Phylogenetic Analysis of Francisella tularensis Group A.II Isolates from 5 Patients with Tularemia, Arizona, USA, 2015-2017.

We examined 5 tularemia cases in Arizona, USA, during 2015-2017. All were caused by Francisella tularensis group A.II. Genetically similar isolates were found across large spatial and temporal distances, suggesting that group A.II strains are dispersed across long distances by wind and exhibit low replication rates in the environment.

Francisella tularensis Transmission by Solid Organ Transplantation, 20171.

In July 2017, fever and sepsis developed in 3 recipients of solid organs (1 heart and 2 kidneys) from a common donor in the United States; 1 of the kidney recipients died. Tularemia was suspected only after blood cultures from the surviving kidney recipient grew Francisella species. The organ donor, a middle-aged man from the southwestern United States, had been hospitalized for acute alcohol withdrawal syndrome, pneumonia, and multiorgan failure. F. tularensis subsp. tularensis (clade A2) was cultured from archived spleen tissue from the donor and blood from both kidney recipients. Whole-genome multilocus sequence typing indicated that the isolated strains were indistinguishable. The heart recipient remained seronegative with negative blood cultures but had been receiving antimicrobial drugs for a medical device infection before transplant. Two lagomorph carcasses collected near the donor's residence were positive by PCR for F. tularensis subsp. tularensis (clade A2). This investigation documents F. tularensis transmission by solid organ transplantation.

From Squirrels to Biological Weapons: The Early History of Tularemia.

After George McCoy accidentally discovered a new infection in 1911 while investigating bubonic plague in squirrels, he transmitted the disease to experimental animals and isolated the causative organism. He called it Bacterium tularense, after Tulare County, California. In 1919, Edward Francis determined that an infection called "deer-fly fever" was the same disease, naming it "tularemia." He demonstrated that it occurred in wild rabbits and inadvertently showed that it was highly infectious, for he and all his laboratory assistants contracted the illness. This characteristic led to studies of its potential as a biological weapon, including involuntary human experimentation by Japan among civilian, political and military prisoners, and its probable use in warfare during World War II. Later, in the United States, voluntary human experimentation occurred in the 1950s-1960s with penitentiary inmates and non-combatant soldiers. Soviet Union scientists allegedly developed a vaccine-resistant strain, which they tested as a biological weapon in 1982-1983.

Tularemia in Germany-A Re-emerging Zoonosis.

Tularemia, also known as "rabbit fever," is a zoonosis caused by the facultative intracellular, gram-negative bacterium Francisella tularensis. Infection occurs through contact with infected animals (often hares), arthropod vectors (such as ticks or deer flies), inhalation of contaminated dust or through contaminated food and water. In this review, we would like to provide an overview of the current epidemiological situation in Germany using published studies and case reports, an analysis of recent surveillance data and our own experience from the laboratory diagnostics, and investigation of cases. While in Germany tularemia is a rarely reported disease, there is evidence of recent re-emergence. We also describe some peculiarities that were observed in Germany, such as a broad genetic diversity, and a recently discovered new genus of Francisella and protracted or severe clinical courses of infections with the subspecies holarctica. Because tularemia is a zoonosis, we also touch upon the situation in the animal reservoir and one-health aspects of this disease. Apparently, many pieces of the puzzle need to be found and put into place before the complex interaction between wildlife, the environment and humans are fully understood. Funding for investigations into rare diseases is scarce. Therefore, combining efforts in several countries in the framework of international projects may be necessary to advance further our understanding of this serious but also scientifically interesting disease.

Molecular investigation of tularemia outbreaks, Spain, 1997-2008.

Tularemia outbreaks occurred in northwestern Spain in 1997-1998 and 2007-2008 and affected >1,000 persons. We assessed isolates involved in these outbreaks by using pulsed-field gel electrophoresis with 2 restriction enzymes and multilocus variable number tandem repeat analysis of 16 genomic loci of Francisella tularensis, the cause of this disease. Isolates were divided into 3 pulsotypes by pulsed-field gel electrophoresis and 8 allelic profiles by multilocus variable number tandem repeat analysis. Isolates obtained from the second tularemia outbreak had the same genotypes as isolates obtained from the first outbreak. Both outbreaks were caused by genotypes of genetic subclade B.Br:FTNF002-00, which is widely distributed in countries in central and western Europe. Thus, reemergence of tularemia in Spain was not caused by the reintroduction of exotic strains, but probably by persistence of local reservoirs of infection.

