Transmission dynamics of TBDs

Vertebrate hosts can be regarded best as amplifying hosts for TBDs, their prominent role is to produce a sufficient number of newly infected ticks to close the enzootic cycles of pathogens. The infection dynamics of pathogens in vertebrate hosts varies in host range, tissue tropism and infection time. The host range of some pathogens, for example B. lusitaniae and A. phagocytophilum ecotype II, is relatively small with only a few vertebrate species being able to act as amplifying hosts, whereas the host range of others, such as B. afzelii and A. phagocytophilum ecotype I, is much broader. Tissue tropism varies from skin (B. afzelii), to blood (Babesia species), immune cells (A. phagocytophilum, N. mikurensis), endothelium (R. helvetica) and even to the central nervous system (TBEV, B. garinii). Sometimes, adequate immune responses are developed, for example against B. miyamotoi and TBEV, giving rise to short-term, limited infections. Other pathogens, such as B. burgdorferi (s.l.), A. phagocytophilum and probably also several Babesia species too can evade the immune system and cause chronic, long-lasting infections. Infections with B. garinii appear to be latent in thrushes (Turdus iliacus) for several months, but can then be reactivated by physiological cues [56]. Recurrent bacteremia also occurs in sheep, which remain infected persistently with A. phagocytophilum [57].

Transmission dynamics can also be affected at the (vertebrate) community levels via many, often poorly understood, mechanisms. For example, most vertebrates often are simultaneously or sequentially infected with multiple pathogens. Patterns of (co-)infection arise because infection by one microorganism affects susceptibility to others or due to inherent differences between hosts [58]. Another example is the dilution effect hypothesis, where diluting the abundance of transmission-competent hosts with non-competent hosts will reduce the probability of ticks feeding on transmission-competent hosts and consequently decreases the infection prevalence of pathogens in ticks [59]. This mechanism probably applies only in certain circumstances for a few TBPs, and even less often if considering abundance rather than prevalence of infected ticks [60]. Recently, we showed that mesocarnivores can lower the number of ticks feeding on reservoir-competent hosts, which implies that changes in predator abundance may have cascading effects on tick-borne disease risk [61].

Transmission dynamics can also be affected by weather and climatic conditions. The seasonal synchrony of larval and nymphal stages is an important driver of non-systemic transmission of TBEV via co-feeding of infected nymphs with uninfected larvae. This synchrony in tick activity and feeding, in turn, is affected by temperature patterns, in particular autumn cooling and spring warming [62, 63]. Climate change might therefore not only affect the distribution of ticks themselves, but also the distribution and nymphal infection rate of TBEV, and maybe also of other TBPs [41, 64].

These infection dynamics are important drivers for the abundance and spread of infected ticks, and therefore have major clinical implications, implications on the incidence, but also on the risk management and control of the associated diseases. For example, the geographical distribution of TBEV is multifocal [63] with relatively low infection rates, whereas Lyme spirochetes are more widespread with relatively high infection rates in I. ricinus [65]. Five genospecies of B. burgdorferi (s.l.) are commonly associated with LB in Europe: B. afzelii, B. garinii, B. burgdorferi (sensu stricto), B. spielmanii and B. bavariensis [23]. Borrelia afzelii is predominantly involved in cutaneous manifestations, such as erythema migrans (EM) and acrodermatitis chronica atrophicans (ACA), B. garinii and B. bavariensis in neuroborreliosis (LNB), and B. burgdorferi in Lyme arthritis (LA) [23, 66]. The incidence of the different manifestations of LB can be partially explained by their pathogenicity and by the relative occurrences of different genospecies in questing ticks [34]. Specific associations have also been found between vertebrates and Borrelia genospecies. For example, rodents and voles appear to contribute most to the transmission cycle of B. afzelii, whereas thrushes contribute most to the B. garinii and B. valaisiana cycles [29]. It is to be expected that local abundances of these animals in tick suitable recreational areas determine the risk of acquiring the specific disease manifestations [38, 45].

