Introduction 

Tularemia is a disease due by the bacterial organism Francisella Tularensis. The disease usually spreads in animals like rodents, hares, and rabbits and is typically transmitted to humans through the bite of deer flies and ticks, handling of infected animals, inhaling the airborne bacteria, or by consuming contaminated food and water.¹ As it originates from animals, Tularemia is described as a zoonotic disease found in rural areas of Europe, the United States, and Asia and a higher occurrence in Scandinavian countries and Siberia.² Despite its widespread characteristics, it is still considered a relatively rare disease with only around 100-200 cases in the USA each year.³ In terms of its prevalence, it can occur at any age, and reports suggest that there is a higher rate amongst men than women.⁴ Additionally, certain risk factors increase the likelihood of developing the disease, including people who handle the infected animals or the microorganism, like laboratory technicians, farmers, veterinarians or butchers.⁵

In terms of its clinical progression, symptoms vary widely and are dependent on the specific type of tularemia. The interest in Tularemia has increased over the last few years, not only due to the serious complications but also because of its potential to be used as a biological weapon, as it can be transmitted by inhalation, therefore, symptom recognition is crucial.⁶

Forms of tularemia and their symptoms

The signs and symptoms of Tularemia are dependent on several factors, which include the infective dose, route, widespread of the disease, the strain's virulence, and the host’s immunity. There are four subspecies of Francisella Tularensis, including tularensis (Type A,) which is localised to North America, holarctica (Type B), which is widespread throughout the world, mediasiatica, and novicida, which is the least harmful as it has low virulence. There are also six different forms, each with their own unique set of symptoms. These forms include: Ulceroglandular, Glandular, Oculoglandular, Oropharyngeal, Pneumonic, and Typhoidal disease. There is also the systemic spread of Tularemia, which is called Septicemic tularemia, which is a very rare and serious form.⁵

For Tularemia, the time between exposure to the infectious microorganism and the start of symptoms is on average 3-5 days, but can range from 1 to 20 days. In some individuals, there may be no symptoms or the onset of the disease may be sudden, and all of the clinical forms can have several shared features. ⁷

Common symptoms of all forms of tularemia

Although there are several different types of Tularemia, there are clinical manifestations that all of them share, and these include: 

• Fever and sweating: sudden onset of a high temperature, which can be as high as 104°F ⁸
• Chills: usually occurring with a high fever as a method of adjusting the body temperature, usually in the early stages of the disease
• Headaches: may be intense and form part of the influenza-like symptoms
• Muscle and Joint pain
• Generally feeling tired and ill²

Ulceroglandular tularemia symptoms

This is the most common form of tularemia. The transmission route is through the skin, whereby an infected deer fly or tick bites the human skin, allowing Francisella Tularensis to enter the body. An alternative way is through handling an infected animal.⁸

Hallmark symptoms

• At the site of bacterial entry, a painful, erythematous papule begins to form, which over a few days increases and becomes an open ulcer. If it enters through a break in the skin, then the ulcer with raised edges is typically located on the hands or the fingers. If it is through a bite, then it usually occurs in the armpit, trunk, or even the groin² 
• If it enters from the bloodstream or the lymphatic system, then the bacteria travel to the lymph node, which becomes painful and swollen, a condition called lymphadenopathy. As the disease progresses, the lymph node can break down and the dead material can accumulate as pus. In this form, there is generalised inflammation of the tissues and lymph nodes⁹
• Once the disease has resolved, the inoculation site ulcer typically forms a scar with black eschar, which is a piece of dead tissue that easily falls off the skin 
• If it is Type A tularemia, then this can co-occur with pneumonia and pleural effusion⁴ 

Glandular tularemia symptoms

Glandular Tularemia has a similar presentation to ulceroglandular Tularemia but without the hallmark sign of an ulcer. The route of transmission is the same, either through a bite or the handling of infected animals. It is the second most common type, but diagnosis is typically more difficult without recognition of the ulcer.¹⁰

Hallmark symptoms

• There are swollen and tender lymph nodes (lymphadenopathy), but the skin ulcers do not form
• It involves one or more lymph nodes 
• Diagnosis may also be delayed in this form, as fever may be absent or reduced¹¹

