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Louping ill

Louping ill

R SWANEPOEL AND M K LAURENSON

GENERAL INTRODUCTION: FLAVIVIRIDAE

Introduction

Louping ill (louping in Scottish dialect = leaping) is an acute encephalomyelitis caused by a tick-borne flavivirus. It occurs in hill farming and certain other areas of Scotland, England, Wales and Ireland, and affects mainly sheep, less frequently cattle and rarely other livestock. Closely related or identical viruses are thought to cause encephalomyelitis of sheep in Norway, Spain, Turkey and Bulgaria, and the disease may be more widespread in Eurasia than is realized at present.72, 76 Louping ill (LI) is a zoonosis associated with occasional infections in laboratory workers or persons engaged in the livestock industry who are exposed to tick bites or to infected animal tissues.

A disease fitting the description of LI has been known in Scotland for at least two centuries, but the causative agent was not isolated until 1929. Shortly thereafter it was demonstrated that the virus is transmitted by ticks.64, 73, 76

Aetiology

Louping ill virus (LIV) is a member of the Russian springsummer encephalitis (RSSE) antigenic complex of flaviviruses, also referred to as the tick-borne encephalitis (TBE) complex. Despite marked variation in pathogenicity, members of the complex are very closely related antigenically. In the past they could only be separated with difficulty in tests involving polyclonal antisera,16, 17 but can now be differentiated by use of monoclonal antibodies.103 Members of the complex, which occur in temperate latitudes throughout the northern hemisphere,13, 14, 69 include:

  • LIV, which is present in Great Britain, Ireland and possibly elsewhere in Eurasia;
  • Central European TBE in Europe;
  • RSSE (also known as Far Eastern TBE) in eastern Europe and the former USSR;
  • Omsk haemorrhagic fever in Siberia;
  • Kyasanur Forest disease in the Indian subcontinent;
  • Langat in Malaysia;
  • Negishi in Japan;
  • Powassan in North America and parts of the former USSR; and
  • four viruses in Asia that have no known veterinary or medical significance: Karshi, Royal Farm, Phnom-Penh bat and Carey Island.

Viruses that have been isolated in association with encephalomyelitis of sheep in continental Eurasia are as yet incompletely characterized, but they are considered to be either identical or similar to LIV. No strain diversity of LIV has been established in Great Britain and Ireland.76 It is curious that no member of the RSSE complex has been isolated in the southern hemisphere.

Phylogenetic analysis of nucleotide and deduced amino acid sequences of either the entire envelope gene of LIV or a portion of the gene that spans a hypervariable region of LIV isolates, collected from representative regions of the British Isles and Norway, revealed the presence of three major geographical populations of LIV in the British Isles.67 ‘British’ LIV occurs throughout Scotland, England, Ireland and Norway, whereas ‘Irish’ and ‘Welsh’ LI viruses occur only in Ireland and Wales, respectively. Phylogenetic analysis also suggests that LIV initially emerged in Ireland and that a descendant was then introduced into Great Britain via Wales, being subsequently transported to the borders of Scotland. From there it may have dispersed throughout Scotland, northern England and Norway. More recently, the British LIV was reintroduced into Ireland and also into south-west England. Dates of lineage divergence, calculated from the synonymous substitution rate, indicate that LIV emerged in the British Isles less than 800 years ago and most LIV dispersal occurred during the last 300 years.67

Biological differences in the virulence of viruses from different regions are also apparent as manifested by differences in mortality rates in infections in mice and plaque sizes in cell culture.30, 66 ‘Irish’ LIV appears to be more virulent than viruses from other regions. However, there is little detectable association between the sequence of the envelope protein and the virulence characteristics, implying that the LIV virulence is multigenic and other genomic regions must be investigated to understand the determinants of virulence.66

