Diseases

Theileria

Download as PDF Download as XLS Download summary

Chapter select

Control Tools

  • Diagnostics availability

  • Commercial diagnostic kits available worldwide

    IFA, ELISA and PCR can be used. ELISA’s have been successfully developed for the detection of antibodies to T. annulata and have shown that they can detect the antibodies for a longer period in affected animals but are not commercially available anymore (OIE October 2009). A lateral flow device (LDF) was also developed.

    List of commercially available diagnostics can be consulted here (Diagnostics for Animals).

    GAPS:

    • Development of T. lestoquardi diagnosis.
    • A standardised sensitive antigen lacking cross reactivity with related parasites and adaptable to a penside test.

  • Commercial diagnostic kits available in Europe

    None for the moment.

    List of commercially available diagnostics can be consulted here (Diagnostics for Animals).

  • Diagnostic kits validated by International, European or National Standards

    None.

  • Diagnostic method(s) described by International, European or National standards

    The OIE refers to the use of IFA, ELISA and PCR with Giemsa stained smears from blood or lymph node biopsies being used for diagnosis.

    GAPS:

    • Reason of low execution of lymph node smears by field veterinarians? Mainly, the lymph node smear should be done immediately in the field.

  • Commercial potential for diagnostic kits in Europe

    Unlikely, an ELISA kit is new under development by a German company.

  • DIVA tests required and/or available

    With the potential development of suitable sub-unit vaccines it may be necessary to develop a DIVA test, but currently there is none available.

  • Opportunities for new developments

    N.A.

  • Vaccines availability

  • Commercial vaccines availability (globally)

    Despite the fact that vaccination with the cell culture vaccine against T. annulata has been available for more than three decades the use of this vaccine has been limited. The concern about the introduction of vaccine related parasites into the field tick population has led to countries developing vaccines from local isolates. On this basis therefore there does not appear to be a universally commercialised vaccine or standard method of production. Only two vaccines are available, one in Turkey and another one in India (. The sub-unit vaccines are still in development.

    GAPS:

    • Little work is being undertaken on subunit vaccines against T. annulata in the EU.

  • Commercial vaccines authorised in Europe

    None.

  • Marker vaccines available worldwide

    None.

  • Marker vaccines authorised in Europe

    None.

  • Effectiveness of vaccines / Main shortcomings of current vaccines

    The current live attenuated vaccines carry risks associated with the breakdown of the cold chain, disease due to immunisation and the possibility of introducing other contaminating pathogens caused by inadequate quality control during preparation. Moreover, the introduction of new strains into the area by live attenuated vaccines through vaccinated animals.

  • Commercial potential for vaccines in Europe

    There is currently a limited market in Europe for vaccines against theileriosis caused by T. annulata.

  • Regulatory and/or policy challenges to approval

    There is currently no regulatory or policy challenge to approval of vaccines against theileriosis.

  • Commercial feasibility (e.g manufacturing)

    Whilst it is feasible, the commercial viability of developing such a vaccine would depend on uptake and therefore whether the investment in research and development would be repaid in later sales. If also applicable to T. parva in Africa, then it might be commercially viable.

  • Opportunity for barrier protection

    This is not considered to be a possibility in the current situation.

  • Opportunity for new developments

    Identification of protective antigens and delivery strategies associated with induction of protective immunity.

    Development of a per os delivery method of an anti-tick vaccine using plant expressed concealed tick antigen(s).

    GAPS:

    • Per os immunisation methodology resulting in good humoral protective responses.

  • Pharmaceutical availability

  • Current therapy (curative and preventive)

    Theilericides such as buparvaquone are marketed for therapeutic use and are effective if given in the early stages of the disease although they are less effective if treatment is delayed. However, animals that recover following treatment have decreased productivity for months. Recently drug-resistant parasites have been noted which suggests that this molecule may become less effective over time. There are currently no curative drugs registered in EU countries.

    GAPS:

    • No “legal” curative therapy in Europe.

  • Future therapy

    New theilericides may be developed in the future and it may be possible to develop compounds that could be continuously available in the blood of the cattle (by administering via the feed for example), such that when ticks feed, the sporozoites are neutralised before having the chance to invade and start infection the host cells. This will inhibit expansion of infected cells thereby enhancing control by the immune response.

    GAPS:

    • Buparvaquone is an excellent molecule. The emergence of resistance might justify the development of new drugs with the same efficiency.
    • Identification of novel therapeutics and parasite targets are required.

  • Commercial potential for pharmaceuticals in Europe

    The current level of infection in Europe would suggest that there is limited commercial potential in Europe. Yet, some areas in Europe might have an evident need of the drugs. The use of buparvaquone for Theileria equi piroplasmosis could also justify its registration in some European countries.

  • Regulatory and/or policy challenges to approval

    There is currently no regulatory or policy challenge to approval of therapeutic theilericides. Yet, buparvaquone has not been registered in any European country in spite of its need in Spain/Portugal for instance.