Tularemia in Alaska, 1938 - 2010.

Tularemia is a serious, potentially life threatening zoonotic disease. The causative agent, Francisella tularensis, is ubiquitous in the Northern hemisphere, including Alaska, where it was first isolated from a rabbit tick (Haemophysalis leporis-palustris) in 1938. Since then, F. tularensis has been isolated from wildlife and humans throughout the state. Serologic surveys have found measurable antibodies with prevalence ranging from < 1% to 50% and 4% to 18% for selected populations of wildlife species and humans, respectively. We reviewed and summarized known literature on tularemia surveillance in Alaska and summarized the epidemiological information on human cases reported to public health officials. Additionally, available F. tularensis isolates from Alaska were analyzed using canonical SNPs and a multi-locus variable-number tandem repeats (VNTR) analysis (MLVA) system. The results show that both F. t. tularensis and F. t. holarctica are present in Alaska and that subtype A.I, the most virulent type, is responsible for most recently reported human clinical cases in the state.

The 'Hittite plague', an epidemic of tularemia and the first record of biological warfare.

A long-lasting epidemic that plagued the Eastern Mediterranean in the 14th century BC was traced back to a focus in Canaan along the Arwad-Euphrates trading route. The symptoms, mode of infection, and geographical area, identified the agent as Francisella tularensis, which is also credited for outbreaks in Canaan around 1715 BC and 1075 BC. At first, the 14th century epidemic contaminated an area stretching from Cyprus to Iraq, and from Israel to Syria, sparing Egypt and Anatolia due to quarantine and political boundaries, respectively. Subsequently, wars spread the disease to central Anatolia, from where it was deliberately brought to Western Anatolia, in what constitutes the first known record of biological warfare. Finally, Aegean soldiers fighting in western Anatolia returned home to their islands, further spreading the epidemic.

The biblical plague of the Philistines now has a name, tularemia.

An epidemic thought to have been the first instance of bubonic plague in the Mediterranean reveals to have been an episode of tularemia. The deadly epidemic took place in the aftermath of the removal of a wooden box from an isolated Hebrew sanctuary. Death, tumors, and rodents thereafter plagued Philistine country. Unlike earlier explanations proposed, tularemia caused by Francisella tularensis exhaustively explains the outbreak. Tularemia fits all the requirements indicated in the biblical text: it is carried by animals, is transmitted to humans, results in the development of ulceroglandular formations, often misdiagnosed for bubonic plague, and is fatal. Moreover, there is the evidence from the box and rodents: mice, which are known carrier for F. tularensis and can communicate it to humans, were credited by the very Philistines to be linked to the outbreak, and are small enough to nest in the box. Mice also explain the otherwise odd statement in the biblical text of a small Philistine idol repeatedly falling on the floor at night in the building where the Philistines had stored the box as mice exiting the box would easily have tipped over the statuette. Tularemia scores yet another point: an episode of the disease is known to have originated in Canaan and spread to Egypt around 1715 BC, indicating recurrence for the disease, and suggesting Canaan was a reservoir for F. tularensis in the 2nd millennium BC.

Tularemia: history, epidemiology, pathogen physiology, and clinical manifestations.

Francisella tularensis has been recognized as a human pathogen for almost 100 years and is the etiological agent of the zoonotic disease tularemia. Soon after its discovery, it became recognized as an important pathogen in several parts of the world, for example, in the United States and Soviet Union. The number of tularemia cases in the two countries peaked in the 1940s and has thereafter steadily declined. Despite this decline, there was still much interest in the pathogen in the 1950s and 1960s since it is highly infectious and transmissible by aerosol, rendering it a potent biothreat agent. In fact, it was one of the agents that was given the highest priority in the offensive programs of the United States and Soviet Union. After termination of the offensive programs in the 1960s, the interest in F. tularensis diminished significantly and little research was carried out for several decades. Outbreaks of tularemia during the last decade in Europe, for example, in Kosovo, Spain, and Scandinavia, led to a renewed public interest in the disease. This, together with a massive increase in the research funding, in particular in the United States since 2001, has resulted in a significant increase in the number of active Francisella researchers. This article summarizes, predominantly with a historical perspective, the epidemiology and clinical manifestations of tularemia and the physiology of F. tularensis.