Epidemiology of TBDs

Measuring incidences and cost of illness (humans) or production loss (livestock) can guide decision-makers to prioritize health policies and initiate cost-effective actions to control diseases with the highest economic or societal impact [67]. As TBE is notifiable in many European countries, incidences and sometimes also cost of illness have been estimated [68]. This information has enabled the calculation of the cost-effectiveness of vaccination strategies against TBE in several countries [69], which further aided the formulation of various strategies to control TBE, from creating awareness alone to incidence-, travel- or profession-based vaccination advises to mass-vaccination campaigns [9, 70].

The epidemiology of LB is more complex. In most European countries LB is not notifiable and incidence estimates are often based on passive reporting laboratory surveillance or on incidental, systematic investigations [71, 72]. Early stages of LB are underreported in laboratory surveillances, because most cases are serologically negative at presentation. Furthermore, laboratory testing at that stage is often not required, hence not recommended by guidelines, for the diagnosis of EM. Most importantly, the clinical manifestations of LB differ enormously in incidence and disease burden. In the Netherlands, 95% of the LB cases are EM, 2% LNB, 2% LA, 0.9% ACA, 0.4% borrelial lymphocytoma, 0.1% Lyme carditis and 0.1% had ocular manifestations [71]. In Germany, comparable proportions were observed [73]. A recent study estimated the total disease burden of LB for the Netherlands. Although ~91% of the LB cases had EM, it only constitutes ~6% of the disease burden, whereas the ~5% cases which displayed persisting symptoms attributed to LB accounted for almost 90% of the disease burden [74]. Thus, controlling the incidence of patients with persisting symptoms attributed to LB, will have the highest impact on reducing disease burden, but hardly on the disease incidence.

Only a few studies have investigated the incidence of other TBDs transmitted by I. ricinus, such as anaplasmosis and babesiosis, in Europe [75]. For example, a sero-epidemiological study estimated between 10 and 40 human anaplasmosis cases in Belgium per year [11, 76]. Human cases of other TBDs are being reported in the literature, mostly as case studies or series. In contrast, the exposure through bites of infected ticks in the general population and in risk groups such as forest workers is high. Based on molecular evidence alone, the probability of infection with a TBP other than Lyme spirochetes after a tick bite is roughly 2.4% [12]. Similarly, among patients with EM, the probability of a co-infection with another TBP is approximately 3% [12]. How often these infections cause disease or to what extent co-infections affect the course of LB needs further investigation. Infections with TBDs in humans is supported by many serological studies where antibody titers against for example A. phagocytophilum have been found in a few percent of human populations [77–79]. Nonetheless, the incidence and severity of the medical problems caused by these TBPs in many, if not all, European countries are unknown. One of the reasons for that is that current diagnostic tools for many of the TBDs are non-existing, of questionable quality, or poorly validated in the European setting. As a consequence, the awareness of other TBDs among physicians and the public is generally low. Therefore, to gain more knowledge on the incidence and nature of TBDs it is imperative to improve laboratory diagnostic tests and awareness.

Domestic animals are more prone to exposure to ticks than humans, as they generally spend more time outdoors, are in closer proximity to the ground and vegetation, and have coats that facilitate tick attachment. Since none of the TBDs associated with I. ricinus are notifiable in Europe, official information on TBD incidence in animals is not available. One exception is Q-fever caused by Coxiella burnetii, but the role of ticks in the epidemiology of the disease is considered to be negligible [80]. Most reports concern case descriptions, seroprevalence studies or molecular surveys looking at the occurrence of pathogens in ticks collected from the vegetation or animals, which says little about the actual incidence of clinical disease in animals.

Clinical presentation of LB and TBE

LB is divided in three partially overlapping stages, reflecting the duration of the infection and the severity of the disease [23, 81]. The first stage is characterized by the hallmark EM, an erythematous expanding skin lesion at the site of the tick-bite (Fig. 1), usually occurring 1–2 weeks after the tick-bite. When left untreated or unnoticed the infection can disseminate and cause early disseminated and eventually late disseminated LB, the second and third stage respectively [81]. The characteristic manifestations of early disseminated LB include other skin manifestations, such as lymphocytoma and multiple EM, carditis, oligoarthritis and neurological symptoms, such as meningo-(poly)radiculitis (Bannwarth syndrome) with or without cranial nerve involvement [82], amongst other rare manifestations. The central nervous system or the joints can also be affected in late disseminated disease, but the hallmark clinical manifestation of late LB is ACA [83].