    It can be used in Menorca with a special authorization of AEM (Spanish Drug Agency) but complex application and delay of several months.

  • Commercial feasibility (e.g manufacturing)

    Buparvaquone is available on the Africa, Asia and Middle-East markets. The main costs are related to the registration procedure and this could be too high in the EU in respect of the currently limited market potential due to the sporadic nature of the disease in Europe.

  • Opportunities for new developments

    New theilericides may be developed in the future and it may be possible to develop compounds that could be continuously available in the blood of the cattle, (by administering via the feed for example), such that when ticks feed, the sporozoietes are neutralised before having the chance to infect. This will inhibit expansion of infected cells thereby enhancing control by the immune response.

  • New developments for diagnostic tests

  • Requirements for diagnostics development

    With the development of the subunit vaccines it may be possible to develop marker vaccines and thus there would be a requirement to develop diagnostics that can differentiate vaccinated and naturally infected animals (DIVA approach).

    The detection of carrier animals remains a challenge: carrier animals do not always carry specific antibodies. They present low parasitaemia that are difficult to detect using the parasitological and even molecular methods, although sensitive but more expensive molecular assays are available for research use.

    GAPS:

    • Specific and sensitive field tests to detect carrier animals and possibly also quantify parasite loads.

  • Time to develop new or improved diagnostics

    This could be significant depending on what was required.

  • Cost of developing new or improved diagnostics and their validation

    The cost of developing new or improved diagnostics and especially their validation under different field conditions could be significant.

  • Research requirements for new or improved diagnostics

    Affordable pen-side tests could prove valuable in the field, especially in non-EU endemic regions.

  • Technology to determine virus freedom in animals

    Not applicable. However, parasite freedom in animals would be very difficult to demonstrate due to the fluctuating low parasitaemia in carrier animals. It will need repeated testing of the same animal both serologically and molecular.

  • New developments for vaccines

  • Requirements for vaccines development / main characteristics for improved vaccines

    The main challenge is to stimulate cell-mediated immunity, which has so far been done using live cell lines. Live vaccines present the storage difficulty as main constraint. The use of attenuated cell-line vaccines do not confer good protection against heterologous strains which might be present in the same country. New vaccine developments should either focus on storage improvement or completely new vaccination type (e.g. DNA vaccines). Recent studies showed that a sporozoite antigen can provide a synergistic response with an attenuated cell line imply that the cell-mediated mechanisms may not be directed against specific antigens. Antigen delivery and adjuvant development are probably required, particularly for candidate CD8+ T cell antigens that have yet to be validated in trials against the related T. parva. Research into anti tick vaccines identified various concealed tick antigens, but becomes difficult to apply in the field due to the need of repeated injections.

    GAPS:

    • There is a requirement to establish exactly how attenuated vaccines engender protective immunity. Route of successful delivery for CD8+ T cell antigens.

  • Time to develop new or improved vaccines

    Variable because of research time needed. Medium to long term (>5 years)

  • Cost of developing new or improved vaccines and their validation

    The cost could be substantial bearing in mind the animal studies that would be required for registration. The potential return on investment bearing in mind the geographical location of this disease may also influence any decision to proceed.

  • Research requirements for new or improved vaccines

    Identification of protective antigens, identification of correlates for protective immune response read outs. Delivery and testing of recombinant antigens identified.

    GAPS:

    • Route of successful recombinant/inactivated antigen delivery.

  • New developments for pharmaceuticals

  • Requirements for pharmaceuticals development

    Bearing in mind the perceived resistance to current theilericides future pharmaceutical development would need to concentrate initially on new theilericides compounds, and there is little compelling current evidence that new therapeutic breakthroughs in other apicomplexa’s like Plasmodium or Toxoplasma will be applicable to Theileria.

  • Time to develop new or improved pharmaceuticals

    Variable because of research time needed and the fact that the active ingredient, once established, needs to be a compound that is produced under GMP.

  • Cost of developing new or improved pharmaceuticals and their validation

    The cost could be substantial bearing in mind the animal studies that would be required for registration. The potential return on investment bearing in mind the geographical location of this disease may also influence any decision to proceed.

    GAPS:

    • No interest from commercial firms to develop new theilericidal drugs since the market is restricted and concerns mainly low-income countries.

  • Research requirements for new or improved pharmaceuticals

    Option of mining the apicoplast metabolism pathways for new therapeutics. Genes encoding apicoplast proteins were obtained for T. parva and nine potential drug targets with a match to other apicomplexan apicoplast genes identified. An in silico metabolic map of the Theileria apicoplast was generated (Lizundia et al., 2009).. A range of putative apicoplast inhibitors was tested against macroschizont infected cells. The results were not particularly encouraging, certainly relative to buparvaquone the standard that, ideally, all new drugs should aim for. Recent screens using compound libraries tested on malaria or cancer have not identified a candidate superior to buparvaquone, but at least two compounds showing promise for further development were identified.

