CASE NOTES


EXOTIC THEILERIOSIS

David Thomson, North Coast LHPA

Posted Flock & Herd March 2012

INTRODUCTION

Various forms of Theileriosis are widely recognized as possibly the most economically significant vector-borne diseases affecting ruminant livestock production worldwide. They are especially significant for production in sub-Saharan east and far northern Africa, Mediterranean eastern Europe, Middle East, south-central Asia, the Indian sub-continent and China.

In sub-Saharan east Africa, East Coast Fever, arguably the most pathogenic variant caused by Theileria parva, precipitates outbreaks in susceptible and introduced stock with mortality and morbidity rates approaching 100%. It is believed to be responsible for more than 1.1million cattle deaths and vastly more lost production annually (14) and has been estimated in Tanzania to cost producers of the order USD205.00 per breeding cow (6). In similar vein, Tropical Theileriosis in north Africa, middle east and Asia causes outbreaks amongst susceptible introduced stock approaching 90%.

Far less pathogenic types of theileria generally classified as 'benign' cause outbreak mortality rates approaching 30% in susceptible introduced stock in Korea, Japan, south-east Asia and more recently appear to be emerging in eastern sub-tropical and temperate Australia.

Knowledge of these exotic diseases and their complex biology is as essential for the ongoing well-being of livestock production in Australia as vigilant surveillance for potential incursions and incursion pathways.

This paper will endeavour to focus on those Theileria spp. exotic to Australia that are capable of causing severe diseases with high, sustained losses amongst cattle, buffalo, sheep and goats, namely T. parva, T. annulata, T. lestoquardi, and some generally less pathogenic variants that have demonstrated occasional capacity to cause significant losses amongst introduced, immunologically naive cattle, buffalo, sheep, and juvenile animals.

CLASSIFICATION AND DISTRIBUTION

Taxonomic classification within the Theileria genus is complex, sometimes confusing and in a relatively high state of flux. Several species are comprised of recognized 'types' commonly differentiated by molecular techniques and there are also numerous loosely recognized 'strains' within some of these types differentiated by phenotypic and genotypic expression and discrete molecular characteristics.

For practical purposes the genus can be broadly classified based on parameters of:

Table 1, below, summarizes the respective relative pathogenicity, host specificity and geographic distribution for the highly pathogenic and sometimes pathogenic Theileria spp.

In particular microcosms, however, there may be considerable variability in relative pathogenicity, particularly with regard to Theileria parva (East Coast Fever), for which cross-protection after exposure to different sub-types and strains is weak or does not occur, and for several species generally classified as 'benign', but which can sometimes present initially as potentially severe diseases when juvenile and/or immunologically naive, introduced livestock are exposed to them for the first time.

Table 1: Classification of Theileria spp. for relative pathogenicity, host animal and geographic distribution
Pathogenicity Theileria spp. Hosts Vectors Distribution
High Theileria parva parva, Theileria parva lawrencei, Theileria parva bovis (East Coast Fever, Corridor Disease, January Disease) Cattle, buffalo, waterbuck, eland, blue wildebeest Rhipicephalis appendiculatus, Rhipicephalis zambeziensis, Rhipicephalis duttoni. (Three-host ticks) Sub-Saharan east Africa from South Sudan to RSA, including eastern Democratic Republic of Congo, Rwanda, Kenya, Uganda, Tanzania, Swaziland, Mosambique, Zambia, Zimbabwe, Botswana and Angola
Theileria annulata (Tropical Theileriosis, Mediterranean Theileriosis) Cattle, buffalo Hyaloma anatolicum (3-host), Hyaloma detritum (2-host), Hyaloma excavatum (3-host), numerous other lesser Hyaloma spp. North Africa including northern Sudan to Egypt (Nile River valley), Tunisia, Libya, Morocco, Algeria, Turkey, middle east, south-central Asia, Indian sub-continent, western China.
High Theileria lestoquardi (formerly T. hirci) (Malginant ovine and caprine theileriosis) Sheep, goats Hyaloma spp. as for T. annulata North Africa including Egypt, Tunisia, Libya, Morocco, Algeria, Turkey, middle east, south-central Asia, Indian sub-continent, western China.
Benign - Low to Moderate (the latter in juvenile and introduced animals) New species (unnamed) NB. Closely related to T. orientalis and has caused >50% losses amongst introduced stock. Sheep Haemaphysalis quinghaiensis China
Theileria taurotagi (sometimes associated with outbreaks of Turning Disease) Cattle, buffalo, Eland, sheep, goats NB. Infection in sheep and goats is usually apathogenic and, in some older publications, appears to have been mis-referred to as T. sergenti. Rhipicephalis appendiculatis Sub-Saharan east Africa from Kenya to Republic of South Africa
Benign - Low to Moderate (the latter in juvenile and introduced animals) Theileria mutans Cattle, buffalo Amblyoma spp. Sub-Saharan east Africa, Madagascar Carribean Islands, USA (recorded in 1950 and again in 1975)
Theileria equi Horses, asses, mules, zebra Rhipicephalis spp.
Hyaloma spp.
Dermacentor spp.
Southern Europe, Africa, Asia, southern USA, central and south America
Benign - low to moderate Theileria orientalis sergenti,- Ikeda sub-type (often also variously referred to as either T. sergenti or T. buffeli and maybe not a discrete species) Cattle Haemaphysalis spp. Including H. longicornis (uni-sexual biotype) - 3-host ticks Japan, China, Korea, eastern sub-tropical and temperate Australia
Theileria felis Cats Undefined Southern USA
Benign - very low Theileria orientalis orientalis (often also variously referred to as T. sergenti or T. buffeli and maybe not a discrete species) Cattle, Asiatic buffalo Haemaphysalis spp. Including H. longicornis, H. bispinosa and others - 3-host ticks Far eastern maritime Russian Federation, Japan, Korea, China, SE Asia