Flavivirus particles measure 37 to 50 nm in diameter and consist of a spherical ribonucleoprotein core surrounded by a lipoprotein envelope. There are three structural proteins: a 13–16 × 103 MW nucleocapsid or core protein (C) that is intimately bound to the genome, a non-glycosylated 7–9 × 103MWmembrane protein (M) bound to the core, and a 51–59 × 103 MW envelope protein (E) that is usually glycosylated and is inserted as spikes or projections into the lipid bilayer envelope derived from host cell membranes. The E protein is presumed to carry recognition sites for the attachment of virus to receptors on susceptible cells and is responsible both for the haemagglutinating property exhibited by most flaviviruses and for stimulating the production of antibody demonstrated in haemagglutination-inhibition tests and protective immune responses in the host. It bears separate antigenic determinants that are either serotype specific, cross-reactive within an antigenic complex, or group-reactive with all flaviviruses.69, 97 The structure of the E protein appears to be at least one of the determinants of virulence in flaviviruses: comparison of virulent and vaccine strains of yellow fever virus reveal differences in the amino acid composition of the E protein, fuelling speculation that the changes may affect interaction with host cell receptors, thereby altering affinity or tropism of the virus for critical target organs.21, 42

The flavivirus genome consists of a non-segmented, single-stranded, positive- or messenger-sense (i.e. infectious) RNA of 3,8–4,2 × 106 MW.

Attachment, entry and uncoating of flaviviruses in susceptible cells is as yet incompletely understood, but in common with certain other viruses they display the phenomenon of immune enhancement whereby the uptake of virus by cells with Fc receptors is greatly increased when virus is complexed with non-neutralizing antibody (which can be groupspecific, so that partial immunity or cross-immunity to a second flavivirus can increase the efficiency of the infective process). This may represent an important immunopathogenic mechanism in some flavivirus diseases.36, 43–45

Being enveloped, flaviviruses are inactivated by lipid solvents and lipases. Infectivity is also destroyed by proteases and by low concentrations of aldehydes, halogens, hydrogen peroxide and beta-propriolactone. Mosquito-borne flaviviruses are optimally stable at pH 8,0, whereas the tickborne viruses can resist pH 6,0 or below, which facilitates oral transmission, as in infected milk. Flaviviruses are readily inactivated by ultraviolet irradiation, gamma-irradiation and heating to 56 °C for 30 minutes, but are stable at temperatures below −60 °C.69

Flaviviruses replicate with cytopathic effect or plaque formation in primary and continuous cell cultures derived from a wide variety of mammals and birds. They tend to replicate with high virus yields in cell cultures derived from arthropods without producing marked cytopathic effect, and there is a strong tendency for mosquito-borne and tick-borne viruses to replicate most efficiently in mosquito and tick cells, respectively.69, 97 Pig kidney cell lines are favoured for the culture of LIV, and plaque techniques can be used with these cells for the performance of sensitive assays of infectivity and neutralizing antibody.20, 88 However, intracerebral inoculation of suckling or weaned mice apparently remains the most sensitive method for the primary isolation of LIV.76 Hamsters and suckling rats are also susceptible to the virus, monkeys are susceptible by the intracerebral route, young guinea pigs are partially susceptible, and rabbits are resistant to infection.76

Epidemiology

Ixodes ricinus, the ‘Castor bean tick’, which is widely distributed in Europe, appears to be the only natural vector of LIV.5, 76 Transstadial transmission has, however, been demonstrated experimentally with Rhipicephalus appendiculatus (African) and Hyalomma anatolicum (Asian) and the implication is that, in common with other tick-borne viruses, LIV may be capable of transmission by a wide range of ixodid ticks.3, 4, 104 Louping ill virus has been isolated on only one occasion from eggs and from larval progeny of experimentally infected female Ixodes ricinus ticks104 although it occurred more frequently with Rhipicephalus appendiculatus-infected ticks in laboratory experiments.31 There is no epidemiological evidence to indicate that transovarial transmission of the virus occurs in nature, which is in marked contrast to the position with Central European TBE and RSSE viruses. However, transstadial transmission of LIV in tick instars feeding in successive years ensures that it is perpetuated in endemic foci.

In the British Isles, I. ricinus is most prevalent in unimproved pastures where coarse vegetation, such as rushes, provides a suitable microhabitat for egg laying, hatching and moulting of engorged ticks.63 Patterns of tick activity vary seasonally with both unimodal and bimodal patterns of peak activity observed in the British Isles. Unimodal patterns, where peak activity is recorded in spring or early summer (March to July), are more commonly observed in the drier east and colder north of the Isles including Northumberland and adjacent border counties and north-eastern Scotland, whereas a bimodal pattern of peak activities in spring (March to May/June) and autumn (August to November) is more typical in western and warmer areas, including Ireland, Wales and western England and Scotland.15, 39, 57 However, sheep management systems can influence these patterns.102 Ticks that feed in spring and autumn, respectively, generally represent separate populations and each instar feeds in a subsequent season of activity, with a life cycle duration of three years.15, 57 Some movement of ticks between spring and autumn populations can occur, however, leading to a shorter or longer life cycle. The duration of the life cycle of unimodal tick populations may also be three years in many situations, but in northern Scotland this may be prolonged for four or five years when ticks feed too late in the season to moult over winter.52