Disease details

  • Description and characteristics

  • Pathogen

    Theileria spp. are obligate intracellular tick-borne protozoan parasites infecting several mammalian hosts.

  • Variability of the disease

    There is a high number of species that infect cattle with Theileria spp.; however, the two most important species are T. parva and T. annulata. Theileria parva (East Coast fever) is restricted to sub-Saharan Africa whilst T. annulata (Tropical/Mediterranean Theileriosis) occurs in southern Europe as well as North Africa and Asia.

    Theileria annulata can occur in cattle, yaks, water buffalo and camels (Camelus dromedarius, so far with no pathological significance) and is transmitted by ticks of the genus Hyalomma. Tropical Theileriosis is more severe in European breeds, with a mortality rate of 40 – 90% in non-treated exotic breed while the mortality rate in indigenous cattle breeds from endemic areas can be as low as 3%. Studies indicate potential for significant economic loss in infected crossbreeds.

    In Spain, T. annulata infections are mainly restricted to the Southern and Mediterranean areas like Menorca Island, where the tick vector (Hyalomma lusitanicum) is present. In Northern Spain, reports on the presence of H. lusitanicum ticks are only sporadic, as well as T. annulata infections. However, their distribution might change due to changes in climatic conditions. Fatal cases have been reported in southern Portugal where prevalence approached 30%. In Greece (Macedonia region) 2.0% of tested cattle were seropositive to T. annulata.

    Theileria orientalis/buffeli is transmitted by Haemaphysalis spp. ticks and occurs widely spread around the world. Infection is generally subclinical; however, disease can occur in cattle depending on many epidemiological factors (including previous exposure to Theileria, stress/health status, variations in the species pathogenicity as reported recently in Japan, Australia and New Zealand).

    T. lestoquardi also transmitted by Hyalomma ticks (mainly H. anatolicum and R. turanicus) is the only species of economic significance infecting small ruminants and it also occurs in Africa (Sudan and Tanzania), the Mediterranean basin (Tunisia with PCR evidence and Turkey) and Asia. In sheep and goats the morbidity rate from T lestoquardi can reach 100% with a mortality rate of 46 – 100% in the most susceptible breeds.

    Theileria uilenbergi and Theileria luwenshuni are pathogenic ovine piroplasms described in northwestern China, but similar (by sequence comparison). Theileria parasites have been found in sheep in Northern Spain and Turkey, but apparently with a low pathogenicity.

    T. ovis is a non pathogenic parasite, affecting sheep.

    GAPS:

    • The potential for different strains (genotypes) of T. annulata (and other Theileria species) to cause disease pathology.
    • Epidemiology of small ruminant Theileriosis including consequences of co-infection with multiple Theileria species.

  • Stability of the agent/pathogen in the environment

    Obligate intracellular protozoan. Can survive in ticks for several months (up to 6 months or more, depending on ecology of tick vector).

  • Species involved

  • Animal infected/carrier/disease

    All Theileria species give rise to a carrier status. They can infect cattle, yaks, water buffalo and camels. Once infected, assuming recovery, the animal becomes a carrier and can be infective for months or years.

    T. lestoquardi infects small ruminants like sheep and goats.

    GAPS:

    • Dynamics and cost of the carrier status.
    • What is the epidemiology of the carrier state as defined by length of carrier status, infectivity of the host over time etc.

  • Human infected/disease

    Hyalomma can attach to humans but both T. annulata and T. lestoquardi have never been reported in humans. Human theileriosis has been diagnosed mainly in USA and is caused by T. microti. Mice are the reservoir of this pathogen, it is transmitted by ticks of the Ixodes genus. But genomic analysis shows that the species belongs to a separate genus (neither Babesia or Theileria).

  • Vector cyclical/non-cyclical

    T. annulata is an obligate intracellular protozoan and uses the ticks of the genus Hyalomma as the definite host in a cyclical life cycle. Hyalomma‘s present in Europe are 3 host ticks except for H. marginatum (2 host tick). The Haemaphysalis species of ticks (3 host tick) act as a vector for T. orientalis/buffeli. Transmission is only transstadial.

    All Theileria species except T. parva can be transferred iatrogenically by blood inoculation and the inadequate use of contaminated needles.

    GAPS:

    • Other tick genus involved, especially for T. lestoquardi?
    • The significance of iatrogenic transmission (assumed to be minor and of academic interest only) in the development of the Theileria lifestage in the tick (it is not clear what is the impact from iatrogenic introduction).

  • Reservoir (animal, environment)

    The reservoir for T. annulata and T. orientalis/buffeli involves infected mammalian species and infected species of the tick that act as the vector. There is no known environmental reservoir.

