Knowledge gaps in the human host

Tularemia manifests with a wide spectrum of clinical presentations depending upon factors, such as the transmission route, the affected entry site, and the subspecies of the pathogen involved. F. tularensis subsp. tularensis (type A) is known to cause more severe disease forms compared to F. tularensis subsp. holarctica (type B). Ulceroglandular and glandular tularemia are the most commonly observed syndromes in humans, followed by the less common oculoglandular, oropharyngeal, pneumonic, and typhoidal tularemia syndromes. Atypical manifestations are diverse and include fever of unknown origin, endo- and pericarditis, appendicitis, peritonitis, liver abscess, cerebellitis with ataxia, meningitis, encephalitis, osteoarticular infections, rhabdomyolysis, and venous thrombosis [7]. Treatment of tularemia typically involves the use of antibacterial agents including aminoglycosides (gentamycin and streptomycin), fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) or doxycycline [7]. Despite the current understanding of tularemia, there are several knowledge gaps that need further investigation:

(1)

Regional (glandular, ulceroglandular, oculoglandular, and oropharyngeal) vs. disseminated disease: In regional tularemia, suppuration is a frequent complication, often necessitating hospitalization and surgical intervention. Identification of risk factors could facilitate timely diagnosis and appropriate antibacterial treatment. Additionally, the role of specific clades and host immunological factors in the development of localized disease requires further exploration. This can be achieved by analyzing clinical data from affected humans and animals, alongside comprehensive microbiological data.

(2)

Subclinical vs. clinical disease course: The reasons for varying individual susceptibility to tularemia remain unclear. Seroprevalence and genetic studies in human hosts could help elucidate these factors.

(3)

Disease patterns and treatment response between children and adults: Data on clinical presentation, disease spectrum, management, treatment type, and outcomes, particularly in children, are scarce. Treatment options such as ciprofloxacin or doxycycline are often used but formally are off-label. Systematically assessed pharmacokinetic and safety data are missing. Treatment studies in children are essential. Moreover, it is crucial to determine whether the currently recommended dosages are optimal for both children and adults with tularemia.

(4)

Serology vs. culture/PCR diagnostics: Prompt and accurate diagnosis is crucial for effective management of tularemia. While serology testing can be informative, pathogen-specific IgG may persist for years and may not accurately represent recent exposure, unless a titer increase is demonstrated. More specific confirmatory tests are often required. In addition to culture-based diagnosis, direct pathogen detection can be achieved through pathogen-specific PCR or bacterial broad-spectrum PCR targeting the 16S rRNA. However, these diagnostic tools are underutilized or not readily available in many settings. There are two PCR-based approaches used by most laboratories in Switzerland: species-specific PCR and 16S + based broad-spectrum PCR, followed by sequencing. Some laboratories use different systems (e.g., different primers). The use of PCR during the recent years is shown in Table 1. Although not giving a fully comprehensive picture, it is a snapshot from the largest laboratories where samples are submitted to, showing a clear increase of PCR requests.

Table 1 Diagnostic data provided on the positivity rate of PCR testing on samples in suspected tularemia cases from 2016 to 2022 from the four most consulted laboratories in Switzerland (Spiez, Bern, Zurich, and Lausanne) (5)

Disease awareness: It is imperative to assess whether healthcare professionals, including pediatricians or adult practitioners in both hospital and out-patient settings, are sufficiently informed about tularemia and its manifestations. Public health initiatives should aim to improve knowledge about the disease and its prevention among healthcare providers and the general population.

Reservoirs and ecology of F. tularensis: knowledge gaps and implications for disease control

Our understanding of the role of reservoir hosts and environmental reservoirs for F. tularensis is currently incomplete. Contaminated water and soil play an important environmental reservoir role, as F. tularensis is highly adaptable and can persist in these environments for extended periods. Wild lagomorphs (hares and rabbits), small rodents, and arthropods (ticks, flies) serve as reservoirs for F. tularensis. However, lagomorphs and small rodents do not represent a long-term reservoir source as they often die from tularemia, particularly subspecies tularemia and less so when infected with subspecies holarctica [8]. This is not true for rats, who often survive infection [9]. In Switzerland, the terrestrial life cycle is common, so it is postulated that ticks, lagomorphs, and rodents are the main reservoir hosts [9, 10]. However, given the scarcity of European wild rabbit (Oryctolagus cuniculus) and the vulnerable status of the European brown hare (Lepus europaeus) in Switzerland, alternative reservoir species, such as abundant and widespread small rodent species, must be considered [10]. Future studies on F. tularensis distribution should engage veterinarians and biologists as experts to identify the most suitable host species for each geographic area and collect the most relevant samples.

