Introduction

Tularemia is categorised as an acute febrile zoonotic illness caused by the highly infectious Gram-negative organism - Francisella tularensis. The symptoms can demonstrate variability owing to a dependence on the route.

We have not yet managed to find a gold standard for the diagnosis of tularemia. The diagnosis still has a reliance on serological tests. The isolation and identification of F. tularensis by culture are meticulous and show results with less than 10% of positive cultures in immunocompetent patients. However, methods based on PCR can be used to provide an early diagnosis when performed on tissue, skin ulcer, and other biological sample types. 

According to a study conducted by Olivier Bahuaud and colleagues, 48% of the patients had positive blood cultures for F. tularensis. Most of the cases of F. tularensis bacteremia have been previously reported to have an association with pneumonic tularemia, which agrees with the results of this study. This gives way to highlighting the severity of tularemia in immunocompromised patients as well, as bacteremia is associated with outcomes that are derogatory. 29% of the patients went through serological testing and demonstrated positive results in 80% and 100%, respectively. These findings might point towards the fact that the diagnosis was rarely suspected initially. However, on performance, these tests gave way to the confirmation of the diagnosis. This undoubtedly lays an emphasis on the significance of better or more refined knowledge of the characteristics of tularemia for physicians to enable them to suspect this diagnosis effectively and set up the most relevant diagnostic strategy in affected or concerned patients.

The treatment of tularemia has a reliance on antimicrobial therapy utilising quinolones, cyclins, and aminoglycosides as the primary class of antibiotics recommended. In this study, patients received either one or a combination of these antibiotics, demonstrating a favourable outcome in 94% of the cases. Therefore, we can probably expect a similarity in terms of susceptibility to antibiotics between immunocompromised patients and the general population with respect to the heterogeneity of the durations of treatment presented in different study scenarios.

A more frequent pulmonary involvement has been identified among immunocompromised patients presenting with tularemia. A dreary, or rather time-consuming, diagnosis is often involved with clinical symptoms and radiological findings that show minimal specificity, exhibiting pulmonary lesions or mediastinal adenopathy indistinguishable from malignancies. In this context, methods that are PCR-based can be employed and are useful for the purpose of allowing a faster diagnosis as compared with serological tests. Thus, this infection should have probable suspicion in immunocompromised patients presenting with fever and respiratory symptoms or a history of potential exposure.

More frequent contamination through inhalation is the basis of pneumonic presentation, emphasising the importance of preventive measures in case of immunocompromised patients living in areas of high risk of tularemia, involving the use of surgical masks during outdoor activities, and avoidance of contact with dead animals. It should be encouraged to monitor tularemia in wildlife via surveillance networks as it allows the identification of areas with high risks of outbreaks.¹

Therefore, in future years, a persistent increase in the animal reservoir can be expected, owing to the phenomenon of global warming. This includes an elevation in hosts within a wide range of species, in addition to the vectors, as it has already been witnessed for other infectious diseases in humans or animals (e.g., dengue virus, malaria, blue tongue virus, Lyme disease, etc.). Moreover, the development of novel immunosuppressive therapies will, in turn, lead to an increase in the number of immunocompromised patients. Thus, it appears important to highlight the characteristics of tularemia in this cohort. 

Exploration of the effects, risks, and management of tularemia in immunocompromised individuals

Although clear literature data about the specific characteristics of this disease in immunocompromised patients is lacking, clinical reports seem to provide a description of a different presentation of tularemia in the patients included in.¹ Moreover, atypical clinical presentations added to the fastidiousness of pathogen identification seem to be responsible for a delayed or misdiagnosis, leading to a” loss of chance” for immunocompromised patients.¹

General overview of tularemia

Zoonotic diseases or zoonosis (zoonotic disease or zoonoses -plural) are infectious diseases that are transmitted between species from animals to humans (or from humans to animals).

The bacterium Francisella tularensis is responsible for causing Tularemia, or “rabbit fever”. Tularemia is typically found in animals, especially rodents, hares and rabbits. 