  • Description of infection & disease in natural hosts

  • Transmissibility

    T. annulata and T. lestoquardi are transmitted by ticks of the genus Hyalomma. Theileria sporozoites are transmitted to animals in the saliva of the feeding tick. Ordinarily T. annulata sporozoites only mature and enter the saliva after the tick attaches to a host; a tick must usually be attached for a few days (appr. 3 days) before it becomes infective. However, if environmental temperatures are high infective sporozoites can develop in ticks on the ground and may enter the host within hours of attachment. Transovarial transmission has never been reported for Theileria spp. parasites. Inside the mammalian host the Theileria sporozoites undergo a complex life cycle involving the replication of schizonts in leukocytes, production of merozoites and formation of piroplasms in erythrocytes. Free tick stages can remain infected for up to 2 years depending on climatic conditions. Antigens specifically expressed by stages present in the tick have recently been identified.

    GAPS:

    • The molecular mechanisms that control sporozoite production (and parasite stage differentiation) are not fully understood. Blocking this event or production of piroplasm-infected erythrocytes would effectively block transmission. Efficacy of transmission blocking candidate antigens.

  • Pathogenic life cycle stages

    The schizont is recognised as the most pathogenic stage as it causes lymphoid proliferation and later induces lymphoid destruction. However, the piroplasm stage in erythrocytes may also be described as pathogenic in that it can cause haemolysis inducing jaundice, anaemia and in some cases haemoglobinuria.

    GAPS:

    • The pathogenesis of T. orientalis/buffeli.
    • The contribution of the erythrocytic phase (or schizont phase) to economic loss. Pathogenicity associated with production loss in carriers.

  • Signs/Morbidity

    The clinical signs associated with infection of T. annulata are dependent on the acuteness of infection but generally include generalised lymphadenopathy, fever, anorexia and loss of condition with sometimes sudden decrease in milk yield. Petechiae and ecchymoses may be found on the conjunctiva and oral mucous membranes, they are observed in severe cases and are signs of bad prognosis. Lacrimation, nasal discharge, corneal opacity and diarrhoea can also be seen. Terminally ill animals often develop pulmonary oedema, severe dyspnoea and a frothy nasal discharge. The destruction of red blood cells can cause jaundice, anaemia, and in some cases haemoglobinuria. Abortions might be the most important sign in non-milking animals (appr. 30%). With T. orientalis/buffeli, clinical pathological changes are reflective of a haemolytic anaemia. The impacts may be variable depending on the balance between optimal tick habitat and cattle exposure. The interaction between these two variables and others produces spatial variation in impact. Paradoxically regions with less than optimal tick habitat may have a cattle population that is the most severely affected. A regenerative anaemia is generally present. In northern Spain, T. buffeli infections present a benign course with red cell parameters within normal ranges.

    GAPS:

    • Effects of mixed infections (Babesia spp. or Anaplasma spp. including variations of the same Theileria species) on disease severity is relatively frequent in endemic areas but not well studied.

  • Incubation period

    The incubation period is thought to be approximately 1 to 3 weeks.

  • Mortality

    Primary infections are often fatal in highly productive European breeds of cattle in which the mortality can reach 40 – 90% when untreated and appr. 10% when treated. The mortality in indigenous cattle from endemic areas can be as low as 3%.

    GAPS:

    • Agent specific mortality rates of cattle and small ruminants in the EU resulting from infection with Theileria species.

  • Shedding kinetic patterns

    T. annulata is an obligate intracellular protozoan and therefore shedding does not occur. Carrier animals remain infective to ticks for several years (one study determined a maximum of 11 years, likely representing the limits of detection of the agent through molecular methods).

    GAPS:

    • Length and dynamics of carrier state in production animals.

  • Mechanism of pathogenicity

    The sporozoites of T. annulata and T. lestoquardi preferentially invade cells of myeloid lineage (monocytes/macrophages and B cells). The parasite has the ability to transform its host cell (similar to oncogenic transformation). Signal transduction pathways are triggered leading to uncontrolled activation of a protein kinase called casein kinase II. This results in production of IL-2 and IL-2R. As a result an autocrine or paracrine loop is established where infected cells secrete IL-2 that in turn stimulates their growth. It is also evident that host cell infection causes constitutive activation of factors that regulate the inflammatory response (e.g. NF-kB). As the schizont stage develops within leucocytes, infected cells enlarge to form blasts and begin to proliferate. Since the parasite can divide synchronously with its host cell there is rapid clonal expansion of parasitized cells. Parasite infected cells also gain the ability to metastasize many tissues and organs. This involves activation of AP-1, expression of cytokines, surface receptors and proteases. Pathology is mainly caused by the accumulation of parasitized leukocytes in vital organs causing severe inflammation and pyrexia. To some extent, pathology is also caused by haemolytic anaemia.

    The other Theileria are mainly found in red blood cells and are assumingly not transforming parasites.

