Tickborne fever, also known as pasture fever, is a rickettsial disease of domestic and free-living ruminants in the temperate regions of Europe. Disease is transmitted by the hard tick Ixodes ricinus. The main clinical signs are sudden fever (in sheep) and listlessness, weight loss, and decreased milk production (in cattle). Diagnosis can be confirmed by demonstration of intracytoplasmic inclusions in granulocytes and neutropenia in peripheral blood during the period of bacteremia and by PCR assay. Oxytetracycline is the most effective treatment. There is no vaccine. Any control strategy should aim to carefully balance exposure of susceptible animals at an appropriate age with the judicious use of antimicrobials and acaricides in food-producing animals to enhance the development of immunity without severe disease.
Tickborne fever is a febrile disease of domestic and free-living ruminants. It is prevalent in sheep and cattle in the UK, Ireland, Norway, Finland, the Netherlands, Austria, and Spain. The disease is caused by the bacterium Anaplasma phagocytophilum and transmitted by the hard tick Ixodes ricinus.
Although tickborne fever has been described mainly in the temperate regions of Europe, similar conditions have been described in South Africa and India. Furthermore, Ehrlichia ondiri, the rickettsial parasite that causes bovine petechial fever (ondiri disease) in the highlands of Kenya and Tanzania, infects granulocytes. This organism was originally classified as Cytoecetes ondiri, indicating its antigenic relationship with Cytoecetes phagocytophila—which was, at that time, the name of the causative agent of tickborne fever.
Tickborne fever should not be confused with tick fever, the term used to describe bovine babesiosis and anaplasmosis in Australia and New Zealand. In contrast to tickborne fever, tick fever is due to Babesia bovis, B bigemina, or Anaplasma marginale, organisms reported to be transmitted by the hard tick Rhipicephalus (formerly Boophilus) microplus.
Etiology of Tickborne Fever in Ruminants
The causative organism of tickborne fever, A phagocytophilum, was first named Rickettsia phagocytophila. The bacterium was subsequently known as Cytoecetes phagocytophila and Ehrlichia phagocytophila. It is now classified as a member of the order Rickettsiales, family Anaplasmataceae, which includes other granulocytic agents formerly known as Ehrlichia phagocytophila: Ehrlichia equi and Ehrlichia ewingii, the agent of human granulocytic ehrlichiosis (HGE). A phagocytophilum is also the cause of equine anaplasmosis.
A phagocytophilum infects eosinophils, neutrophils, and monocytes, in that order. Cytoplasmic inclusions are visible as grayish-blue bodies in Giemsa-stained blood smears and may contain one or more rickettsial particles of variable size and shape (see intracytoplasmic inclusions image). The varied morphological types in the cytoplasmic inclusions do not represent stages of development, as with chlamydial infection, but rather are rickettsial colonies within cytoplasmic vacuoles.
Courtesy of Dr. Zerai Woldehiwet.
Tickborne fever is transmitted by the hard tickI ricinus (see separate topic on Ixodes spp). Adult ticks infected as larvae or nymphs can transmit the disease, as can nymphs infected as larvae; however, infections do not appear to pass from the adult female to the larva via the egg.
Rickettsiae can survive in infected ticks for long periods, and because I ricinus can survive unfed for > 1 year awaiting a new host, ticks infected in their previous instar (developmental stage between moults) can still be infective after long periods of hibernation. The ready transmission of infection by injection of infected blood suggests that the organism could be transmitted mechanically by biting insects. In addition, if the organisms reported to cause a similar disease in ruminants in India and South Africa are indeed A phagocytophilum, it is likely that ticks other than I ricinus are involved in transmission.
Clinical Findings of Tickborne Fever in Ruminants
After ruminants are infested with infected ticks, the incubation period of tickborne fever may be 5–14 days; however, after ruminants are injected with infected blood, the incubation period is only 2–6 days. In sheep, the main clinical sign is sudden fever (40.5°C–42.0°C [105°F–108°F]) for 4–10 days. Other clinical signs are either absent or mild, but infected animals generally appear listless and may lose weight. Respiratory and pulse rates are usually increased, and a cough often develops.