Within endemic areas, isolation of virus and/or demonstration of antibody has shown that LIV infection occurs in sheep, cattle, horses, pigs, red deer (Cervus elaphus), dogs and humans, as well as in wild vertebrates, such as red grouse (Lagopus lagopus scotticus), roe deer (Capreolus capreolus), feral goats (Capra hircus), mountain hares (Lepus timidus), short-tailed voles (Microtus agrestis), badgers (Meles meles), common shrews (Sorex araneus) and wood mice (Apodemus sylvaticus).1, 6, 8, 26, 27, 29, 59, 60, 76–79, 101, 107, 109, 112, 113 Clinical disease is seen most commonly in sheep and less frequently in cattle, which are less susceptible than sheep, and it has been recorded on rare occasions in the remaining domestic animals mentioned above.6, 76 A report of LI in farmed red deer suggests that free-living deer may be subject to the disease, but they were found to be only moderately susceptible to experimental infection.77, 85 The only recognized disease problem in wild vertebrates exists in red grouse, which have a commercial hunting value.78, 90, 109, 113

The disease has been described in laboratory workers, farmers, a veterinarian and abattoir workers, most of whom suffered and recovered from encephalitis of varying severity, but there was one fatality.8, 18, 19, 28, 56, 58, 91, 94, 95, 98, 110, 112

Louping ill virus is not present in all localities infested by the vector, and in infected areas the prevalence of antibody to the virus and the prevalence of disease varies markedly in both domestic and wild hosts.1, 90 In areas with high challenge rates, virtually all adult animals are immune and the disease is classically confined to a low proportion of young animals in which colostrum-derived immunity has waned.40, 76, 78, 99 Owing to the inherently moderate pathogenicity of the virus, the mortality rate in sheep generally amounts to less than 5 per cent of weaners and yearlings, and, since losses of up to 10 per cent from all causes are commonly considered to be acceptable, the effects of the disease may pass unrecognized in epidemiologically stable areas with high challenge rates, particularly where animals are run on extensive pastures.76 Indeed, where lambs are highly likely to be infected whilst still protected by declining levels of colostrum-derived antibody, they may acquire active immunity without clinical disease developing and a situation of endemic stability may arise.55 However, in areas with low and fluctuating challenge rates, or where management systems are suddenly changed, outbreaks of disease can affect sheep of all ages.76, 99, 104

The pathogenicity of LIV varies markedly in sheep and probably also in other susceptible species following experimental infection, and it is postulated that simultaneous infection with the agent of tick-borne fever, Cytoecetes phagocytophila , is one of the factors which precipitates severe disease in natural infections.37, 63, 64, 73, 82, 99, 116 In contrast to LIV, the infection rate of ticks with C. phagocytophila is high, and maternally derived immunity is not protective against tick-borne fever.104, 108, 116 Consequently, in areas with high tick infestation rates, lambs become infected with tick-borne fever at an early age while they are still protected by maternal immunity against LIV infection. However, losses from LI may be high when fully susceptible sheep are introduced into areas with a high challenge rate, and mortality rates may exceed 60 per cent.9, 38 Red grouse and ptarmigan (Lagopus spp.) appear to be particularly susceptible to infection with experimental laboratory infections, leading to mortality rates of 80 and 100 per cent respectively, but in field conditions mortality rates in red grouse may be lower, but still substantial at around 50 per cent of infections. 52

Threshold intensity of viraemia for the infection of the various instars of I. ricinus ticks through the engorgement of blood meals has been calculated as ranging from 103,7 to 104,7 plaque forming units (PFU) of virus per millilitre. Although these levels may be exceeded on occasion in experimental infections of sheep, cattle, goats and horses, viraemia of significant duration and intensity only occurs consistently in sheep.7, 76, 84, 86, 88, 104, 106 Viraemia in sheep may have a duration of up to seven days, with a maximum recorded intensity of 107,8 PFU/ml.88 Sheep and red grouse emerged from laboratory investigations as being the most likely vertebrates to serve as sources of virus for the infection of ticks in areas where LI is present.74–76, 85, 87, 90, 92