Theileria ovis (possibly several species) Sheep and goats Rhipicephalis spp. South-eastern Europe, Asia, Africa, Madagascar
Adapted from 4
Figure 1: Mapped distribution of the most pathogenic Theileria spp. affecting cattle and buffalo
Reproduced from 19

BASIC BIOLOGY AND LIFE CYCLES

Theileria species are respectively relatively highly mammalian host specific. There tick vectors are typically relatively theileria species-specific, multi-host ticks (ie. not mammalian host specific throughout their multi-stage life cycles) that spend short periods attached feeding and longer periods unattached in the environment moulting, hardening, in various states of extended diapauses and egg laying. Theileria vectors generally persist in areas with annual rainfall not less than 500mm and seasonally mild to warm sub-tropical to tropical conditions.

Theileria transmission within vector ticks is transtadial (across successive moults within the vector's life cycle). Transovarial transmission (trans-generationally via eggs) does not occur. Larval stage ticks are uninfected when they initially attach, vector ticks must feed on an infected carrier host to become infected, and once infected they remain infected for the remainder of their life. Low parasitaemias in carrier hosts are usually infectious for ticks, but the rate of vector infection is higher amongst ticks that feed on animals with higher parasitaemias (eg. clinical cases versus resistant persistently infected carriers).

Under favourable climatic and environmental conditions infected, unfed vector ticks can usually survive for many months to years in the environment with larvae being generally less persistent than nymphs which are, in turn, less persistent than adults. (13), (14).

Theileria sporozooites in vector salivary glands do not usually complete maturation to infectiveness until 48-72 hours after feeding has commenced, but under warm conditions maturation can sometimes occur before reattachment whilst the ticks are in the environment and transmission can occur almost immediately (13). Very low tick infestation rates are required to transmit theileriosis to susceptible mammalian hosts - a single infected tick is commonly sufficient.

Figure 2 depicts the life cycle of Theileria parva (East Coast Fever).

Figure 3 depicts the 3-host life cycle of Rhipicephalus appendiculatus, the principal vector of East Coast Fever.

Breeding cycles of vectors can be variable within their respective ranges relative to seasonal climatic conditions. For example, in cooler sub-tropical to temperate climatic conditions principal vectors display very seasonal life cycles and only complete one life cycle per annum. Larvae predominate in the autumn and/or winter, nymphs in the spring and adults during the warm, moist summer wet season and early autumn period. However, in relatively moist, more tropical environs, vectors are much less seasonal and are likely to complete several (up to 3) life cycles per annum with all life cycle stages evident concurrently (at variable relative proportions) throughout most of the year and a much less seasonal pattern of disease transmission. (13) (20)