In cattle, tickborne fever is known as pasture fever in many parts of Europe, including Finland, Norway, Austria, Spain, and Switzerland. The disease occurs annually as a minor epidemic when dairy heifers and cows are turned out to pasture in spring and early summer. Within days, cows are lethargic and show a marked decline in appetite and milk production. Affected cows usually suffer from respiratory distress and coughing. Clinical signs are more obvious and last longer in newly purchased animals than in home-bred animals. Often, veterinary advice is sought after a sudden drop in milk production.
Susceptible ewes and cows newly introduced onto tick-infested pastures during the last stages of gestation typically suffer abortions 2–8 days after the onset of fever. Except for aborting ewes, death due to tickborne fever is rare. The semen quality of infected rams and bulls can be greatly decreased. Variations in severity of clinical effects may be related to differences between strains of A phagocytophilum or to host susceptibility.
Perhaps the most consequential effect of infection is significant impairment of humoral and cellular immunity, which results in increased susceptibility to secondary infections such as:
Hematologic Changes
Tickborne fever is characterized by transient but distinct hematologic changes. Moderate neutrophilia develops 2–4 days after natural or experimental infection and is followed by severe leukopenia, lymphopenia, and neutropenia.
Lymphopenia lasts 4–6 days, whereas neutropenia develops progressively and becomes more marked approximately 10 days after infection. Studies with monoclonal antibodies that recognize surface markers for lymphocyte subsets have shown that both T and B lymphocytes are decreased. The number of circulating eosinophils is also decreased for up to 2 weeks.
After the febrile period has subsided, the number of circulating monocytes may increase. At the peak of reaction, > 90% of circulating neutrophils and eosinophils may be infected. Monocytes are predominantly infected during the later stages of bacteremia, whereas granulocytes are usually infected throughout the period of bacteremia.
The number of circulating thrombocytes is also reported to be decreased during the febrile period, and the occasional hemorrhagic syndromes associated with tickborne fever are probably related to the decrease in circulating thrombocytes. Hemorrhagic diathesis in rams, hemorrhagic enteritis in sheep, and thrombocytopenia in sheep have been reported in cases A phagocytophilum infection (1, 2, 3, 4).
Diagnosis of Tickborne Fever in Ruminants
Clinical signs
PCR assay
In sheep, the onset of high fever in tick-infested areas during the spring and summer, in association with hematologic changes and the presence of inclusions within granulocytes or the detection of specific DNA by PCR assay, is diagnostic for tickborne fever. PCR assay and other molecular methods are particularly useful for diagnosis during the late stages of primary bacteremia and during persistent infection when it is difficult to detect inclusion bodies in blood smears.
Unlike bacterial strains that cause HE that are cultivated in mammalian cells, such as the promyelocytic cell line HL60, the ruminant-specific variants of A phagocytophilum have not been cultivated in vitro. However, these variants can be cultivated in cell lines derived from I ricinus and I scapularis (see intracytoplasmic inclusions photomicrograph).
Courtesy of Dr. Zerai Woldehiwet.
Clinical signs of disease usually are observed only in young lambs born in tick-infested areas or in older animals newly introduced to such areas. Demonstration of typical inclusion bodies in blood smears or specific DNA by PCR assay should indicate the association of tickborne fever with cases of tick pyemia and abortions, particularly when abortions occur after pregnant animals are moved from tick-free to tick-infested pastures. Infection also may be established retrospectively by demonstrating a rise in antibody titers to A phagocytophilum by indirect immunofluorescence or ELISA.
In affected dairy cattle, the main clinical signs of tickborne fever are abortions and a sudden drop in milk production. Another common clinical sign in infected cattle is respiratory illness after a herd is introduced to tick-infested pastures. Tickborne fever must also be considered when abortions and stillbirths, particularly in heifers, occur soon after animals are introduced to tick-infested pastures. Therefore, in areas where tickborne fever is enzootic, blood samples must be examined for the presence of large intracytoplasmic inclusions in granulocytes, suggestive of infection with A phagocytophilum, in all cases of abortion in sheep and cattle and of sudden drops in milk production soon after the animals have returned to pasture.
Positive results can be demonstrated by the presence of intracytoplasmic inclusions in blood smears, isolation of A phagocytophilum in tick cell lines, or by PCR assay, using primers specific to A phagocytophilum.
