Tularaemia is a rare but highly infectious disease that causes fevers and damage to key organs. There are various ways of diagnosing this condition in a clinical environment, which gives key information to help guide treatment. As tularaemia often mimics other disorders, accurate diagnosis is essential so that the correct treatment can be started as early as possible and potentially severe health outcomes can be prevented. 

What is tularaemia?

Tularaemia is an infectious disease caused by the Francisella tularensis bacteria. It is a zoonotic infection, meaning that it is transmitted from animals to humans. It is sometimes referred to as rabbit fever, as it can be transferred to humans through tick bites from wild game. Tularaemia can affect many different body parts, typically causing fevers and swelling of lymph nodes.

It requires a remarkably low number of bacteria for the infection to take route, only 10-50 individual units to cause infection¹, much lower than other comparable bacterial infections.

How is tularaemia spread?

Tularaemia can be caught from animal sources, and those who work closely with commonly infected animals, or in regions of the world where tularaemia is endemic, are at the highest risk of infection.² This is particularly common in rural parts of the northern hemisphere, including North America and Northern Europe.

Tularaemia can infect the body through:

• Direct contact with broken skin, for example via animal bites
• Insect bites, including ticks and mosquitos – in particular, the Lonestar tick (Dermacentor americanum), the Wood tick (Dermacentor andersoni) and the Dog tick (Dermacentor variablis)³
• Contaminated water (either from drinking or swimming in infected spots)
• Inhalation

What are the typical symptoms of tularaemia?

Tularaemia comes in several different subtypes, classified according to their symptoms. In general, most forms of tularaemia will cause the following symptoms:⁴

• Fever
• Headache
• Malaise (a feeling of being generally unwell, feeling achy and tired)
• Swollen lymph glands (lymphadenopathy)
• Sepsis in severe cases (damage to important organs as a result of an aggressive infection)

What are the different types of tularaemia?

Depending on the group of symptoms, it is possible to separate tularaemia into specific forms:⁵

• Glandular tularaemia (common) – characterised by swollen lymph nodes
• Ulceroglandular tularaemia (common) – characterised by swollen lymph nodes and ulcers, affecting skin and body cavities such as the mouth
• Oculoglandular tularaemia – characterised by swelling to the lymph nodes in front of the ears (pre-auricular) and conjunctivitis
• Typhoid or systemic tularaemia – characterised by fever, without the other early signs typically seen in tularaemia
• Oropharyngeal tularaemia – characterised by sore throat (pharyngitis), swellings and ulcers to the mouth (stomatitis) and swollen neck lymph nodes (cervical lymphadenopathy)
• Gastrointestinal tularaemia – characterised by vomiting, stomach cramps and diarrhoea, in addition to the other typical symptoms
• Respiratory tularaemia – characterised by tularaemia complicated by pneumonia or pleurisy

Initial clinical assessment and patient history

Due to the broad range of potential symptoms, clinicians will also want to rule out several other diagnoses in addition to investigating tularaemia. The clinician will ask about the above symptoms and perform a clinical examination.

 One may also be asked about:

• Recent outdoor activities
• Contact with animals or wildlife (especially wild deer and rabbits)
• Insect bites
• Recent travel to high-risk areas such as rural areas of countries in the northern hemisphere

Laboratory testing for tularaemia

Confirming a diagnosis of tularaemia can be difficult. Several laboratory tests may be used to facilitate this.

Standard blood markers

Most clinical centres will have the facility to perform basic blood tests. These do not isolate tularaemia specifically; however, they can indicate the presence of an infection. This can include looking for elevated white blood cells (a key part of the immune response) and analysing changes found during the inflammation generated in response to tularaemia, including elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).

Microscopy, culture and antibiotic sensitivity testing

The traditional process of isolating bacterial infections is culture, microscopy and sensitivity assessment, which one may see abbreviated as MC&S. Samples are taken from the body, such as blood samples, sputum samples, swabs of ulcers, cerebrospinal fluid and lymph node sections (a biopsy).⁶

These samples are cultured in a laboratory setting, which allows the bacteria to grow in a controlled environment. This usually takes a few days, but once enough of the bacteria has formed, it can be analysed under a microscope and tested to see which antibiotic therapy will be the most effective at treating it.