Apart from these clear-cut manifestations, there are patients with non-characteristic complaints such as myalgia, arthralgia, fatigue, which are sometimes attributed to LB. These complaints are often long-lasting and can even be debilitating. The constellation of these symptoms is sometimes referred to as chronic Lyme, however this term seems to be an umbrella name for a variety of diseases and syndromes [22, 84]. Examples thereof include late disseminated LB, post-treatment LB syndrome (a post-infectious syndrome), a persisting B. burgdorferi (s.l.) infection after antibiotic treatment, or one of many other diagnoses misattributed to LB [85]. How to define “chronic Lyme” is more than a semantic discussion as a proper diagnosis [84], i.e. the identification of the nature and cause of an illness, greatly determines the care and cure of patients [85], and could lower the disease burden and medical costs.

Exposure to Lyme spirochetes in animals in Europe is common, with reported seroprevalences in Europe in healthy dog populations ranging from 0.3% in southern Italy [86] to 26% in Serbia [87] and 7% in horses from in Italy [88] to 30% in France [89], but clinical disease with a conclusive LB diagnosis is rare. Clinical LB caused by B. burgdorferi (s.s.) has nonetheless been reported in dogs, horses and cats [90–95]. A broad spectrum of clinical signs has been associated to Borrelia infections in animals, including fever, lethargy, weight loss, (shifting) lameness, ataxia, uveitis, polyarthritis, glomerulopathy and neuritis [96–98]. This variation might to some extent be the result of unapparent co-infections with other pathogens, such as A. phagocytophilum [99, 100].

Ixodes ricinus ticks transmit the European variant of TBEV [101]. Although the majority of human infections are asymptomatic, the first symptoms are displayed between 2–28 days (median = 8) after a tick bite [102, 103]. Infections with the European TBEV usually display a typical biphasic course with a viremic phase of 2–10 days and a neurological phase of 1–21 days, separated by a period (median = 7 days) without symptoms [104]. In the first phase the most common symptoms are fever, fatigue and headaches [103]. After a temporary recovery, neurological symptoms appear in the second phase, ranging from mild meningitis to severe meningoencephalomyelitis [103]. Although TBEV-EU mortality is relatively low (1–2%), neurological sequelae, which can greatly affect the quality of life, often occur [105]. TBEV may also affect dogs and result in fever, change in behavior and various neurological symptoms (reviewed in [106]). A variant of the TBEV, Louping Ill virus causes acute encephalomyelitis, resulting in severe illness and death in livestock, especially sheep and red grouse [18].

Clinical presentation of other TBDs

The clinical spectrum of human granulocytic anaplasmosis ranges from subclinical and self-limiting to subacute, chronic or severe in the immunocompromised [107]. The incubation period is 1–2 weeks, after which non-characteristic symptoms (e.g. fever, flu-like symptoms) arise, accompanied by nausea, vomitus, abdominal pain and arthralgia in approximately one-third of the patients. A skin rash or neurological symptoms are less frequently observed, and the estimated fatality rate is less than 1% [108–112]. Animal species that may be affected by A. phagocytophilum include dogs, cattle, horses and sheep and clinical signs vary in severity but are usually non-specific such as fever, lethargy and anorexia [113]. To date, there are dozens of case reports of human neoehrlichiosis, the disease caused by N. mikurensis, describing acute and chronic infections characterized by fever, headache, nausea, arthralgia, haemorrhages and weight loss [16]. Borrelia miyamotoi causes hard tick-borne relapsing fever (HTBRF). The onset of symptoms starts approximately two weeks after a tick-bite with a sudden onset of high fever with signs of septicaemia accompanied by headache, myalgia, arthralgia, and coughing or even gastrointestinal symptoms. The relapsing fever episodes typically last three days, divided by seven relatively healthy days, although for HTBRF the typical relapsing fever pattern is not that often observed [114]. The general trend of the course of the disease is subsiding and self-limiting, but in rare cases, i.e. in highly immunocompromised individuals, the disease appears to be neuro-invasive [114–118]. The two spotted fever rickettsias transmitted by I. ricinus are R. helvetica and R. monacensis. Their infections may cause vasculitis with fever, headache, myalgia and local lymphadenopathy. An inoculation eschar and generalized maculopapular rash, which are pathognomic for other spotted fever rickettsiosis, are rarely described for these genospecies [115, 119, 120]. The pathogenicity of R. helvetica is only partly established by several case series and reports in Europe [121–126]. Rickettsia monacensis infection is even less defined, although culture, molecular and serological evidence of human exposure has been reported [127–129].