    GAPS:

    • The impact of host cell type on disease pathology is not fully understood but is likely to play an important role, as are host genetic differences in cellular activation and response to infection. The full complexity of how the parasite modulates the host cell and host immune system is not understood but has parallels with cancer.

  • Zoonotic potential

  • Reported incidence in humans

    There is no current evidence that T. annulata or T. lestoquardi or T. buffeli/orientalis are a hazard to humans.

  • Risk of occurence in humans, populations at risk, specific risk factors

    N/A

  • Symptoms described in humans

    N/A

  • Estimated level of under-reporting in humans

    N/A

  • Likelihood of spread in humans

    N/A

  • Impact on animal welfare and biodiversity

  • Both disease and prevention/control measures related

    Infection by T. annulata parasites limits the movement of cattle between countries and induces production losses and high mortality in susceptible animals. Because this disease is most severe in highly productive exotic animals it is a significant constraint on the importation of new breeds or improved stock into endemically affected regions. Hidden production costs in carrier animals are likely.

  • Endangered wild species affected or not (estimation for Europe / worldwide)

    T. annulata is not known to affect any of the endangered wild species, but other Theileria species have been described in wild mammals: T. bicornis (rhinoceros), T. capreoli (deer), T taurotragi (Cape Eland).

    GAPS:

    • The significance of wildlife as reservoirs of Theileria species and tick hosts.

  • Slaughter necessity according to EU rules or other regions

    The compulsory slaughter of infected animals is not currently practised, however, if the disease spreads to new regions or countries, this may become the preferred method of control, especially in Europe. Compulsory slaughtering implies slaughtering all sick, recovered and immune animals. Serial serology associated with PCR screening (for seronegative cases that could be recently infected) would be essential to identify infected animals. Efficient tick control would also be required.

    GAPS:

    • The efficacy of compulsory slaughter on preventing disease spread.

  • Geographical distribution and spread

  • Current occurence/distribution

    Theileria annulata is present from North Africa and Southern Europe through the Middle East and into Southern Asia. Recently, the disease was also reported in Northern Ethiopia. Sporadic cases of T. annulata are reported in northern Spain (Atlantic climate zone) where the vector (Hyalomma spp.) is not established. The disease risk is monitored in Corsica as the vector tick (H. scupense) was recently reported for the first time in this location. T. buffeli/orientalis is present in many countries of the world.

    GAPS:

    • Spatial distribution of vector tick species.

  • Epizootic/endemic- if epidemic frequency of outbreaks

    In Spain, T. annulata infections are described in the southern and Mediterranean (e.g. Minorca) areas, where climatic conditions favour the presence of the Hyalomma tick vector. The situation is very different in different parts of Spain. T. annulata is known to be endemic in the southern, western and Mediterranean areas like Extremadura, Andalucia and Minorca. The parasite is also present in southern Portugal with lower prevalence in central and northern Portugal. Epidemics mostly occur when susceptible animals are introduced in endemic areas or carrier animals are introduced in vector free regions, but infection is also spread through use of needles like in Northern Spain. Outbreaks might also be recorded at the fringes of the geographical distribution. Disease in endemically affected locations may also occur as a result of breakdown in premunity through the occurrence of unrelated disease epizootics affecting the balance between the host and the Theileria agent. Calves are at risk even in endemic areas, on a yearly basis.

  • Seasonality

    Theileria annulata incidence shows a marked seasonality resulting from the vector tick activities. The spring and the end of summer are the periods with acute T. annulata infections in Menorca. In Tunisia, the clinical cases are mainly reported during the summer season. On the other hand and as an extreme configuration, in Sudan, clinical cases are reported throughout the year since the vector tick (H. anatolicum) is active all year around.

    GAPS:

    • The exact distribution of the ticks in some areas is not known.
    • The role (risk) of birds in introducing the vector ticks from endemic areas was never studied.
    • Computer modelling taking into account climate, cattle population and other indices to generate predictive hotspots of infection/disease/impact.

  • Speed of spatial spread during an outbreak

    This is primarily dependant on the movement of infected cattle. It also depends on the presence of vector ticks in the new areas or the concomitant introduction of vector ticks with infected cattle.

  • Transboundary potential of the disease

    The disease is primarily dependant on the habitat of the ticks that transmit it. Movement of infected cattle away from the area known to be inhabited by the tick will not necessarily spread the disease (unless the vector tick is concomitantly introduced) but movement within the habitat of the tick will spread the disease. Extension of tick habitat coupled to cattle movement is likely to have greatest transboundary potential. There is a danger of introduction of North-African species of Hyalomma in Europe through sheep transports. The North African tick vector H. scupense (syn. H. detritum detritum) is endophilic, so a completely different and easier control approach would be needed once introduced.

    GAPS:

    • Frequency of live animal transport between Europe and North Africa.

