Tularemia: A Storied History, An Ongoing Threat (2024)

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Francisella tularensis is so highly infectious that, after its discovery as the cause of tularemia, the Medical Research Council of England declared in 1922 that occupational infection is “an accident which seems…to befall practically all laboratory workers who attempt the cultivation” [1]. Indeed, Dr Edward Francis, the pathogen's namesake, contracted tularemia in 1919 after conducting an autopsy, and all 5 of his assistants were infected over a 2-year period via contact with infected rodents [2]. Although laboratory safety measures have improved in recent decades and reduced the number of laboratory-acquired infections, F. tularensis remains notoriously infectious.

Additional detailed information regarding the infectivity of F. tularensis has come to light since the early years of investigation. In 1958, 4 young men intentionally exposed to only 14–18 aerosolized organisms became clinically ill with pneumonic tularemia [3]. Following a large outbreak of tularemia after a hare hunt in 2005, investigators determined that many participants likely were infected simply by standing within 5 meters of where disemboweled hares had been rinsed with a water hose [4]. A 2016 outbreak of tularemia in Germany occurred after an estimated 10⁹ to 10¹⁰ bacteria from an infected dead rodent contaminated 730 liters of grape must (fermented juice), some of which was ingested by 8 individuals. Six of the individuals subsequently developed oropharyngeal tularemia—an attack rate of 75% [5].

With high infectivity comes dark potential. F. tularensis has been studied and prepared as a bioweapon by the United States, the Soviet Union, Japan, Britain, and likely other countries [2]. A disturbing example was Japan's notorious bioweapons program, which conducted research on military and civilian prisoners before and during WWII. These experiments involved infecting prisoners with often fatal inocula of F. tularensis and other pathogens to study disease effects and pathophysiology [2]. During the 1950s and 1960s, F. tularensis was one of several biological weapons stockpiled in the United States and the Soviet Union [6]. Moreover, the United States conducted operation Red Cloud in Alaska from 1966-1967, releasing F. tularensis via mechanical disseminators into a spruce forest to study distribution and biological decay rates [7]. In the 1970s-1980s, the Soviet Union conducted a focused research program with the sole purpose of creating multi-drug resistant strains of F. tularensis [8].

F. tularensis is easily stored in dried form, can cause life-threatening infection by inhalation, and has been engineered as an antibiotic-resistant organism [9]. For these and other reasons, F. tularensis is currently classified as a Tier 1 Select Agent, the highest US risk category for potential bioweapons [10]. According to World Health Organization predictions, aerosolization of 50 kg of F. tularensis under certain atmospheric and wind conditions in a metropolitan area with a population of 5 million would lead to an estimated 250 000 incapacitated individuals and 19 000 deaths. Effects would linger for weeks to months, as some survivors experience prolonged illness or relapse. Moreover, distribution of the bacteria could establish new enzootic reservoirs in mammals, sparking subsequent outbreaks [11]. Although the use of biological weapons was officially prohibited by an international treaty signed in 1972, the threat of bioterrorism persists today [2, 10, 12].

F. tularensis is also a pathogen of concern due to war-related disease. The potential for widespread impact due to naturally propagated F. tularensis infections was illustrated during World War II, when massive increases of infected rodent populations in the former Soviet Union led to hundreds of thousands of human cases annually [2]. Natural outbreaks also occurred during the Continuation War in Finland and more recently during the civil wars in Bosnia and Kosovo, where tularemia had not been described previously [6]. Collectively, this suggests that tularemia is a disease that will thrive under deteriorating sanitary conditions such as war or natural disasters.

Tularemia remains a threat to public health as a naturally acquired disease in many parts of the northern hemisphere, even outside of war-torn areas. Notably, the epidemiology of tularemia has markedly changed over the last century. Whereas a large number of cases were identified in the United States and the Russian Republic of the Soviet Union between 1920 and 1960, the annual number of cases occurring recently in these countries does not exceed a few hundred, and most are sporadic and isolated [13]. In contrast, European countries have experienced more frequent large outbreaks in recent decades. In Finland and Sweden, the number of tularemia cases has increased recently and, for example, Sweden recorded 4422 cases total between 2000 and 2018, despite a rather small population of 10 million [14]. The reasons for these increases are unclear. In Turkey, tularemia is a reemerging disease, with 1500–2000 cases reported in peak years [13]. Many aspects of F. tularensis ecologic cycles and transmission dynamics remain a mystery, including why human-to-human transmission is exceedingly rare.