Despite the vaccination of sheep for several decades, the level of LI in some areas of Scotland has not declined. This, and the results of recent work with closely related Thogoto or tick-borne encephalitis virus,48, 50 in which it was reported that virus transmission can occur between infected and uninfected ticks co-feeding on a vertebrate host that has very low or undetectable viraemia, led to a reassessment of the role of other vertebrate hosts on moorland in both transmitting virus from tick to tick and also maintaining tick populations.46 A factor associated with the salivary glands of ticks has been shown to potentiate this mode of virus transmission between co-feeding ticks.48, 51

Recent work also suggests that the oral route may also be important for viral transmission in some species.34 Although it was known that direct ingestion of virus, for example in milk, could cause infection,75 laboratory and field studies have now shown that red grouse chicks can be infected by eating the tick vector. Red grouse chicks appear to be susceptible to infection by this route in just the first few weeks of life, when they are also most likely to ingest ticks, and that a substantial amount of infection may be occurring in this species by this route.34

Ticks feed on a wide range of wild animal species, including red deer, roe deer, mountain hares and small mammals. None, however, develops a viraemia above the threshold of infection, with the exception of a small percentage (approximately 2 per cent) of short-tailed voles (Microtus agrestis).75 This species, however, is not thought to be involved in the epidemiology of LI, since densities and tick burdens are low.33 Laboratory experiments on mountain hares revealed that LIV could be transmitted between co-feeding ticks on naive hares, with an average of 44 per cent of engorged cofeeding ticks becoming infected.48 There was no relationship between the level of virus in the blood and the proportion of ticks that attached. These ticks were moulted through to the next instar and were infectious. Previously infected hares supported very little transmission, with this occurring only when antibody titres were extremely low. Neither red deer nor New Zealand White rabbits (Oryctolagus cuniculus) supported transmission of LIV.48

Mountain hares have also been shown to be critical in maintaining tick populations. On one site in Scotland where sheep, red grouse and mountain hares were the main vertebrate hosts, they were estimated to be hosts to nearly all of the adult tick populations and approximately half of the nymphal and larval instars.52 When the numbers of hares were reduced, the tick population also declined, with the most rapid decrease occurring in larval numbers. Louping ill virus prevalence also declined, suggesting that mountain hares can be a reservoir for this tick-virus system. Substantial numbers of ticks have also been recorded on red and roe deer in some areas, which could also explain both tick persistence where sheep are vaccinated or treated with acaracide. Theoretically, a combination of red deer as hosts to, particularly, the adult tick and red grouse, as a virus amplifier, can maintain this tick-virus system.35 The epidemiology and control of LIV on moorland areas, where hosts other than sheep are present, may thus be substantially different from other areas where sheep are the most important host in the system.

Pathogenesis

For a long time it was thought that systemic infection by LIV is followed by infection of the central nervous system (CNS) in individuals that succumb to encephalitis, and that factors which facilitate virus penetration of the so-called blood-brain barrier, such as the occurrence of intense viraemia or concurrent infection with the agent of tick-borne fever, are critical to the outcome of infection.64, 99 It is now accepted that the pathogenesis of the disease conforms to a general pattern for encephalitogenic mosquito- and tick-borne flaviviruses, with three possible outcomes to infection:

  • limited systemic replication of virus with or without demonstrable viraemia, but without neuroinvasion as evidenced by failure of antibody to appear in the cerebrospinal fluid;
  • systemic infection with limited invasion of the CNS causing minimal damage, which soon resolves, as appears to occur commonly in LI; and
  • severe systemic and CNS infection, with intense viraemia being a consequence rather than a cause of generalized infection.22, 23, 68–70, 76, 84, 88, 89, 117

Following peripheral introduction of virus there may be low-grade resorbtive viraemia which is difficult to demonstrate, as well as limited replication at the site of inoculation, with lymphatic drainage and replication of virus in the reticuloendothelial system, leading to a spill-over of infection into the bloodstream to produce primary viraemia. This in turn facilitates the occurrence of generalized systemic and CNS infection, resulting in the intensification of viraemia.2, 65 Infection of the CNS occurs at an early stage and mechanisms for the penetration of the blood-brain barrier probably include replication of virus in endothelial cells. There is a strong genetic basis to the susceptibility of vertebrates to flaviviruses, including LIV, and factors such as age, nutritional status and concurrent infections, which predispose to severe disease, are probably associated with impairment of the immune response.11, 12, 47, 71, 76, 80, 81, 83,96, 111