  • Route of Transmission

  • Usual mode of transmission (introduction, means of spread)

    T. annulata is an obligate intracellular protozoan and therefore the usual mode of transmission is via the tick. Theileria is often introduced in a new area through the introduction of a carrier animal and will spread if the tick vector is present.

  • Occasional mode of transmission

    The inappropriate use of infected needles could cause transmission of some Theileria species.

    GAPS:

    • Little relevance as a transmission pathway for T.o Ikeda

  • Conditions that favour spread

    The movement of infected animals (and infected vectors) and the climatic conditions favouring the habitat and proliferation of the tick will favour the spread of the disease.

  • Detection and Immune response to infection

  • Mechanism of host response

    Innate and adaptive immune responses cooperate to protect cattle against Tropical Theileriosis. Intracellular parasites are mostly affected by cell-mediated immunity. Infection of leukocytes by T. annulata activates the release of cytokines, initiating an immune response and helping to present parasite antigen to CD4+ T cells. These cells produce interferon-γ, which activates non-infected macrophages to synthesise tumour necrosis factor α and nitric oxide which destroy schizont and piroplasm infected cells. CD8+ T cells have recently been shown to recognise parasite MHC presented antigens and kill infected leukocytes. B cells produce antibody that along with nitric oxide kill extracellular merozoites and intracellular piroplasms. On the other hand, overproduction of cytokines, in particular tumour necrosis factor α by macrophages generates many of the clinical signs and pathological lesions that characterise tropical theileriosis. The outcome of infection depends on the fine balance between protective and pathological properties of the immune system.

    GAPS:

    • Conclusive identification of parasite antigens that confer protective immunity.
    • The relative importance of different arms of the immune response.
    • The ability of the parasite to combat the immune response.
    • Validation of antigens recognised by CD8+ T cells from immune animals and the impact of antigenic diversity.

  • Immunological basis of diagnosis

    The indirect fluorescent antibody test is the most widely used diagnostic test for T. annulata. It is easy to perform and provides adequate specificity for use in the field but has limitations for large-scale serological surveys. Also, there is a problem of subjective interpretation when dealing with weak positive sera. Serological tests based on ELISA techniques are increasingly being used for the detection of parasite specific antibodies and have been shown to detect antibodies for a longer period of time than the IFA. PCR and quantitative PCR (real time PCR) tests have been developed and can be used as a diagnostic test of herd infection on pooled samples. A Lateral Flow assay has also been developed.

    GAPS:

    • A standardised sensitive diagnostic test that is routinely employed across endemic regions. ELISA for T. lestoquardi.

  • Main means of prevention, detection and control

  • Sanitary measures

    Control of the disease by the use of acaricides (mainly pour-on formulations) involves more or less continuous use during seasons of tick challenge and is difficult to maintain. It has a high cost (price of the acaricide, labour cost and withdrawn milk). In addition to environmental concerns, continuous use of acaricides is known to result in the selection of acaricide-resistant ticks. Treatment is effective if given in the early stages of the infection, but creates a carrier status, source of infection for the vector. Slaughtering might be the most effective measure when spreading to a new area.

    GAPS:

    • Effective strategies for disease eradication (if desirable). Definition of urgent measures to mitigate an incursion into a previously “free” region assuming the time between introduction and detection was short i.e. operational specifications given early detection.

  • Mechanical and biological control

    There are no effective means of mechanical control. It is conceivable that biological control of the ticks could be exercised by using a natural enemy of the tick but this does not appear to have been tried as a serious means of control to date. Preventing animals from contact with exophilic vectors (H. lusitanicum) by keeping them inside might not help since ticks can be introduced with hay or grass and hide in stable walls. Similarly, preventing animals from contact with endophilic vectors (H. scupense) by keeping them outside might not help since there is a population that lives in the field under rocks. Upgrading the building by smoothing the outer and inner surfaces could represent an excellent solution to eradicate H. scupense on a farm but is very expensive.

    GAPS:

    • Effect of different management systems on infection prevalence. What management systems reduce the frequency in the use of acaricides and incidence of theileriosis?

  • Diagnostic tools

    Serological tests as IFA, ELISA and PCR assays, together with identification of schizonts in Giemsa-stained smears from blood or lymph node biopsies are used for diagnosis. The best technique to identify clinically infected animals is Giemsa stained blood smears; it is a rapid, easy and cheap test. It allows also quantifying the intensity of infection. Moreover, it allows the identification of co-infected animals: Theileria – Babesia or Theileria – Anaplasma. Lymph node smears allows identification of early infections, unfortunately, this technique is not standard practice by most field veterinarians since they have to prepare the smear immediately after sampling the animal.

    GAPS:

    • Quick test kit for Theileria spp, Babesia spp. and Anaplasma spp.

