness. The following specimens are acceptable for the various forms of illness as specified: whole blood, serum, respiratory secretions, swabs of visible lesions, aspirates from lymph nodes or lesions, tissue biopsies, autopsy materials (lymph node, lung, liver, spleen, cerebrospinal fluid, and bone marrow)
Definite diagnosis of tularemia requires isolation of the causal agent. Culture provides a conclusive diagnosis of infection and an invaluable resource for molecular epidemiology, subtyping and discovery of novel species and subspecies. Whenever possible, culture should be attempted. F. tularensis grows well on several types of cysteine/cystinesupplemented agar.
The diagnosis of tularemia is mainly based on serological analysis, because isolation of the causative agent is time-consuming, extremely hazardous and requires biosafety level-3 containment in order to avoid risks of laboratory infection. Agglutination, either microagglutination or tube agglutination, is the standard serological test used for determining the presence of antibody to F. tularensis. More recently an ELISA (directed against LPS) combined with Western blot (against antigen extracted from whole killed cells) showed very good sensitivity and specificity for diagnosis of infection.
PCR can be a valuable diagnostic tool when organisms are non-cultivable or when culture is not recommended due to biosafety concerns.
In severe tularaemia which requires hospitalization, parenteral administration of an aminoglycoside is the first choice for treatment. Gentamicin is preferred at 5 mg/kg daily, divided into two doses and monitored by assay of serum concentrations of the drug. If streptomycin is available, it is an alternative given by intramuscular injection 2 g daily, divided in two doses, for 10 days.
In severe cases the treatment period will depend on clinical response, and may comprise more than 10 days. In less severe cases or in a mass casualty setting, oral ciprofloxacin or doxycycline is preferred. Ciprofloxacin 800–1000 mg daily, divided into two doses, may be given intravenously or by oral administration. The treatment period should be 10–14 days. An alternative is doxycycline, 200 mg daily, divided in two oral doses and, due to the bacteriostatic nature of the drug, given for at least 15 days.
In cases which require hospitalization, parenteral administration of an aminoglycoside is preferred. The drug of choice is gentamicin, 5–6 mg/kg divided into two or three doses and monitored by assay of serum concentrations of the drug. If available, streptomycin 15 mg/kg twice daily (up to 2 g daily) is an alternative. In milder cases, particularly in areas endemic for the less virulent type B tularaemia, ciprofloxacin 15 mg/kg twice daily (up to 1 g daily), is a feasible alternative. Irrespective of the antibiotic chosen, treatment should be continued for at least 10 days.
This is a situation where potential side-effects have to be weighed against the benefits of treatment of a severe infection. Even though gentamicin and ciprofloxacin are not approved for administration in pregnancy by the Food and Drug Administration of the USA, their use in pregnancy in tularaemia has been recommended by a working group on civilian biodefence. Ciprofloxacin is an option and a brief course of gentamicin treatment is an alternative. Doses are the same as for non-pregnant subjects and the treatment period should be individualized.