Clinical signs

The incubation period following experimental tick transmission of LIV infection to sheep varies from two to five days.63, 64, 104 Fever is commonly biphasic, with rectal temperatures initially remaining above 40,5 °C for two to four days, followed by a remission of one to three days and a second bout of fever lasting two to four days or longer, but remission of fever does not occur in infections that are complicated by tick-borne fever. During the initial fever, sheep show hyperpnoea, have a serous nasal discharge and may appear to be slightly depressed with heads held low.

Pathognomonic nervous signs of the disease supervene at the onset of the second fever, six to eight days after subcutaneous infection, by which time viraemia is frequently no longer detectable and antibodies may already be present in high concentration. The nasal discharge is dirty and crusted at this stage and the sheep develop an alert stare, roll their eyes, hold their ears at odd angles, and twitch and lick their lips. There may be slight tremors of the head and fore quarters (trembling is an alternative name for the disease in some parts of Scotland), and the sheep react in exaggerated fashion to any visual or auditory stimulus. Nine or ten days after subcutaneous infection, the trembling becomes marked and there is involuntary jerking or stamping of limbs and trampling motions. The sheep progressively develop cerebellar ataxia, torticollis, characteristic, high-stepping gait of the forelimbs and swaying of the hindquarters as they move forward at an angle. They become progressively weaker, supporting themselves against walls or other objects, proceeding in a shuffling gait with the back arched, and struggling to rise from a prone position, or assuming a sejant posture like a dog sitting on its haunches. Depression becomes marked as the disease progresses and the sheep are not easily aroused; they remain with their heads lowered and eyes closed as they grind their teeth. Dyspnoea sets in, the animals gasp for breath and froth at the mouth and nose. Ultimately, the sheep go down, and in lateral recumbency may have bouts of galloping motions with fore and hind limbs, while the frothing at the mouth and nose becomes copious. Death generally occurs 9 to 14 days after infection. Some sheep may die after exhibiting only depression and lassitude for a short time. There are reports of sheep recovering with residual paralysis, but severely affected animals seldom survive the harsh conditions and steep slopes which exist on hill farms.

In moderately severe cases, sheep may exhibit transient nervous signs including rolling of the eyes and holding of the ears at odd angles, tremors of the head and neck, and posterior paresis. They may become extremely excitable, attempting to climb walls or over other sheep if aroused. Recovery of normal muscular function may proceed over a period of weeks.

Mild cases may exhibit only hyperpnoea during the pyretic phase while others also show transient excitability. However, loss of condition is common even in mild cases. Despite the fact that anorexia is not a marked feature of the disease, affected animals may lose 10 to 20 per cent of their body weight.104

The disease is less frequently severe or fatal in other domestic animal species, but is essentially similar to that in sheep. Humans also experience biphasic illness, with headache, retro-orbital pain, photophobia, malaise, drowsiness, nausea, myalgia and arthralgia characterizing the first fever, and severe headache, diplopia, confusion and sometimes slurred speech, delirium, ataxia, and drowsiness or coma occurring during the second fever.100

Pathology

Little is known of the clinical pathology of LI in domestic animals beyond the fact that there is panleukopaenia from about the second day following experimental infection until the fifth or sixth day, following which there may be transient leukocytosis.

No macroscopic lesions which may be considered diagnostic of LI are evident at necropsy. There may be evidence of loss of condition, hydrothorax, and congestion and oedema of the lungs. Lymph nodes may be oedematous and swollen, and the spleen is atrophied as a result of a depletion of lymphoid tissue. Congestion of the brain and meninges appears to be a consistent finding.10, 26, 104, 114

Histopathologically, non-suppurative encephalo-myelitis is the predominant lesion in LI, the grey matter of the brain being more severely affected than the white.76 The changes include round cell infiltration of the meninges, perivascular cuffing, neuronal degeneration and necrosis, neuronophagia and focal gliosis in the cerebrum, cerebellum and medulla. There is a tendency for the distribution and severity of lesions to vary in different hosts, with Purkinje cell destruction being prominent in sheep. Similar lesions may occur in the spinal cord.10, 22–26, 114