Figure 2: Life cycle of Theileria parva (East Coast Fever)
Reproduced from 10
Figure 3: Life cycle of the 3-host tick, Rhipicephalis appendiculatus
Reproduced from 9

Highly pathogenic theileria species (namely, T. parva, T. annulata and T. lestoquardi) appear to differ significantly from lesser pathogenic species with respect to the speed, scale and site of primary replication within susceptible hosts. The highly pathogenic species undergo a dominant stage of expansive, lymphoproliferative clonal replication in lymphatic tissues, including lymph nodes and major organs of the lung, liver and gastrointestinal tract. Less pathogenic species undergo most replication during the piroplasm stage in the spleen and blood. These differences are reflected clearly by the pathology demonstrated by respective species (4).

It should be noted, however, that amongst the benign bovine theileriosis species, somewhat pathogenic types appear to replicate and dominate much faster within susceptible hosts than apathogenic types, including when mixed infections occur (per comm. B. de Vos, 2011).

PATHOGENSIS AND CLINICAL SIGNS IN MAMMALIAN HOSTS

Pre-patent period

The pre-patent period following initial tick bite varies somewhat between respective Theileria species. In general the pre-patent period for T. parva is between 7 and 15 days. For T. annulata, it usually ranges from 10 to 25 days. For benign theileriosis, it is usually longer between 21 and 35 days.

Clinical signs of highly pathogenic theileriosis

The defining clinical difference between highly pathogenic theileriosis and benign theileriosis is the occurrence of gross lymphadenopathy in the former associated with expansive proliferative clonal replication of shizonts in lymphatic tissues. Highly pathogenic strains present initially with prominent lymphadenopathy (often beginning with the drainage system for the tick bite site before generalizing) and high fever (up to 420C). As highly pathogenic theileriosis progresses other defining features develop rapidly including pulmonary oedema, generalized peticheal/ecchymotic haemorrhages on mucous membranes and serosal surfaces, corneal opacity and blood-tinged dairrhoea, all symptoms that are rarely associated with benign theileriosis. During the mid to latter stages of clinical progression, a proportion of East Coast Fever cases, and also occasionally relatively benign T. taurotagi cases, develop neurological signs associated with obstruction of capillaries in the cerebrum by lymphoid proliferation, commonly referred to as 'Turning Disease' where they circle slowly. Signs may eventually progress after several days to include anaemia and related blood pathology (particularly Tropical Theileriosis).

Signs of Malignant Ovine/Caprine Theileriosis in sheep and goats generally mirror those of Tropical Theileriosis in susceptible cattle except for relatively common occurrence of pronounced ventral oedema of the neck during the early to mid stages of clinical progression.

In contrast, benign theileriosis usually presents initially as anaemia and related blood pathology with modest or no fever and no discernible lymphadenopathy.

Morbidity rates generally reflect burdens of infected vector ticks, but can approach 100% over periods of days to weeks when stock are pastured on heavily infested ground. Mortality rates amongst untreated immunologically naive, susceptible, cattle usually range over several weeks between 50% and 100% for East Coast Fever and 30% and 90% for Tropical Theileriosis. Under conditions of endemic stability, however, mortalities amongst untreated calves are typically more prominent and can range between 5% and 50% for both highly pathogenic species, whilst concurrent rates amongst (previously exposed, unvaccinated) mature and semi-mature stock can also be as high as 10%.

Figure 5: Clinical East Coast Fever - early to mid stages.
From fao.org
Figure 6: East Coast fever - Terminal.
From fao.org

Gross pathology

The pathology of severe acute theileriosis associated with T. parva and T. annulata is quite distinctive and closely aligned with observable clinical signs. Predominant gross pathology includes:

Gross pathology associated with benign theilerisos is not definitive and changes are usually primarily associated with acute anaemia, including low to very low PCV, jaundice, enlarged pale friable liver, darkened renal cortex, and dark brown urine.

Microscopically, post mortem laboratory diagnosis of severe acute theileriosis usually relies on confirmation of abundant shizonts in stained specimens of lymphoreticular tissues, particularly dried, methanol-fixed impressions of liver, lung and lymph node, with or without the presence of piroplasms in the red blood cells and merozooites in circulating macrophages. Squash impressions of cerebral tissue may also reveal capillaries congested with lymphoid cells.