Oculoglandular tularemia symptoms

This occurs when the bacteria enter through the eye of the person, specifically the conjunctiva. Usually, this is when an individual rubs or touches their eyes after contact with infected animals or materials, through splashes or even aerosols.⁸ It is an uncommon presentation of Tularemia and can be followed by Ulceroglandular Tularemia.⁴ 

Hallmark symptoms

Symptoms are usually unilateral and include: 

• Inflammation of the conjunctiva membrane of the eyes is known as conjunctivitis. This can lead to painful, red, and itchy eyes. The regional lymph nodes can be swollen and can produce purulent discharge that is yellow in colour and crusty. 
• Ulcers formed on the cornea and conjunctiva
• Photophobia: sensitivity to light 
• Watery eyes/ Lacrimation 
• Edema of the eyelid 
• In some severe cases, it can even affect vision and can lead to blindness¹¹

Oropharyngeal tularemia symptoms

Another rare form of Tularemia occurs after consuming contaminated food or water. Typically, the food is undercooked and infected meat.³

Hallmark symptoms

• Swollen and enlarged tonsils (tonsillitis) and some patients may have exudative pharyngitis with the development of a yellow-white pseudomembrane.  
• Sore mouth and throat: including mouth ulcers⁹
• Gastrointestinal issues: abdominal pain, nausea, vomiting, diarrhoea, and even stomach bleeding. If the diarrhoea progresses, it can cause complications such as colon ulcerations⁶
• Cervical lymphadenopathy: swollen lymph glands in the neck¹⁰

Pneumonic tularemia symptoms

This form is uncommon but most severe. It occurs through inhaling the bacteria directly, or by Bacteria in another region of the body, which spreads through the blood circulation and into the lungs. It is more likely to occur in those who deal with aerosol versions of the bacteria, such as laboratory workers.⁸

Hallmark symptoms

• A dry cough, difficulty breathing, and chest pain due to inflamed pleura, which are the layers that separate the lungs from the chest wall⁶
• Additional conditions in the lungs include infection in the lungs known as pneumonia, lung abscesses, and additional fluid around the lungs known as pleural effusion.
• Bilateral hilar adenopathy may also occur⁹
• In some patients, this can be complicated by the development of acute respiratory distress syndrome¹⁰

Typhoidal tularemia symptoms

A very severe presentation of general symptoms of Tularemia. In most cases, the source of this type can not be identified due to the absence of skin ulcers and regional lymphadenopathy. 

The bacteria spread through the bloodstream and is usually due to Type A or B Tularemia.⁹

Hallmark symptoms 

• A combination of fever, muscle pain, lack of energy, weight loss, and chills 
• It can be accompanied by neurological symptoms³

Septicemic tularemia

This is the widespread version of the illness where the bacteria spread through the entirety of the bloodstream and can lead to multiple organ failure. It is often fatal and severe, and the complications can lead to mortality.⁶

Hallmark symptoms

• Disseminated intravascular coagulation, causing bleeding, can occur when the blood decreases substantially, leading to a decrease in blood pressure, an increase in fluid in the lungs, and the loss of clotting factors
• Other complications of this type are neurological symptoms, septic shock, meningitis, septicaemia, haemorrhages, systemic inflammatory response syndrome, severe acute respiratory syndrome, and multiple organ failure⁴

Summary 

This article explains the various presentations of Tularemia and how they are dependent on the infective dose, route, the widespread the disease, the strain virulence, and the host’s immunity. In particular, there are several forms of Tularemia, including Ulceroglandular, Glandular, Oculoglandular, Oropharyngeal, Pneumonic, Typhoidal, and Septicemic Tularemia, that have different hallmark symptoms.⁵  

Ulceroglandular Tularemia is usually associated with ulcers at the site of entry,² Glandular Tularemia has tender lymphadenopathy,¹¹ Oculoglandular typically presents with conjunctivitis,¹¹  Oropharyngeal affects the mouth, and tonsils causing Gastrointestinal symptoms,¹⁰ Pneumonic presents with a dry cough and lung complications,⁹ Typhoidal involves generalised symptoms and Septicemic tularemia is the widespread complications of the disease.³ 

All forms share a set of common influenza-like symptoms.⁸ Symptom recognition is important to reduce mortality in today's society, where bacteria can potentially be used in bioterrorism.⁶