Vaccination is a potentially important measure for prevention of tularemia. Vaccine research and development for F. tularensis has a long history dating back to the 1930s–1940s, when the Soviet Union and the United States developed live attenuated and killed vaccines, respectively. Approximately 60 million individuals were immunized with live tularemia vaccines until 1960 in the Soviet Union [15]. One of these live vaccine strains was transferred to the United States in 1956 [9] and, after being passaged multiple times, was found to confer protection in various animal models. During the Cold War, the US Army immunized volunteers with this vaccine, designated the Live Vaccine Strain (LVS), and subsequently challenged these volunteers using a highly virulent F. tularensis isolate. The vaccine, when administered via scarification, conferred protection against low inocula of F. tularensis but only incomplete protection against higher inocula [16]. After the US Army Medical Research Institute of Infectious Diseases administered the LVS vaccine to laboratory staff, the incidence of laboratory-acquired typhoidal and pneumonic tularemia was substantially reduced compared with the preceding period when killed vaccines had been used [6, 16].

Recent research has indicated that cell-mediated immune responses persist for at least 3 decades after LVS vaccination, whereas antibody levels markedly decline within a few years [17]. These findings, together with the protection conferred against laboratory-acquired infection, imply that the LVS vaccine provides cell-mediated protection for many decades, at least against the presumably low inocula that could be generated during laboratory work. The vaccine has never been licensed in any country but has been administered as an Investigational New Drug to thousands of US laboratory staff who handled F. tularensis. However, in view of the incomplete protection conferred by LVS and its lack of licensing, there is need for a more effective vaccine for at-risk individuals. A number of promising vaccine candidates are currently in development [6, 17].

Despite the potential for F. tularensis to cause severe and even fatal infection, tularemia is treatable with antimicrobials. Existing US guidelines for treatment of tularemia were published in 2001 and recommend streptomycin or gentamicin as preferred choices for small outbreaks, with doxycycline, ciprofloxacin, or chloramphenicol as alternatives. In cases of large outbreaks or for post-exposure prophylaxis, doxycycline and ciprofloxacin are the drugs of choice [18]. The Robert Koch Institute of Germany, on the other hand, recommends treatment based on disease severity—ciprofloxacin or doxycycline for mild-moderate disease, or gentamicin combined with ciprofloxacin for severe infections [19].

Although several classes of antimicrobials are effective for treatment of tularemia, information on the relative effectiveness of these antimicrobials is extremely limited. Controlled trials on tularemia treatment in humans have been conducted only rarely and >60 years ago [20, 21]. Is streptomycin superior to gentamicin, as suggested by some researchers [22]? Should fluoroquinolones be a first-line option for all forms of disease or used preferentially for certain manifestations? Additionally, macrolides such as azithromycin might have some activity against type A strains (subspecies tularensis) but not type B (subspecies holarctica), although data are sparse. Given the threat of intentional release and engineered resistance, it is critical to evaluate all potential options for treatment and prophylaxis of tularemia.

Preparation, communication, and clear guidelines are key to responding effectively to a bioterrorism event or naturally occurring outbreak of tularemia. Currently, the Centers for Disease Control and Prevention is collecting and summarizing evidence on tularemia manifestations and treatment to develop updated clinical guidelines for antimicrobial treatment and prophylaxis of tularemia. In this supplement, readers will find valuable animal model data [23] and comprehensive in vitro studies of antimicrobial susceptibility for hundreds of F. tularensis strains isolated in the United States [24]. We also present results from systematic literature reviews and analyses of US surveillance data that add to the evidence base on antimicrobial treatment of human tularemia [25, 26].

In addition to noteworthy descriptions of specific disease manifestations [27, 28], outbreaks [29], and affected populations [30, 31], this supplement also includes an article describing a unique case of tularemia with convincing laboratory evidence of F. tularensis infection spanning a 3-year time frame [32]. Given the patient's ongoing pulmonary nodules and course of disease, chronic tularemia is the most likely explanation. This surprising finding has implications for bioterrorism response in particular, due to the potential for suboptimal or delayed treatment of initial infection among patients during an emergency response situation.

With these curated publications, we hope to advance the knowledge base on tularemia treatment, clinical manifestations, and unique disease considerations. Along with other data sources, these publications will serve as a robust evidence base for crafting clinical guidelines that can ultimately enhance US preparedness and improve patient outcomes.

Notes

Acknowledgments. This supplement is the product of considerable effort by federal scientists, clinicians, academic investigators, fellows, and students. The authors thank all contributors for their important work. For this editorial, the authors also thank Alison Hinckley for reviewing drafts and Jessica Winberg for assistance with references.

Disclaimer. The conclusions in this supplement are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).

Financial support. This project was supported by the CDC and the Administration for Strategic Preparedness and Response.

Supplement sponsorship. This article appears as part of the supplement “Tularemia: Update on Treatment and Clinical Findings,” sponsored by the Centers for Disease Control and Prevention.

References

Author notes

Potential conflicts of interest. C. N. and A. S. report no potential conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.

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