Paediatric oropharyngeal tularaemia requiring surgical intervention.

Tularaemia is a rare infectious disease endemic in most European countries caused by the bacterium Francisella tularensis 1 Patients often show acute non-specific symptoms, which causes a delay in diagnosis and proper treatment, potentially resulting in significant morbidities such as deep neck abscess, meningitis, endocarditis and septic shock. The authors present a case of a 5-year old boy with a 4-day history of fever, sore throat and painful cervical lymphadenopathy, whose clinical progression worsened despite being treated with recommended antibiotics as per WHO guidelines once the diagnosis of Tularaemia was confirmed by serologic tests. He developed a parapharyngeal abscess and a persistent left necrotic cervical lymph node, which both were surgically drained and excised, respectively, and an extended course of antibiotic was given. Subsequently, the patient fully recovered from the illness and the follow-up was negative for relapse.

Tularemia - zoonosis carrying a potential risk of bioterrorism.

Tularemia, otherwise known as “rabbit fever”, is a zoonotic disease caused by a gram-negative intracellular bacterium - Francisella tularensis. The species is considered as a potential bioterrorism agent due to its high infectivity, the fact of being relatively easy to culture, the absence of human vaccine, and the potential for spreading through aerosol. In the Czech Republic, infection is usually caused by a tick bite, less frequently by a mosquito bite, direct contact with infected animals, or ingestion of contaminated water. The aim of this review is to provide a comprehensive view of tularemia, its diagnosis, clinical symptoms and treatment, along with the military perspective on a potential risk of F. tularensis to be misused as a biological weapon.

Tick-Borne Illnesses in the United States.

Close interaction with nature can lead to tick-borne illnesses, which are seen most frequently in primary care clinics when patients present symptoms. Considerable morbidity can result from untreated infections. Fortunately, these illnesses are often easily managed when diagnosed early.

Imaging Findings of Ulceroglandular Tularemia.

Francisella tularensis, the causative organism in Tularemia, is a relatively rare disease. There are a few radiological clues to elucidate its presence when suspicion arises. There should be strong consideration for Tularemia in the differential of any patient with its classic symptoms, diffuse cervical lymphadenopathy with evidence of necrosis, and enlarged adenoids. Ultrasound may demonstrate suppurative lymphadenopathy suggestive of infection, as in the case presented. CT often will demonstrate the extent of lymphadenopathy. On chest radiography, tularemia pneumonia is often the presenting finding, which may demonstrate bilateral or lobar infiltrates. Additionally, hilar lymphadenopathy and pleural effusions are often associated findings. Cavitary lesions may be present, which are better delineated on CT scan. We present a case of a 7-year-old male who presented with a painful right-sided palpable neck mass for 9 days, who was diagnosed with Tularemia after numerous admissions.

Notes from the Field: Francisella tularensis Type B Infection from a Fish Hook Injury - Minnesota, 2016.

On June 27, 2016, the Minnesota Department of Health (MDH) Public Health Laboratory (PHL) was notified of a suspected Francisella tularensis isolate cultured at a hospital laboratory. The isolate was confirmed as F. tularensis type B at MDH PHL by reverse transcription-polymerase chain reaction, culture, and direct fluorescent antibody testing. Francisella tularensis subspecies tularensis (type A) and holarctica (type B) bacteria are the causative agents of tularemia.

Clinical management of potential bioterrorism-related conditions.

The agents most likely to be used in bioterrorism attacks are reviewed, along with the clinical syndromes they produce and their treatment.

Immunopotentiation for bacterial biodefense.

Activation of the innate immune system can enhance resistance to a variety of bacterial and viral infections. In situations where the etiological agent of disease is unknown, such as a bioterror attack, stimulation of innate immunity may be particularly useful as induced immune responses are often capable of providing protection against a broad range of pathogens. In particular, the threat of an intentional release of a highly virulent bacterial pathogen that is either intrinsically resistant to antibiotics, or has been weaponized via the introduction of antibiotic resistance, makes immunopotentiation an attractive complementary or alternative strategy to enhance resistance to bacterial biothreat agents. Francisella tularensis, Yersinia pestis, Bacillus anthracis, and Burkholderia mallei or pseudomallei can all be easily disseminated via the respiratory route and infections can result in high mortality rates. Therefore, there has been a marked increase in research on immunotherapeutics against these Tier 1 select agents over the last 10 years that will be covered in this review. In addition, immunopotentiation against non-Tier 1 select agents such as Brucella spp., and Coxiella burnetii has also been studied and will be reviewed here. In particular, we will focus on cellular targets, such as toll-like receptors (TLRs), carbohydrate receptors and cytokine receptors, which have been exploited by immunomodulatory regimens that confer broad-spectrum protection against virulent bacterial pathogens.

[Tularemia in Germany]. / Die Tularämie in Deutschland.