Distribution, vectors, and seasonality

Two studies analyzing data from 2009 to 2015 and 2017 to 2022 identified tick-infested areas primarily north of the Alps as risk regions for human tularemia cases in Switzerland [11, 12]. Consequently, two F. tularensis clades were reported from Switzerland: the B.11 genotype, found in Western Europe and Switzerland, and the derived B.45 genotype, spread across most of the Swiss terrain below 1500 m altitude. Although of low prevalence (0.02%), F. tularensis was detected in Ixodes ricinus tick species in Switzerland [11, 12]. However, other potential arthropod vectors besides ticks have not been investigated for F. tularensis presence in Switzerland.

Hence, several unanswered questions concerning ticks and other potential sources should be investigated: (i) the detection limit of F. tularensis in ticks and mosquitoes has not been definitively determined. A study introducing a multi-target real-time PCR for F. tularensis detection in complex samples suggests sensitivity levels between 1 and 44 genome equivalents, depending on the target gene [13]; (ii) only a few studies have examined F. tularensis survival in ticks [14] and mosquitoes [15] under laboratory conditions. Cultivating this fastidious bacterium is challenging and necessitates BSL-3 facilities (in Switzerland this is necessary for all F. tularensis subspecies, including. holarctica); (iii) other sources of F. tularensis infections, such as water or soil, need further evaluation.

Consequently, it is crucial to conduct methodological studies to understand the degree of underrepresentation in the existing data, encompassing more candidate reservoirs and potentially new vectors to better comprehend the environmental dynamics of the F. tularensis life cycle. Enhancing our knowledge of the ecological niches of F. tularensis in Switzerland could help redefine risk areas and to control case numbers in humans and animals. Since 2017, the Swiss FOPH data show that tularemia cases have been reported earlier each year, suggesting a shift in seasonality toward former colder months [5]. Furthermore, data from Swiss Federal Office of Meteorology and Climatology (SwissMeteo) show that average monthly temperatures for the month of July in northern Switzerland (below 1000 m above sea level) show an upward trend with + 0.5 ℃ per 10 years from 1961 to 2023. The warming trends were also statistically significant across the whole of Switzerland when looked at for each season [16]. Relative humidity of 70–80% close to the soil including adequate vegetation cover is favorable for ticks. These tick favorable areas have spatially increased in northern Switzerland as observed in a study during the years 2009 and 2018 [17]. Multiple factors may contribute to these phenomena, including: (1) better reporting due to heightened awareness among physicians, (2) improved implementation of surveillance systems, (3) climate changes affecting the ecology and distribution of reservoir hosts and vectors, (4) an increase in the prevalence of known F. tularensis vectors, or (5) the emergence of new vectors.

The imperative for a One Health approach in Switzerland and beyond

The evident increase in tularemia cases in Switzerland demands a thorough evaluation and a comprehensive strategy to address this pressing public health concern. Given that F. tularensis can be transmitted through multiple routes, it is crucial to adopt a One Health approach that fosters interdisciplinary collaboration among experts in public health, human medicine, vector ecology, diagnostics, and veterinary medicine. This holistic approach will enable a more nuanced understanding of the interaction between the environment, animals, humans, and vectors in the transmission cycle of F. tularensis. Modern surveillance should encompass not only traditional epidemiological data, such as case numbers in animals and humans, but also incorporate cutting-edge techniques like whole genome sequencing. This integrated approach will facilitate the monitoring of F. tularensis distribution with high spatio-temporal resolution. Platforms such as the Swiss Pathogen Surveillance Platform (www.spsp.ch) could be employed to collect, manage, and analyze data, enhancing surveillance and research efforts.

Furthermore, engaging the public through citizen science projects may be helpful to contribute to this One Health approach, by for, e.g., the collection and submission of data on vector localization, environmental factors, and by the delivery of removed vectors from humans and animals for pathogen detection and monitoring. This collaborative effort will allow for a more comprehensive understanding of the dynamics of tularemia and inform targeted interventions.

The call for action should not be limited to Switzerland; it is imperative to extend this One Health approach across Europe to effectively address the challenges posed by tularemia and other zoonotic diseases. By fostering collaboration among experts from diverse fields, we can work together to ensure the health and well-being of humans, animals, and the environment.