Sources of infection and routes of transmission

Multiple routes of transmission:

• arthropod bites (predominantly tick or mosquito bites), which probably cause 10 – 90% of tularaemia cases in humans in Europe 
• direct transmission from an animal reservoir, which might have an occurrence through handling an infected animal (especially a hare), ingestion of undercooked meat prepared from an infected animal, or an animal bite 
• spread through direct contact or ingestion of contaminated water and soil
• inhalation of infective aerosols, e.g. during farming activities

Synopsis of the infection

• Pathogen: Francisella tularensis bacterium
• Transmission Methods: Inhalation, ingestion, direct contact with infected animals, or bites from ticks, flies, etc. 
• Symptoms and Severity: Sudden fever, skin ulceration, swollen lymph glands, pneumonia in severe cases
• Geographic Prevalence: Common in North America, Europe, and parts of Asia

Immune system basics

The immune system is intricate and complicated, and can be categorised in two divisions: i) the innate branch, non-specific, that consists of the activation and participation of mechanisms including the natural barriers (skin and mucosa) and secretions; and ii) the adaptive branch, specific, targeted against a specific microorganism or antigen that has gained preceding recognition. Thus, in case of the host getting infected by a new pathogen, there is initial recognition by the innate immune system, followed by the activation of the adaptive immune response. 

Innate immune system

The innate immune response is the antecedent mechanism fulfilling the purpose of host defence and is found in all multicellular organisms. This system has undergone development and evolution to protect the host from a variety of toxins and infectious agents, including bacteria, fungi, viruses and parasites.

Innate immunity consists of different components involving physical barriers (tight junctions in the skin, mucus, epithelial and mucous membrane surfaces); anatomical barriers; other cells and proteins.

Following the entry of the interaction host-invader pathogen, there is initiation of a signalling cascade resulting in the enhancement of the immune response and activating specific mechanisms. This natural immune response leads to: a) elimination of invading pathogens, b) prevention of infection, and c) stimulation of the acquired immune response.²

Adaptive immune system

Our adaptive immune system saves us from sudden death by infection. Looking at the case of an infant born with a severely defective adaptive immune system, the infant will soon die unless extraordinary measures are put in place in order to isolate it from a host of pathogens. Indeed, it is an essential need of all multicellular organisms to defend themselves against infection by such potentially harmful invaders, collectively known as pathogens. There is utilisation of relatively simple defence strategies having a reliance chiefly on protective barriers, toxic molecules, and phagocytic cells ingesting and destroying invading microorganisms (microbes) and larger parasites (such as worms), in the case of invertebrates. Vertebrates employ such innate immune responses as a first line of defence; however, they are capable of mounting much more sophisticated defences as well, called adaptive immune responses. The innate and adaptive immune responses work in collaboration for the elimination of pathogens. 

Unlike innate immune responses, the adaptive responses demonstrate high specificity to the particular pathogen that elicited them. They also have the ability the provide long-standing protection. 

Adaptive immunity is essential for host protection from infectious diseases and malignancies, but also has the potential to contribute to autoimmunity and inflammation under pathophysiological conditions. The adaptive immune system is the collection of cells, factors, and effector mechanisms that are involved in the recognition of and responses to specific antigens, which can be derived from entities outside the body. 

The adaptive immunity is specific and undergoes a delayed activation, in contrast with the more rapid and relatively non-specific innate immune response. Further, the adaptive immune system is defined by the emergence of immune memory, the remarkable capacity of lymphocytes to rapidly and precisely respond to a pathogen-derived antigen they previously encountered, thereby mediating improved protection from re-infection. To accomplish this, the adaptive immune system utilises an array of diverse immune cell types acting as individual but interdependent effectors, along with numerous critical interactions with stromal and parenchymal cells throughout tissues.