In Europe, human babesiosis is caused by B. microti, B. divergens and B. venatorum [12, 130–132]. All Babesia species infect erythrocytes and cause haemolysis, leading to the clinical manifestations of fever, anaemia, jaundice, haemoglobinuria and potentially also renal insufficiency. Over 40 human babesiosis cases have been reported in Europe, mostly in asplenic patients. Other risk factors are immunosuppression, depletion of mature B-cells and old age [21]. Judging from the discrepancy between case reports and seroprevalence, an asymptomatic and/or self-limiting course is common [133]. Although serious infection appears to be uncommon, when acquired, the disease has a mortality rate of 42% in B. divergens and 5% in B. microti [134]. Babesia divergens is the causal agent of bovine babesiosis in Europe. The clinical picture is similar to that seen in humans, with a bimodal seasonal occurrence of the disease that is associated with I. ricinus activity. In cattle, an inverse age resistance phenomenon is present in which calves up to the age of 9–12 months are susceptible for infection, but resistant to disease [21].

Human infections with multiple TBDs and even with non-tick borne pathogens have been described [135, 136]. Co-infections have been shown to affect the course of LB causing a longer and more disabling course of disease [137–142]. Although co-infections in ticks are the rule rather than the exception [25, 34], the opposite is probably true in humans: co-infections seem to occur only occasionally [129, 143–146]. Our recent findings indicate that among patients with EM the probability of a co-infection with second TBP is merely 3% [12]. To date, there is no convincing evidence that infection with any other TBP or any other infectious agent, is associated with chronic Lyme [147, 148].

Diagnosis of LB

In diagnosing LB, the foremost tool for a physician is a thorough history and physical examination. An EM is considered a clinical diagnosis and additional laboratory testing for EM is discouraged [82]. For many other disseminated forms of LB, laboratory work-up, including a search for alternative explanations, may serve to aid the physician. Serology is the current standard as it has good diagnostic parameters with a sensitivity and specificity of more than 90–95% in LB patients with late (disseminated) manifestations [149]. Serology has some disadvantages. First, the sensitivity is low in early stages of LB, approximately 50% [149], which may lead to a wrong or delayed diagnosis. Secondly, approximately 5% of the general population - and even higher depending on the age, geographical region and the population examined - have antibodies against Lyme spirochetes, while not having active LB [150]. Thus, serology cannot always differentiate well between a past and a current Borrelia infection [151–153]. Additional tests include PCR or culture, which are only recommended for specific manifestations and specific tissues or fluids: on synovial fluid/tissue in the case of LA, on a skin biopsy in the case of an ACA or in some specific cases of LNB on cerebrospinal fluid (CSF) [154, 155]. For LNB, other laboratory tests are available, such as leukocyte count, intrathecal antibody production, or intrathecal CXCL-13 concentration, to support the presence of an infection in the central nervous system or other inflammatory conditions [156].

The diagnosis of any form of chronic Lyme is far more complicated. Some of these patients may benefit from (additional) antibiotic treatment, while others may be better helped with other forms of treatment or rehabilitation. A laboratory test that is able to adequately differentiate between a past and active Borrelia infection is desired for these patients. It has been hypothesized that cellular tests have this ability. Several of these tests are already commercially available, but their accuracy has not been adequately determined [157–160] and, therefore, warrants more research before they can be used in clinical practice [159]. In addition, there are many alternative methods, which are said to test for LB, but sound evidence for these methods (e.g. as dark field microscopy directly on blood, VEGA-test or bio-resonance) is lacking [161].