Post-mortem laboratory diagnosis of benign theileriosis is usually based on suggestive clinical and gross pathological findings combined with moderate to abundant presence of piroplasms in circulating RBC's, regenerative anaemia and histiopathological evidence of a haemolytic crisis.

Correlation between apparent parasitaemia and clinical severity is very limited for acute, severe T. parva and somewhat limited for benign theileriosis. In the latter, parasitaemias are usually evident, but there is variable clinical correlation with parasitaemia rates in RBC's between 5% and over 30%.

Serology is very useful to assess the status and infection/exposure rates across herds and within respective geographical areas. Available tests include IFA and indirect ELISA, with the latter now proving to be the more sensitive and specific. Serology has limited application for assessment of individual animals, eg. for detection and exclusion of potential persistently infected carriers, because it frequently fails to detect all carriers reliably. Serology is not reliable to differentiate between respective types and there is cross-reactivity between the major species, T. parva and T annulata.

PCR is commonly applied to confirm parasitaemia in infected and carrier animals or pooled blood, but again, it is not considered reliable for detection and exclusion of individual persistently infected carriers because many carriers are not always parasitaemic. PCR tests based on the 18S ribosomal RNA gene sequence, however, have a major application for differentiation between infections caused by different species and types of theileria. This capability has been a major diagnostic advance and is extremely useful for establishing the epidemiology of prevailing theileria occurrence.

Resistance and Immunological cross-protection

Buffalo and Bos indicus cattle breeds are generally more resistant to highly pathogenic theileriosis, but high mortalities are inevitable if immunologically naive animal are exposed to infected vectors. European Bos taurus breeds, particularly dairy breeds, are generally very highly susceptible. The Japanese Black breed has some noted resistance to benign Theileria orientalis (Ikeda type).

Cross-protection after exposure to different strains of highly pathogenic theileria is variable. There is no cross protection for East Coast Fever if livestock are exposed or vaccinated against Tropical Theileriosis and vice versa. Cross protection occurs between all strains of tropical theileriosis (T. annulata), but does not occur between respective types or strains of East Coast Fever (T. parva).

Concurrent mixed infections with highly pathogenic T. parva and benign African species (eg. T. mutans, T. taurotagi and/or T. velifera) is believed to enhance the pathogenicity of T. parva.

Passage of T. parva lawrenci (Corridor Disease type) from infected cattle through vector ticks into cattle increases pathogenesis considerably relative to theileria tick- passaged directly from buffalo.

Amongst susceptible stock, there is no age-related difference in susceptibility to highly pathogenic theileria species.

Livestock that recover from highly pathogenic or benign theileriosis usually remain persistently infected carriers for lengthy periods, probably for life.

CONTROL STRATEGIES

Control regimes commonly involve integration and simultaneous application of:

Treatment

Treatment of clinical cases is a vital ongoing requirement within areas affected by acute, severe theileriosis and as a protective response measure for areas that can support epizootic infection and/or are free from disease. Highly pathogenic species of theileria are able to overcome other protective measures such as vaccination and losses of 10%-20% or more can be incurred in 'immunologically resistant' cattle if treatment is not available and administered during the early clinical stages of the disease, particularly for calves and higher producing European Bos taurus dairy breeds.

A number of therapeutic agents are variably effective, including:

The effectiveness of all available treatments declines substantially if treatment is delayed after the onset of clinical signs, however, bupavaquone generally remains the most effective drug of choice for treatment of highly pathogenic theileriosis.

Vaccination

Numerous studies have demonstrated repeatedly the cost effectiveness and necessity of vaccination in highly pathogenic theileria infected areas. Cattle production is commercial unviable without vaccination in many areas across sub-Saharan east Africa, north Africa, Middle East and the Indian sub-continent. (12), (2), (16), (18), (14), (6)

The prevailing vaccination method is the 'inoculate and treat' method. It involves inoculation with live sporozooites derived from ticks in the case of East Coast Fever or cultured in macrophages in the case of Tropical Theileriosis. Inoculated animals are coincidentally treated, usually with long acting oxytetracyclines. Vaccine reactions occur at a low incidence, but losses are very acceptable relative to the alternative of non-vaccinated stock, including relatively resistant breeds of stock.

Subunit vaccines based on expressed sporozooite and/or shizont antigens alone or in combination are being developed with the hope of reducing vaccine production costs, reliance on cold chains, and to circumvent the need for coincidental treatment. There are promising candidates under development, but as yet none have matched the approximately 93% efficacy of existing live vaccines.