The bacterium Francisella tularensis is known for more than 100 years by now as the etiological agent of the disease tularemia, a zoonotic infection with a worldwide distribution in the Northern Hemisphere. The prevalence of tularemia shows a wide geographic variation, being comparably infrequent in Germany. Tularemia can present itself with multiple clinical manifestations including ulceroglandular, glandular, oropharyngeal, oculoglandular, respiratory and typhoidal forms. Due to the low prevalence and the unspecific symptomatology, a rapid diagnosis and early start of an effective therapy are rarely obtained. Thus, in this article we summarize important aspects concerning etiology, ecology and routes of transmission, recent epidemiologic situation, clinical picture, diagnostics and treatment of tularemia, focusing on the situation in Germany.

New therapeutic approaches for treatment of tularaemia: a review.

Antibiotic treatment of tularaemia is based on a few drugs, including the fluoroquinolones (e.g., ciprofloxacin), the tetracyclines (e.g., doxycycline), and the aminoglycosides (streptomycin and gentamicin). Because no effective and safe vaccine is currently available, tularaemia prophylaxis following proven exposure to F. tularensis also relies on administration of antibiotics. A number of reasons make it necessary to search for new therapeutic alternatives: the potential toxicity of first-line drugs, especially in children and pregnant women; a high rate of treatment relapses and failures, especially for severe and/or suppurated forms of the disease; and the possible use of antibiotic-resistant strains in the context of a biological threat. This review presents novel therapeutic approaches that have been explored in recent years to improve tularaemia patients' management and prognosis. These new strategies have been evaluated in vitro, in axenic media and cell culture systems and/or in animal models. First, the activities of newly available antibiotic compounds were evaluated against F. tularensis, including tigecycline (a glycylcycline), ketolides (telithromycin and cethromycin), and fluoroquinolones (moxifloxacin, gatifloxacin, trovafloxacin and grepafloxacin). The liposome delivery of some antibiotics was evaluated. The effect of antimicrobial peptides against F. tularensis was also considered. Other drugs were evaluated for their ability to suppress the intracellular multiplication of F. tularensis. The effects of the modulation of the innate immune response (especially via TLR receptors) on the course of F. tularensis infection was characterized. Another approach was the administration of specific antibodies to induce passive resistance to F. tularensis infection. All of these studies highlight the need to develop new therapeutic strategies to improve the management of patients with tularaemia. Many possibilities exist, some unexplored. Moreover, it is likely that new therapeutic alternatives that are effective against this intracellular pathogen could be, at least partially, extrapolated to other human pathogens.

Immunotherapy for tularemia.

Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (> 30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia.

Biowarfare and bioterrorism.

Bioterrorism is not only a reality of the times in which we live but bioweapons have been used for centuries. Critical care physicians play a major role in the recognition of and response to a bioterrorism attack. Critical care clinicians must be familiar with the diagnosis and management of the most likely bioterrorism agents, and also be adequately prepared to manage a mass casualty situation. This article reviews the epidemiology, diagnosis, and treatment of the most likely agents of biowarfare and bioterrorism.

The binding sites of monoclonal antibodies to the non-reducing end of Francisella tularensis O-antigen accommodate mainly the terminal saccharide.

We have previously described two types of protective B-cell epitopes in the O-antigen (OAg) of the Gram-negative bacterium Francisella tularensis: repeating internal epitopes targeted by the vast majority of anti-OAg monoclonal antibodies (mAbs), and a non-overlapping epitope at the non-reducing end targeted by the previously unique IgG2a mAb FB11. We have now generated and characterized three mAbs specific for the non-reducing end of F. tularensis OAg, partially encoded by the same variable region germline genes, indicating that they target the same epitope. Like FB11, the new mAbs, Ab63 (IgG3), N213 (IgG3) and N62 (IgG2b), had higher antigen-binding bivalent avidity than internally binding anti-OAg mAbs, and an oligosaccharide containing a single OAg repeat was sufficient for optimal inhibition of their antigen-binding. The X-ray crystal structure of N62 Fab showed that the antigen-binding site is lined mainly by aromatic amino acids that form a small cavity, which can accommodate no more than one and a third sugar residues, indicating that N62 binds mainly to the terminal Qui4NFm residue at the nonreducing end of OAg. In efficacy studies with mice infected intranasally with the highly virulent F. tularensis strain SchuS4, N62, N213 and Ab63 prolonged survival and reduced blood bacterial burden. These results yield insights into how antibodies to non-reducing ends of microbial polysaccharides can contribute to immune protection despite the smaller size of their target epitopes compared with antibodies to internal polysaccharide regions.

Neutrophils: potential therapeutic targets in tularemia?