When deciding to test for a given condition, whether it be LB or any other disease, it is important not to only take into consideration what the technical performance of a test is, but to also consider the pre-test probability that the patient has the disease [155]. When the pre-test probability of LB is low, then - taking into account the current diagnostic parameters of serological tests and the incidence of IgG-seropositivity in the general population - the added value of testing is limited. Furthermore, the various LB manifestations, the pre-test probabilities as well as the population under study and their expectations vary greatly between primary, secondary, and tertiary care. This might also affect recommendations for the use of Borrelia serology in current guidelines and requires further investigation. In that regard, although not recommended in most guidelines, it could be argued that testing for LB in patients with longer-lasting symptoms with a low pre-test probability in the primary care setting, could actually be helpful. In this situation, a negative test result would make an LB manifestation extremely unlikely, whereas a positive test result would require further investigation, e.g. referral to secondary or tertiary care center. Nevertheless, in some situations testing for LB is discouraged altogether, specifically when the patient is clinically diagnosed with an EM.

The non-specific clinical picture, together with a high seroprevalence, also complicate the diagnosis of LB in animals. The combination of a history to tick exposure within an endemic region, clinical signs consistent with LB, a positive test result, exclusion of differential diagnoses and response to treatment are required for a presumptive LB diagnosis in animals [162].

Diagnosis of TBE and other TBDs

TBEV infection is associated with general non-specific infectious biochemical and blood count results. CSF analysis usually shows pleocytosis with polymorphonuclear cells early, and mononuclear cells late, in the disease development [163]. Serology can be performed on both liquor and serum by IgM/IgG ELISA, which is the most common diagnostic method for TBEV-infection in dogs as well [106]. A four-fold rise in TBEV-specific antibodies in liquor or serum confirm the diagnosis. A neutralization assay is recommended in flavivirus endemic regions to avoid a false positive result [104, 164]. Imaging of the brain and/or myelum may result in focal abnormalities; however it does not contribute greatly to the diagnosis [163].

Diagnosis of other TBDs is based on the assembly of specific clinical characteristics, laboratory findings together with diagnostic tools in a setting of relevant epidemiological exposure. The main non-specific laboratory findings associated with other TBDs are general parameters found in infection, such as elevated inflammation parameters (C-reactive protein, erythrocyte sedimentation rate), leukopenia or leucocytosis, thrombocytopenia and anaemia, with or without elevated liver enzymes or kidney dysfunction. Especially in A. phagocytophilum and N. mikurensis infection, leukopenia is observed due to leukocyte infection [108, 165]. Babesia spp. can cause a distinct haemolytic anaemia due to erythrocyte infection with accompanying elevated bilirubin, reticulocytosis and decreased haptoglobin [166]. Thrombocytopenia appears to be most pronounced in anaplasmosis, babesiosis and HTBRF. In the rare severe cases of anaplasmosis and HTBRF with involvement of the central nervous system, the CSF can reveal pleocytosis [167, 168]. For some TBDs, there are additional, more specific, tests available, such as a buffy coat examination for A. phagocytophilum or peripheral blood smear with Giemsa staining in A. phagocytophilum and Babesia spp. to look for respectively morulae or merozoites by microscopy [169, 170].

Most additional targeted diagnostic tests in TBDs are either in the experimental phase or not widely validated (molecular tests), based on cross-reactivity between other species (serology), time-consuming, or difficult to perform and requiring a high level of expertise (cultures) [171–173]. In general, the sensitivity of available molecular tests for all these TBDs is high in the first week of disease and rapidly decreases over time, and after proper treatment. Therefore, a positive PCR result is helpful, but a negative result does not rule out the diagnosis. As an exception to the rule, Babesia spp. can be detected up to months to years after (un)treated infection [174, 175].