Diagnosis

Louping ill would probably only be encountered in sub- Saharan Africa in imported, non-immunized livestock while they are still being maintained in quarantine after having been introduced from an endemic area during a season of tick activity. In the unlikely event that a quarantine period is inadequate or evaded, it is theoretically possible that a viraemic imported animal could infect indigenous African ticks, which could subsequently infect local animals. Inadvertent importation of the natural vector, I. ricinus, on livestock is rendered improbable by the acaricide treatment, parasite inspection and quarantine period which are common mandatory requirements in the import regulations of most countries, but in any event, the tick requires the maintenance of a relative humidity close to saturation in its microhabitat throughout the year, and is unlikely to survive in most African countries.61, 62 Nevertheless, LI may be suspected when an animal imported from an endemic area develops nervous signs marked by cerebellar ataxia within one to two weeks of arrival.

The presence of histopathological lesions of non-suppurative encephalomyelitis would heighten suspicion of LI but should not be regarded as diagnostic. The presence of viral antigen in nerve tissue has been demonstrated by immunofluorescence, but the technique has not found diagnostic application.22, 23, 76

Antibody to LIV has been demonstrated by immunodiffusion, complement fixation, haemagglutination-inhibition, neutralization and indirect immunofluorescence. The haemagglutination-inhibition test has found the greatest application, but serodiagnosis is usually only of relevance in humans.76, 88, 104, 105, 115

Most commonly, the diagnosis is made by isolation of virus from brain tissue of animals that have succumbed to the disease. Homogenates of cerebellum and brain stem are inoculated onto cell cultures or intracerebrally into mice. Isolates can be identified by immunofluorescence, by preparing and testing haemagglutinin or, definitively, by performing neutralization tests.22, 23, 76

Differential diagnosis

Some of the clinical signs of scrapie strongly resemble those of LI, such as excitability and ataxia, but scrapie has an incubation period of one or more years, is seldom seen in sheep under 18 months of age, and has a protracted course during which the sheep characteristically rub off patches of their wool on fence posts or other objects. In addition, the microscopic nervous lesions of these two diseases differ markedly.

Amongthe endemic diseases of southern Africa, the clinical signs of LI most strongly resemble those of heartwater, poisonings by various plants, the most important of which are annual rye grass (Lolium spp.) and Cynanchum spp., and chemicals, such as lead and organophosphates.49

Control

Control of LI relies on the use of acaracides to control tick populations and biting rates and, in highly infected areas where losses are great, on the use of a vaccine against the LIV. The vaccine in current use is prepared from virus grown in cell cultures, inactivated with formalin and incorporated in an oil adjuvant. It induces high titres of antibody and solid immunity to infection,9 although antibody titres wane over time.93 After vaccination followed by a booster one month later, however, antibody titres remain high. In most situations, shepherds vaccinate their yearling ewes once before turnout in spring, and if no natural reinfection occurs, antibody levels in older ewes may be low or non-existent.54 As the amount of colostral antibody transferred from ewe to new-born lambs corresponds to maternal serum levels and declines with a half life of 14 days,79 lambs that receive only low levels of maternal antibody can become susceptible to the LIV during their first summer at pasture, before they are vaccinated. It is thus recommended that this double vaccination regime is carried out to ensure that lambs are protected for as long as possible throughout their first season on pasture,93 but in most farming systems this does not occur. Although theoretically the virus could persist in vaccinated sheep flocks of sufficient size that graze on tick-infested pasture for sufficient time through amplification of the LIV in lambs before they are vaccinated, these conditions are not met in most management systems in the UK.54

With recent studies revealing the importance of wild hosts, particularly in Scotland, in maintaining tick and virus the control of the disease through the vaccination and acaracide treatment of sheep, although reducing virus levels and sheep losses, will not lead to the eradication of LI. In this situation, if red grouse are an important economic consideration, this control strategy will not prevent severe grouse mortality and population limitation, nor a reduction in the grouse harvest. In this situation, a reduction in wild hosts, at least in the short term until the virus is very much reduced or eradicated, may be the only effective way in which to reduce losses.52 A good tick control programme for domestic animals is also absolutely essential to reduce losses in these species.

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