  • Vaccines

    Live vaccines produced by attenuating parasite-infected leukocytes have been used to vaccinate cattle against T. annulata. In more recent times subunit vaccine research has been focused on surface antigens (recombinant SPAG-1 surface antigen of T. annulata). Antigens recognised by CD8 + T cells and potential transmission blocking candidates have been described, recently. Research into anti tick vaccines identified various concealed tick antigens.

    GAPS:

    • Trials with vaccine against T. lestoquardi on limited scale.
    • Standardised live T. annulata vaccine selection and production. Adjuvants and protocols for correct delivery of recombinant CD8+ antigens.

  • Therapeutics

    Chemotherapeutic compounds such as buparvaquone (BPQ) having theilericidal properties have been used but tend not to completely eradicate the infection thus leading to the development of carrier states. In the case of T. orientalis Ikeda use of BPQ has found to be most effective anecdotally in the pre-clinical period rather than the clinical period. Two treatments were found to be better than one, but the efficacy was very difficult to quantify. Buparvaquone is registered in Turkey but not in EU. Resistance against this drug has recently been reported in Tunisia, Turkey and Iran.

    GAPS:

    • The extent of drug resistance, development of rapid/simple tests for drug resistance monitoring. Identification of resistance genes.
    • The ideal timing and frequency for the use of these anti-theilerial drugs.

  • Biosecurity measures effective as a preventive measure

    In the endemic areas it is unlikely that biosecurity measures would be practical but in theory it would be possible to maintain the animals in a tick-free environment thus removing the necessary vector of disease transmission.

  • Border/trade/movement control sufficient for control

    It is unlikely that the spread of the ticks could be controlled. On the other hand, controlling animal movement would be useful in managing the disease. Pre-movement acaricide treatment or treatment at movement nodes represents an appropriate method of control, particularly when cattle are moved from endemically affected to non-affected areas. It is important also to consider unusual hosts and treat them before their introduction to T. annulata free regions or countries. This is the case of pet animals that are introduced from North Africa to Europe.

    GAPS:

    • Movement patterns of cattle from affected to unaffected regions. Identification of key movement modes useful for the purposes of surveillance and mitigation of spread.

  • Prevention tools

    Vaccination is an efficient prevention tool in endemic areas. Prevention could also rely on the effective use of acaricides and the effectiveness of the use of these compounds in avoiding resistance build up among the tick population. This would mean an almost continuous use of a very efficacious acaricide but necessitates movement controls and the use of zoning to create buffer areas.

    Anti-tick vaccine development combined with a transmission blocking strategy might be another approach.

    GAPS:

    • A lack of efficacious inactivated or subunit vaccines.

  • Surveillance

    Not currently practised. Difficult to get financial support for epidemiological studies. Data collected through research based studies.

    GAPS:

    • The prevalence of disease and distribution of competent vectors within endemic and bordering regions/countries and specifically Corsica.

  • Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

    Eradication using available control measures might be very difficult to achieve, and may be undesirable as it generates a population of highly susceptible cattle. Eradication could be an option under specific conditions of known epidemiology in areas experiencing sporadic disease or spread to new areas. Tick control and vaccination have proven their efficiency under specific conditions.

    GAPS:

    • Current epidemiological situation of T. annulata in EU.

  • Costs of above measures

    The cost of control may be substantial and it is conceivable that part of the reason for lack of effective control is that subsistence farmers in the endemic area are reluctant to commit sufficient resources to control the disease. It is also possible that the true cost of productive losses (subclinical losses) resulting in endemically affected indigenous cattle may not be obvious to farmers. Studies in Tunisia have indicated that subclinical disease has most impact on economic production; and this is likely to be the case in other endemic regions such as India.

    GAPS:

    • The true cost of subclinical disease in indigenous breeds of cattle in endemically affecting regions/countries.

  • Disease information from the WOAH

  • Disease notifiable to the WOAH

    Yes.

  • WOAH disease card available

    Link to technical diseased card.

  • WOAH Terrestrial Animal Health Code

    Link.

  • WOAH Terrestrial Manual

    Link.

  • Socio-economic impact

  • Zoonosis: impact on affected individuals and/or aggregated DALY figures

    N.A.

  • Zoonosis: cost of treatment and control of the disease in humans

    N.A.

  • Direct impact (a) on production

    This can be substantial especially for the subsistence farmers found throughout the affected area. Where the disease occurs in Southern Europe the high producing breeds of animal tend to suffer proportionately higher mortality.

    GAPS:

    • Losses due to subclinical infections.

  • Direct impact (b) cost of private and public control measures

    The cost of the continuous use of acaricides during the tick feeding season can be high (per application: €0.20 for spraying - €3.1 for pour-on) and in fact may not be effective. Cost of chemotherapy is high and beyond subsistence farmers (approximately € 20for a single injection of Buparvaquone, and more than 1 injection might be needed). Surveillance, compulsory slaughtering, production and delivery of vaccine require state/government involvement.

    GAPS:

    • Identification of the less cost-benefit control option in endemic areas and the most cost-effective control option in newly infected areas.