For most TBPs, there are no standardized antigens, or well-defined consensus as to what thresholds constitute a significant antibody titer. As a rule of thumb, serological tests are usually required to show a four-fold rise in antibody titer in convalescent sera. It should be noted that the onset of symptoms sometimes precedes the rise in antibody titer. In addition, because antibodies may persist beyond the clearance of infection, it can be difficult to distinguish between a past, recent or current infection [21, 169, 176]. For A. phagocytophilum, Babesia and Rickettsia spp. indirect fluorescent antibody tests are available, yet they make use of other strains or even genospecies than the ones found in Europe, with the exception of B. microti [166, 171, 177, 178]. Serological tests for B. miyamotoi are in the experimental phase and based on specific antigens (glycerophosphodiester phosphodiesterase (GlpQ) and more recently also variable major proteins (Vmps) identified in the available different isolates from Asia and the USA [179, 180]. These assays do not discriminate between the different relapsing fever Borrelia genospecies. There is no widely available and established serological test for the diagnosis of N. mikurensis infection.

Treatment of TBDs

LB is treated with antibiotics. The prognosis, especially when treated early in the course of the disease is good, although rarely antibiotic failure can occur. In contrast, persisting symptoms can be observed in approximately 5–20% of LB patients despite recommended antibiotic treatment [181, 182]. Therefore, this condition has been referred to as post-treatment LB [169]. It has been shown in multiple placebo controlled randomized trials that prolonged antibiotic treatment is not effective in treating these non-specific yet disabling and long-lasting symptoms [183–187]. LB in animals is also treated with antibiotics, usually with doxycycline given per os at 10 mg/kg every 12 or 24 h for a period of one month [162, 188]. In horses, the intravenous administration of oxytetracycline (5 mg/kg/day) was more effective in clearing experimentally induced Borrelia infections than doxycycline treatment [189].

There is no causal treatment for TBEV. Treatment consists of supportive care and there is no evidence that steroids or immunoglobulins are beneficial [104]. Asymptomatic or subclinical infection frequently occurs for all of the other TBDs and thus infection does not necessarily require treatment. However, when symptomatic, treatment is, or may be, warranted. The large group of intracellular other TBDs, such as A. phagocytophilum, N. mikurensis and spotted fever rickettsia, as well as B. miyamotoi are all susceptible to doxycycline, which is the drug of choice [116, 169, 173, 190] for adults. For younger children, pregnant women and when the central nervous system is affected, specific alternatives exist. Therefore, in countries where doxycycline is recommended as the first line treatment for LB, these pathogens would be concomitantly treated. In countries where beta-lactams are the drug of first choice for LB, clinicians should have a higher level of suspicion for other TBDs, since these are likely not co-treated as such. Moreover, babesiosis requires a different treatment, consisting of azitromycine and atovaquone or clindamycine and quinine depending on the severity of the disease [169]. Cattle suffering from babesiosis are treated with imidocarb diproprionate. In Africa, diminazene aceturate is frequently used to treat bovine babesiosis caused by B. bovis or B. bigemina, but this product is not available in Europe [21].

Personal preventive actions

Control of I. ricinus-borne diseases primarily consist of the promotion of personal preventive actions for the public and for risk groups, such as forest workers, by providing information and education. Such actions include avoiding high-risk habitats, wearing protective clothing, application of repellents, prompt removal of attached ticks, and seeking medical advice when developing symptoms (e.g. fever, skin rash) or another illness in weeks to months after a tick bite. Personal protective measures have poor rates of compliance and their effectiveness has been difficult to demonstrate in terms of reducing disease cases [196, 197]. For example, providing information and education has not resulted in a decline in the incidence of LB in the Netherlands, not even after intensified efforts since 2003 [7].

Environmental-based approaches

Environmental-based approaches mostly rely on reduction of tick suitable habitats, the disruption of the tick life-cycle or interference with pathogen transmission. A major advantage of environmental-based control options is that most of them can readily be applied in various practical situations, as they involve existing nature management options, such as mowing, grazing or fencing [195]. Furthermore, controlling tick abundance or tick exposure reduces the risk of acquiring any TBD for both humans and domestic animals. So far, there has been little interest in Europe in environmentally-based preventive measures. Large-scale and long-term spraying with acaricides was carried out in Russia during the 1970s and 1980s in an attempt to control I. persulcatus, the main vector of the TBEV [198]. The widespread application of acaricides has been publicly criticized and has become socially undesirable, because of their detrimental effects on the ecosystem and biodiversity [191, 199]. Unlike in the USA, only a limited number of studies exploring environmental-based methods to control ticks have been conducted in Europe [30, 195, 200–202]. A wide range of acaricidal products in various formulations, which are effective against I. ricinus, is being used for tick control on domestic animals [203].