Unfortunately, Francisella tularensis is very difficult to grow in this manner, which makes this an unreliable method of confirming the diagnosis.

Serological testing

This is an important means of testing for tularaemia that utilises antibodies to check for the presence of tularaemia⁷, using a method called enzyme-linked immunosorbent assay testing (ELISA for short). In this method, a tray is lined with molecules that will trap the target molecule, called capture antibodies. The sample from the patient (such as blood or urine) is then added, and substances produced by the tularaemia bacteria (antigens) will stick to the capture antibody. Finally, the sample is coated in another separate fluid containing a detection antibody; if an antigen is present, the detection antibody will stick to it, causing a colour change to the sample and confirming the presence of tularaemia infection.

Molecular techniques

Polymerase Chain Reaction (PCR) is a method that works by identifying sequences of DNA that are unique to tularaemia-causing bacteria. It uses high temperatures to break down small fragments of the genetic material found in the bacteria, and then adds enzymes that multiply these fragments into high levels that can be read by diagnostic machines.⁸ These fragments will be specific to the tularaemia bacteria, and so confirm the diagnosis of tularaemia. 

Advantages and disadvantages of the different methods

Each diagnostic method has its own advantages and disadvantages, and the exact technique used will depend on the resources available to the clinical team assessing the patient.

PCR is the quickest and most accurate method, with the analysis complete within a few hours. Unfortunately, it is also expensive and only available at a limited number of testing centres. This limits its use as an intervention and as a first-line assessment tool.

Serological testing is usually accurate, although it is not always the most reliable of the methods. Certain molecules can bind to the antibodies during the ELISA analysis not related to the tularaemia bacteria, giving an incorrectly positive result. It is also expensive and not widely available in smaller hospitals. 

MC&S is very widely available as a testing method due to being the most cost-effective of the three methods, and every laboratory will have the resources and expertise to perform this test. However, due to the difficulties in culturing tularaemia, it is not a particularly reliable way of confirming the diagnosis. If bacteria can be grown, then there is use in testing the bacteria to see what antibiotic therapy they will best respond to. 

Regardless of the method used to identify and diagnose tularaemia, extreme care should be taken when culturing the bacteria due to its highly infectious nature. 

What else could it be?

Another major challenge of diagnosing tularaemia is how it can mimic many other zoonotic infections. The complications of untreated disease can be severe, the correct diagnosis must be arrived at. Other potential diagnoses that may mimic the symptoms of tularaemia include:

• Malaria
• Legionella infection
• Diphtheria
•  Lyme Disease
• Psittacosis
• Q Fever
• Endocarditis
• Brucellosis
• Cat Scratch disease

Treatment options for tularaemia

As this is a bacterial infection, the standard management will involve antibiotics. The exact choice will vary between regions, and healthcare teams will start with an antibiotic that is effective on a broad range of infections. After several days, it will be possible to switch this to a more targeted antibiotic that works against the strain of tularaemia in each particular case.⁹

Prognosis and complications

Tularaemia can be very dangerous if not recognised and treated in the early stages. Studies estimate that, if not treated properly, the death rate can be between 10-50%, and of those who survive, there is often lasting damage to the heart, kidneys and lungs.⁵ 

Complications can include:

• Acute Respiratory Distress Syndrome (ARDS)
• Lung abscess
• Pneumonia
• Kidney injury
• Meningitis

Summary

Tularaemia is a rare infectious disorder and can cause significant problems if left untreated. Accurate and rapid early diagnosis is essential, using laboratory testing including serological testing, molecular testing and bacterial culture, and correlating this with clinical findings and blood tests. This information can help differentiate tularaemia from other diseases with similar symptoms. Early treatment prevents serious complications from developing.