  • Indirect impact

    The main impact is on the security of the food supply for the indigenous people in the endemic area since it is unlikely that significant improvements to production through breeding can be accomplished and even infected indigenous breeds of cattle can show high levels of morbidity with loss of production of meat and milk. Over judicious use of acaricides may increase entry of chemicals into the food chain. Loss of animal draught power, animal by-products used as fuel.

  • Trade implications

  • Impact on international trade/exports from the EU

    Exports from the EU are unlikely to be affected. Exportation of live animals will be subject to restrictions. e.g. disease constrains export of European cattle to India.

  • Impact on EU intra-community trade

    Animals from the endemic area of Southern Europe would be expected to have veterinary certificates indicating they were free of infection and had been recently treated with an acaricide to prevent the inadvertent movement of ticks.

    GAPS:

    • Feasibility of veterinary certification given lower than 100% efficacy of acaricide treatment and carrier status detection. Knowledge of most effective border control measures that have a high sensitivity of preventing entry of ticks.

  • Impact on national trade

    Animals from the endemic area of Southern Europe would be expected to have veterinary certificates indicating they were free of infection and had been recently treated with an acaricide to prevent the inadvertent movement of ticks.

  • Main perceived obstacles for effective prevention and control

    The main obstacle to effective prevention and control would be the eradication of the tick population from the endemic areas and/or lack of effective vaccination regimes that prevent disease and transmission.

    Tick control: expensive infrastructure or expensive products (pour-on), labour costs (time spend to treat animals may be long), residues in milk, meat and environment.

    Vaccination: strain specific, live vaccine requiring storage in liquid nitrogen, good quality control and delivery. Live vaccines might import different genotypes.

    Iatrogenic spread through injecting pharmaceuticals without changing needles also needs to be considered.

    Generation and spread of drug resistance.

    GAPS:

    • The most effective timing/interval for acaricide treatments within age class of cattle and epidemic situation.

  • Main perceived facilitators for effective prevention and control

    An effective and cheap sub-unit vaccine may facilitate the control of this disease.

    GAPS:

    • Identification of protective antigens and delivery strategies associated with induction of protective immunity.

  • Links to climate

    Seasonal cycle linked to climate

    Only in that the biology of the vector tick itself is seasonal or a change in time of year when peak tick challenge occurs – coinciding with calving.

  • Distribution of disease or vector linked to climate

    The disease will follow the geographic distribution of the tick and if the climate favours spread and questing of the tick for new hosts; then spread of the disease will follow.

    GAPS:

    • Tick population dynamics monitoring schemes to study the effects of climate change on the local distribution and abundance of ticks and its seasonality.

  • Outbreaks linked to extreme weather

    Some Hyalomma vector ticks appear to be particularly abundant during extremely warm periods. In these regions, most cases appear towards the end of summer, much more than in spring.

  • Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

    Global warming may influence the geographical distribution of the tick, the tick abundance and the tick’s vectorial capacity, which in turn will affect the distribution and incidence of the disease. Hyalomma ticks are known to occur in drier biotopes compared to most other tick genera so climate change or global warming might favour Hyalomma survival and spread.

    GAPS:

    • Which climate change would cause a spread of the Hyalomma ticks? Differences in vectorial capacity for different Hyalomma species?
    • How is vectorial capacity affected by a change in climatic indices?

Risk

  • The two most pressing potential risks are:

    • In the spread of the disease to other previously uninfected areas due to expansion of the tick habitat as a result of global warming.
    • In the need to develop the production capacity of the indigenous stock in the currently affected areas such that avoidance of food shortages and rural depopulation can be achieved.

Conclusion

  • Some 240 million cattle over a region extending from South Europe, Africa, Middle East and across South Asia are at risk of infection. Livestock are a key resource for the production of milk and meat as well as generating cash for an enormous number of very poor farmers in the tropical and sub-tropical regions of the world. Improvement of the standard of living and nutrition of these farmers can be achieved by improving the productivity of their livestock. It should not be overlooked that indigenous cattle from these regions have a much lower risk of mortality from T. annulata, but that cross breeds are likely to suffer loss from infection. Management level will be instrumental in choosing the appropriate approach to disease control, either low input farming with indigenous cattle or high input farming using higher productive animals.

Sources of information

  • Expert group composition

    Dirk Geysen, independent consultant (former ITM Antwerp) – [Leader]

    Brian Shiels University of Glasgow, UK

    Andrew McFadden, Diagnostic and Surveillance Services, New Zealand

    Theo Schetters, Clinglobal

    Maxime Madder, Clinvet

    Louis Miguel Ortega Mora, Complutense University of Madrid

    Mohamed Gharbi, Ecole Nationale de Médecine Vétérinaire (ENMV) Sidi Thabet, Tunisia

  • Reviewed by

    Project Management Board.

  • Date of submission by expert group

    29 June 2018