Health in All Policies

Most, if not all, of the available environmentally-based preventive and control measures suffer from the fact that they are not highly effective on their own [192]. Probably, long-term implementation of control strategies, i.e. the integrated use of two or more control measures, are necessary to effectively reduce disease risk. Only a few studies on the effectiveness of control strategies have been carried out in the USA, but not in Europe [192]. The successful implementation of environmentally-based preventive and control measures requires involvement of stakeholders from both nature management and human (and animal) health (‘One Health’). Of key importance is that the environmental control options for TBDs are put into the context of other aims and ambitions, such as nature conservation, ecosystem services or heat mitigation in urban areas. Indeed, sectors involved in nature management and environmental planning are often more familiar with a so-called ‘Health in All Policies’ approach. The ‘Health in All Policies’ approach integrates and articulates many health considerations, far broader than infectious diseases alone, into policymaking across sectors. A future challenge is to integrate the risk of TBDs, but also of wildlife- and other vector-borne diseases, into the ‘Health in All Policies’ in local nature organizations, such as Municipal Health Services and nature owners, but also governmental institutions and (inter)national organizations responsible for nature and health.

Healthcare actions

More and better awareness of the epidemiology, clinical presentation and course of the various TBDs amongst physicians could raise a suspicion on these diseases in endemic regions. For example, the communication with health professionals on the presence of B. miyamotoi and TBEV in questing ticks in the Netherlands has resulted in the identification of the first cases of HTBRF and TBE [70, 168]. Clearly, there is room for the improvement of laboratory tests for the diagnosis of LB and especially other TBDs. Both direct (antigen tests, cultivation or molecular tests) and indirect tests (serology or cellular tests) could greatly aid in establishing the diagnosis. Rather than making one guideline for each tick-borne disease separately, it might be more advantageous to have one guideline for all TBDs for primary care centers with clear consensus on diagnostic testing and referral to secondary and tertiary care centers. Specialized guidelines for secondary and tertiary care centers can aid the diagnosis and treatment for more severe manifestations of LB, but also and for all variants of chronic Lyme. Finally, better knowledge on the course of the various diseases after treatment could prevent overdiagnosis and retreatment.

Vaccination

Where the risk of infection is high or the resulting disease severe, vaccines may be the most efficient and cost-effective means of prevention and control [204]. TBE is well under control in Austria because of mass vaccination programs. The available TBE vaccines have an effectiveness of ~98%. With a vaccination rate in the population of 85%, it is estimated that more than 4000 severe cases of TBE were prevented in Austria between 2000 and 2011 [205]. Remarkably, the vaccination coverage in many central and eastern European countries is low [206], despite predictions that TBE vaccination programs in central and eastern Europe can be cost-effective [207]. A vaccine protecting against LB is currently unavailable in Europe, but a potential vaccine has recently been tested in a Phase I/II trial [208, 209], and another LB vaccine is being developed for the European market as well [210]. Based on the experiences with a previous Lyme vaccine that was on the American market, with an effectivity between 62% and 85%, it remains to be seen whether a Lyme vaccine will be widely accepted and used, or only cost-effective for high risk groups [211, 212]. Ideally, one would like to have a single vaccine for humans, protecting against multiple TBDs [213]. Anti-tick vaccines targeting other tick species already exist and are being used in the veterinary field. The strategy behind these vaccines is to locally control Rhipicephalus (Boophilus) tick species, and act as a safe and environmentally friendly alternative to acaricides [214, 215]. Application of anti-tick vaccines was shown to dramatically decrease the incidence of bovine babesiosis [216]. Whether anti-tick vaccines can also be used to (locally) eradicate I. ricinus populations and prevent human TBDs is difficult to predict due to its very large host range, yet is a topic of investigation [213].