Another interesting vaccine development relates to tick vaccines targeting the attachment sites for blood parasites within the gut of ticks that are essential for the parasite to be able to infect vector ticks, mature and transmit. Target loci in a number of key tick species have been defined and vaccine developmental work is continuing, but as yet no suitably efficacious vaccines have emerged.

DISCUSSION

Exotic theileriosis affecting livestock are very serious diseases with generally complex biology that are inherently resistant to uncomplicated methods of control. There are, however, many important parallels and pointers from what is known of exotic theileria, their biology and their epidemiology that can be applied to consideration of benign theileriosis in Australia and its progressive control and management. In particular, knowledge concerning exotic theileria point to key gaps in our current knowledge.

It is perhaps comforting that the theileriosis that appears to be emerging in eastern sub-tropical and temperate Australia is comparatively very benign. The importance of ensuring that highly pathogenic strains do not gain entry and establish, irrespective of whether or not potentially competent vectors species are known to pre-exist must, however, be reinforced. The impact of a mere detection of a more pathogenic theileria species in Australia could have significant and long lasting trade implications and be very difficult to explain satisfactorily in a timely way.

During recent years there has been on-going discussion and speculation about whether the Theileria orientalis, Ikeda type associated with clinical outbreaks in eastern Australia (and also in areas where clinical theileriosis has not been recorded) is the result of a relatively recent introduction or whether it has been present for a long time and only recently recognized. The former proposition presents an ominous consideration - if the Ikeda type has been introduced recently and spread with relative ease to its currently known extent (based on limited systematic epidemiological study), how was it introduced, what is to stop other more serious theileria spp. from entering and what might they do if they gain entry. In contrast, if the Ikeda type has long been present and only recently emerged and been recognized, enhanced vigilance for detection of changing disease symptomatology and patterns, eg. lymphadenopathy as an indicator of increasing pathogenesis, may be indicated.

The presence or otherwise of potential tick vector species is a critical consideration when assessing risks from exotic theileriosis. On initial reflection, it may be somewhat comforting that the known highly pathogenic theileria species in Africa, Middle East and Asia are not know to be transmissible by species of tick resident in Australia. On the other hand, however, a new species of theileria very closely related to Theileria orientalis (if not a sub-species thereof) has recently been identified in China, it affects small ruminants rather than cattle, is capable of causing significant losses in non-immune stock and it is transmitted by a Haemophysalis spp. tick of which Australia has a relative abundance that have proven highly adaptable to both wildlife and multiple species of domestic livestock.

The competence or otherwise of many Australian-resident ticks respectively within the same genus as known vectors of exotic theileria spp. is not well-defined. It should not be assumed that absence of known tick vector species excludes significant risk. For example, Haemaphysalis longicornis (an apparently introduced, naturalized tick in Australia) is recognized as the principal vector of Theileria orientalis and its sub-types in east Asia, but native Australian ticks of the same genus (eg. Haemaphysalis bancrofti and Haemaphysalis humerosa) have proven to be competent vectors for this cattle-associated theileria (an introduced host species) and also proven highly adaptable from native wildlife hosts to introduced domestic livestock and companion animals.

Finally, as veterinarians we may have a natural tendency to focus on the 'disease' in animals. In the case of vector-borne diseases, it is clear that the vector and its biology are at least equally important as the disease or disease agent, so it logically follows that surveillance for potential foreign tick vectors is an important animal health function. In that context, it may be both relevant and sobering to consider what the most likely mechanism for introduction of an exotic theileria spp. to Australia may be. Would it be illegal or sanctioned introduction of a live carrier animal with or without an exotic tick vector aboard, or could it be infected exotic multi-host ticks hitch-hiking amongst inanimate cargo or pasture seed or the personal effects of innocent tourists or returning residents?

During the 20 years 1980-2000, New Zealand MAF detected 63 tick introductions in the course of routine border quarantine inspections(8). Most of these were multi-host tick species, several were associated with the personal effects of travellers and approximately a third of them were not directly associated with live animals. They included multiple Haemaphysalis spp., Dermacentor spp. and Ixodes spp. from diverse international origins. Patterns of rapid international trade and travel continue to expand and intensify and similar rates and patterns of tick detections have prevailed in New Zealand since that time.

REFERENCES

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