The central role of neutrophils in innate immunity and host defense has long been recognized, and the ability of these cells to efficiently engulf and kill invading bacteria has been extensively studied, as has the role of neutrophil apoptosis in resolution of the inflammatory response. In the past few years additional immunoregulatory properties of neutrophils were discovered, and it is now clear that these cells play a much greater role in control of the immune response than was previously appreciated. In this regard, it is noteworthy that Francisella tularensis is one of relatively few pathogens that can successfully parasitize neutrophils as well as macrophages, DC and epithelial cells. Herein we will review the mechanisms used by F. tularensis to evade elimination by neutrophils. We will also reprise effects of this pathogen on neutrophil migration and lifespan as compared with other infectious and inflammatory disease states. In addition, we will discuss the evidence which suggests that neutrophils contribute to disease progression rather than effective defense during tularemia, and consider whether manipulation of neutrophil migration or turnover may be suitable adjunctive therapeutic strategies.

Tularaemia presenting as parapharyngeal abscess: case presentation.

OBJECTIVE: We report an extremely rare case of the oropharyngeal form of tularaemia, causing a parapharyngeal abscess. CASE REPORT: A 48-year-old woman presented with fever, sore throat, breathing difficulty and a right-sided neck swelling. This mass had previously been treated with penicillin without response, and had already been surgically drained once in another hospital. On physical examination, the tonsils were exudative and hypertrophic and the pharynx was hyperaemic. A fluctuant, 4 × 4 cm mass was seen on endoscopic examination, originating from the left parapharyngeal area and protruding towards the pyriform sinus, and partly obstructing the airway. Microagglutination test antibody titres for Francisella tularensis were positive (1/1280). The patient healed completely after definitive drainage of the abscess and antimicrobial therapy for 14 days (streptomycin, 2 × 1 g intramuscularly). CONCLUSION: Tularaemia should be considered in the differential diagnosis of patients presenting with tonsillopharyngitis, cervical lymphadenitis and parapharyngeal abscess who do not respond to treatment with penicillin, even if they do not live in an endemic region.

A Francisella tularensis live vaccine strain that improves stimulation of antigen-presenting cells does not enhance vaccine efficacy.

Vaccination is a proven strategy to mitigate morbidity and mortality of infectious diseases. The methodology of identifying and testing new vaccine candidates could be improved with rational design and in vitro testing prior to animal experimentation. The tularemia vaccine, Francisella tularensis live vaccine strain (LVS), does not elicit complete protection against lethal challenge with a virulent type A Francisella strain. One factor that may contribute to this poor performance is limited stimulation of antigen-presenting cells. In this study, we examined whether the interaction of genetically modified LVS strains with human antigen-presenting cells correlated with effectiveness as tularemia vaccine candidates. Human dendritic cells infected with wild-type LVS secrete low levels of proinflammatory cytokines, fail to upregulate costimulatory molecules, and activate human T cells poorly in vitro. One LVS mutant, strain 13B47, stimulated higher levels of proinflammatory cytokines from dendritic cells and macrophages and increased costimulatory molecule expression on dendritic cells compared to wild type. Additionally, 13B47-infected dendritic cells activated T cells more efficiently than LVS-infected cells. A deletion allele of the same gene in LVS displayed similar in vitro characteristics, but vaccination with this strain did not improve survival after challenge with a virulent Francisella strain. In vivo, this mutant was attenuated for growth and did not stimulate T cell responses in the lung comparable to wild type. Therefore, stimulation of antigen-presenting cells in vitro was improved by genetic modification of LVS, but did not correlate with efficacy against challenge in vivo within this model system.

Identification of Francisella tularensis outer membrane protein A (FopA) as a protective antigen for tularemia.

Francisella tularensis is a highly pathogenic gram negative bacterium that infects multiple sites in a host, including the skin and the respiratory tract, which can lead to the onset of a deadly disease with a 50% mortality rate. The live vaccine strain (LVS) of F. tularensis, while attenuated in humans but still virulent in mice, is not an option for vaccine use in the United States due to safety concerns, and currently no FDA approved vaccine exists. The purpose of the present work was to assess the ability of recombinant Francisella outer membrane protein A (FopA) to induce a protective response in mice. The gene encoding FopA from F. tularensis LVS was cloned and expressed in Escherichia coli. The resulting recombinant protein was affinity-purified from the E. coli outer membrane, incorporated into liposomes and administered to mice via multiple routes. FopA-immunized mice produced FopA-specific antibodies and were protected against both lethal intradermal and intranasal challenges with F. tularensis LVS. The vaccinated mice had reduced bacterial numbers in their lungs, livers and spleens during infection, and complete bacterial clearance was observed by day 28 post infection. Passive transfer of FopA-immune serum protected naïve mice against lethal F. tularensis LVS challenge, showing that humoral immunity played an important role in vaccine efficacy. FopA-immunization was unable to protect against challenge with the fully virulent SchuS4 strain of F. tularensis; however, the findings demonstrate proof of principle that an immune response generated against a component of a subunit vaccine is protective against lethal respiratory and intradermal tularemia.