The core cellular players in this branch of immunity are lymphocytes, specifically T cells and B cells. T cell populations can be further classified as CD4+ helper T cells and CD8+ cytotoxic T cells. Soluble effector molecules called antibodies are secreted by B cells, and these can also function as antigen-presenting cells (APCs), presenting specific antigens to T cells. Antibodies will bind target antigens with high affinity and demonstrate interference with numerous pathogenic processes, leading to the prevention of pathogen entry into cells, which can provide sterilising protection against infection from obligate intracellular pathogens.³

The adaptive immune responses destroy invading pathogens and toxic molecules produced by them. The ability to distinguish foreign from self is a fundamental feature of the adaptive immune system. Occasionally, the system fails to make this distinction and reacts destructively against the host's own molecules, leading to the development of autoimmune diseases that can be fatal.⁴

Immune response to franciscella infection

Production of cytokines during Francisella infection is a very active area of research (for an overview, refer to Figure 2). Similar to other intracellular pathogens, rapid production of pro-inflammatory and Th1-type cytokines is critical for the purpose of controlling Francisella infection. 

During virulent F. tularensis respiratory infection of mice, mRNA levels of essential antimicrobial cytokines such as IFN-γ and TNF-α saw a rise in the lungs between days 2 and 4. Serum/distal organ levels of pro-inflammatory mediators such as RANTES, IL-6, and IL-1β have been detected on days 3–4. Key organs, including the lungs and liver, have been observed to harbour extremely high bacterial burdens following 2 days of unrestricted bacterial growth. Hence, the relatively late up-regulation of antimicrobial host immune mechanisms is too late to prevent death, apparently. 

Indeed, the hypothesis that augmenting production of pro-inflammatory cytokines very early during infection can be beneficial has been supported by a number of studies. 

The widespread up-regulation of multiple cytokines and chemokines by day 3 following murine F. novicida pulmonary infection has resemblance to a “cytokine storm” associated with severe sepsis – a condition characterised by excessive pro-inflammatory cytokine production culminating in capillary leakage, leading to tissue injury, and organ failure. One mediator of severe sepsis, the nuclear DNA-binding protein HMGB-1, has been found to be strongly up-regulated and has extracellular localisation in mouse lungs by day 3 after F. novicida intranasal infection.⁵

How tularemia affects immunocompromised individuals

In conclusion, tularemia should be considered in immunocompromised patients presenting with unexplained fever or pulmonary symptoms. Molecular techniques carried out on pathological tissues might offer improved diagnosis with faster results. Additionally, the pneumonic presentation conveys more frequent contamination through inhalation, putting an emphasis on the importance of preventive measures in immunocompromised patients in areas of high risk of tularemia, involving the use of surgical masks in outdoor activities, and avoiding contact with dead animals. Tularemia monitoring in wildlife via surveillance networks needs to be encouraged as it will allow the identification of high-risk areas for outbreaks.¹

Summary

Tularemia is categorised as an acute febrile zoonotic illness caused by the highly infectious Gram-negative organism - Francisella tularensis. The symptoms can demonstrate variability owing to a dependence on the route.

A more frequent pulmonary involvement has been identified among immunocompromised patients presenting with tularemia. 

A dreary, or rather time-consuming, diagnosis is often involved with clinical symptoms and radiological findings that show minimal specificity, exhibiting pulmonary lesions or mediastinal adenopathy indistinguishable from malignancies.

The bacterium Francisella tularensis is responsible for causing Tularemia, or “rabbit fever”. Tularemia is typically found in animals, especially rodents, hares and rabbits. 

The immune system is intricate and complicated, and can be categorised in two divisions: i) the innate branch, non-specific, that consists of the activation and participation of mechanisms including the natural barriers (skin and mucosa) and secretions; and ii) the adaptive branch, specific, targeted against a specific microorganism or antigen that has gained preceding recognition. 

Production of cytokines during Francisella infection is a very active area of research. Similar to other intracellular pathogens, rapid production of pro-inflammatory and Th1-type cytokines is critical for the purpose of controlling Francisella infection.

Tularemia should be considered in immunocompromised patients presenting with unexplained fever or pulmonary symptoms. 

Molecular techniques carried out on pathological tissues might offer improved diagnosis with faster results. 

Additionally, the pneumonic presentation conveys more frequent contamination through inhalation, putting an emphasis on the importance of preventive measures in immunocompromised patients in areas of high risk of tularemia, involving the use of surgical masks in outdoor activities, and avoiding contact with dead animals.