Treatment and Control of Tickborne Fever in Ruminants
Oxytetracyclines
Short-acting oxytetracyclines are regarded as the most effective treatment for tickborne fever because other antimicrobials (eg, penicillin, streptomycin, and ampicillin) do not prevent relapses. Sulfamethazine has also proved useful.
If dairy cattle are treated with oxytetracyclines (short-acting: 6.6–11 mg/kg, IV, slowly over 5 minutes, every 24 hours for up to 4 days; long-acting: 20–30 mg/kg, IM or SC, once) within a few days of infection, fever decreases quickly and milk production is restored.
There are 3 important aspects of control: vector control, chemotherapy, and immunity. Effective vector control can be achieved by eliminating or markedly decreasing contact with ticks either by grazing sheep and cattle on tick-free pastures in lowland areas or by using acaricides. In sheep practice, this commonly involves keeping ewes and lambs in a fenced, relatively tick-free pasture until lambs are approximately 6 weeks old. With this practice, lambs also benefit from improved nutrition of ewes.
In chemotherapy protocols, dipping lambs within 1–2 weeks of birth is not common practice because of the difficulties of gathering lambs on widely dispersed hill farms, the risks of mismothering, and the relatively short duration of protection provided by acaricides, possibly because of the short fleece and rapid growth rate of lambs. However, dipping twice with a 2- to 3-week interval or applying pour-on preparations or smears before lambs are moved from lambing fields to hill pastures reportedly controls ticks effectively. Pregnant animals should not be moved from tick-free to tick-infested pastures.
In enzootic areas, treatment with long-acting tetracyclines can be used as a prophylactic measure. When susceptible animals, particularly pregnant ewes and cows and newborn lambs, are to be moved from tick-free to tick-infested areas, it may be necessary to combine dipping with prophylactic use of long-acting tetracyclines. Such treatment of lambs in the first 2–3 weeks of life can be protective for up to 3 weeks and helps decrease secondary infections such as tick pyemia, pasteurellosis, and colibacillosis. It may also improve growth rate.
With tickborne fever, several aspects of immunity remain controversial; however, it is generally accepted that sheep and cattle are immune to reinfection after recovery from 1 or 2 bouts of infection. Immunity can last for several months but wanes rapidly if animals are removed from tick-infested areas. Secondary infections are usually milder because residual immunity persists. The extent of cross-protection among strains of A phagocytophilum is variable.
No effective vaccines are available to protect ruminants from clinical tickborne fever. However, if susceptible animals are being brought into tick-infested pastures, it may be sensible to deliberately infect them before introduction and treat them with oxytetracyclines before or immediately after the onset of fever. This protocol allows multiplication of the organism and therefore stimulation of immune responses before development of uncontrolled clinical signs of disease; a minimum duration of bacteremia may be required for protective immunity to develop. Because not all strains of A phagocytophilum are cross-protective, strains specific to the area must be used for this protocol to be effective.
Key Points
Tickborne fever is a rickettsial infection of ruminants in temperate areas of Europe.
The disease is caused by the bacterium Anaplasma phagocytophilum and transmitted by Ixodes ricinus ticks.
The main hosts are sheep and cattle, but goats and deer are also susceptible.
Oxytetracyclines are considered the most effective treatment for tickborne fever.
References
Giadinis ND, Chochlakis D, Ioannou I, et al. Haemorrhagic diathesis in a ram with Anaplasma phagocytophilum infection. J Comp Pathol. 2011;144(1):82-85. doi:10.1016/j.jcpa.2010.04.011
Foster WNM, Foggie A, Nisbet DI. Haemorrhagic enteritis in sheep experimentally infected with tick-borne fever. J Comp Pathol. 1968;78(2):255-258. doi:10.1016/0021-9975(68)90103-5
Foster WNM, Cameron AE. Thrombocytopenia in sheep associated with experimental tick-borne fever infection. J Comp Pathol. 1968;78(2):251-254. doi:10.1016/0021-9975(68)90102-3.
Gokce HI, Woldehiwet Z. Differential haematological effects of tick-borne fever in sheep and goats. J Vet Med B. 1999;46(2):105-115. doi:10.1111/j.0931-1793.1999.00211.x