Did an epidemic of tularemia in Ancient Egypt affect the course of world history?

The dynamics of the spreading, and the identity of a virulent epidemic, similar to bubonic plague or typhus, which hit Ancient Egypt in the middle of the Bronze Age, are hereby presented. Documented in medical papyri as well as archaeological findings, and re-echoed in biblical texts, a plague entered Egypt's main harbor, Avaris, around 1715 BC. As a result, the country was severely weakened at a time when it was already facing serious sociopolitical issues: crumbling central government, immigration, foreign influence, and the rise in power of the army and of warlords. The Hebrews, one of the ethnic groups within the Avaris area, appeared immune amidst the devastation of the plague. This immunity was key to identify the etiological agent of the epidemic: Francisella tularensis, the Gram-negative bacterium passed by ticks, and that causes tularemia. The disease manifests itself as either an ulceroglandular or a typhoid syndrome, accounting for its similarity with bubonic plague and typhus. Cellular immunity provides the main defense against F. tularensis, and is achieved through continuous contact with avirulent strains of the bacterium. Urban dwellers of Avaris, who had a limited contact to animals, would have been defenseless against the virulent strains, unlike the Hebrews, who lived off sheep and other animals. Attempting to consolidate Egypt's central government in the aftermath of the tularemia epidemic, led among others to the internment of the Hebrews in labor camps. The repressive measures against the Hebrews left traces in the subsequent archaeological layer (stratum F) at Avaris. As a corollary, the enslavement would set the stage for the exodus of the Hebrew community from Egypt at a later time.

Tularemia.

Tularemia is a complex clinical disorder caused by the ubiquitous intracellular parasite Francisella tularensis, which has many mammalian and insect hosts. The peak observed incidence of tularemia occurred in 1939, and most present-day clinicians have never seen a case of this disease. Tularemia manifests several different clinical syndromes, depending on the portal of entry. F. tularensis has been used in biological warfare experimentation and it has been weaponized and stockpiled in the past by the United States and other countries. It is classified as a category A critical biological agent by the Centers for Disease Control and Prevention. This article reviews the history, clinical features, diagnostic evaluation, and treatment of this organism with an emphasis placed on its potential role as an agent of biological warfare.

Tularemia and Q fever.

The zoonotic infections caused by Francisella tularensis and Coxiella burnetii, tularemia and Q fever, respectively, are two less commonly encountered clinical illnesses that are becoming increasingly recognized as epidemiologically important human diseases. The prevalence of tularemia and Q fever can be positively impacted by increased awareness of the clinical entities that arise from infection by these arthropod-borne organisms. Improved recognition of these clinical syndromes will lead to greater diagnostic accuracy in recognizing these diseases in patients. Ultimately, more stringent measures to prevent infection may be required, through raising public awareness, since current therapeutic regimens for these two diseases are limited, and knowledge of the pathogenesis of these two organisms are still in developing stages.

A magic sword or a big itch: an historical look at the United States biological weapons programme.

In the late 1950s interest in entomological warfare increased, and literature describing the US biological warfare programmes on the use of the mosquito Aedes aegypti, the vector for transmitting yellow fever, has now been released. Yellow fever was considered as a suitable disease to use in southern regions of the former Soviet Union. The US destroyed its biological weapon stockpiles in the early 1970s. In addition to its offensive biological warfare programme, the US conducted extensive trials to assess its own vulnerability to biological attack. These trials and a later series of threat analyses indicate that biological agents could, indeed, affect large areas of the US if the attackers were allowed to proceed unmolested. Some of the threat analyses present highly questionable scenarios.