Overview of Tickborne Fever
Tickborne fever is a febrile disease of domestic and free-living ruminants in the temperate regions of Europe. It is prevalent in sheep and cattle in the UK, Ireland, Norway, Finland, The Netherlands, Austria, and Spain. Disease is transmitted by the hard tick Ixodes ricinus. A similar disease transmitted by other ticks has been described in India and South Africa. The main hosts are sheep and cattle, but goats and deer are also susceptible.
The causative agent is now classified as a member of the order Rickettsiales, family Anaplasmataceae, as Anaplasma phagocytophilum, which includes the granulocytic agents formerly known as Ehrlichia phagocytophila, Ehrlichia equi, and the agent of human granulocytic ehrlichiosis.
The organism 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. The varied morphologic types in the cytoplasmic inclusions do not represent stages of development, as in chlamydiae, but rather are rickettsial colonies within cytoplasmic vacuoles.
The disease is transmitted by the hard tick I ricinus. Adult ticks infected as larvae or nymphs can transmit the disease as can nymphs infected as larvae, but infections do not appear to pass from the adult female to the larva via the egg. The rickettsiae can survive in infected ticks for long periods and, because I ricinus can survive unfed for >1 yr awaiting a new host, ticks infected in their previous instar can still be infective after long periods of hibernation. The ready transmission of infection by injecting 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 most likely that ticks other than I ricinus are involved.
After infestation with infected ticks, the incubation period may be 5–14 days, but after injection with infected blood, the incubation period is 2–6 days. In sheep, the main clinical sign is a sudden fever (105°–108°F [40.5°–42.0°C]) for 4–10 days. Other signs are either absent or mild, but the animals generally appear dull and may lose weight. Respiratory and pulse rates are usually increased, and a cough often develops.
In cattle, the disease is known as pasture fever in many parts of Europe, including Finland, Norway, Austria, Spain, and Switzerland. The disease occurs as an annual minor epidemic when dairy heifers and cows are turned out to pasture in the spring and early summer. Within days, the cows are dull and depressed, with a marked loss of appetite and milk yield. 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 yield.
Abortions affect susceptible ewes and cows newly introduced onto tick-infested pastures during the last stages of gestation, with abortions occurring 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 may be greatly reduced. Variations in severity of the clinical effects may be related to differences between strains of A phagocytophilum or in host susceptibility.
Perhaps the most significant effect of infection is its serious impairment of humoral and cellular defense mechanisms, which results in increased susceptibility to secondary infections such as tick pyemia, pneumonic pasteurellosis, louping ill, and listeriosis.
Tickborne fever is characterized by transient but distinct hematologic changes. A modest neutrophilia develops 2–4 days after natural or experimental infection and is followed by a severe leukopenia due to lymphocytopenia and neutropenia. The lymphocytopenia lasts 4–6 days, whereas the neutropenia develops progressively and becomes more marked ~10 days after infection. Studies with monoclonal antibodies that recognize surface markers for lymphocyte subsets have shown that both T and B lymphocytes are reduced. The number of circulating eosinophils is also depressed for as long as 2 wk. After the febrile period has subsided, the number of monocytes may increase. At the peak of reaction, >90% of circulating neutrophils and eosinophils may be infected. The monocytes are predominantly infected during the later stages of bacteremia, whereas the granulocytes are usually infected throughout the period of bacteremia. The number of circulating thrombocytes is also reported to be depressed during the febrile period, and the occasional hemorrhagic syndromes associated with tickborne fever are probably related to the reduction in circulating thrombocytes.
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 is diagnostic. PCR and other molecular methods are particularly useful during the late stages of primary bacteremia and during persistent infection when it is difficult to detect inclusion bodies in blood smears. Clinical disease usually is seen 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 should indicate the association of tickborne fever and cases of tick pyemias and abortions, particularly when abortions occur after pregnant animals are moved from tick-free to tick-infested pastures. Infection could be established retrospectively by demonstrating a rise in antibody titers by indirect immunofluorescence or ELISA.
In affected dairy cattle, the main signs are abortions and a sudden drop in milk yield. The other 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 their introduction to tick-infested pastures. Therefore, in areas where the disease is enzootic, blood smears must be examined for the presence of organisms in all cases of abortion in sheep and cattle and when milk yield drops suddenly soon after the animals have returned to pasture.
The short-acting oxytetracyclines are regarded as the most effective treatment, because other antibiotics such as penicillin, streptomycin, and ampicillin do not prevent relapses. Sulfamethazine has also proved useful. If dairy cattle are treated with oxytetracyclines within a few days of infection, the pyrexia is reduced quickly and milk yield restored.
There are three important aspects of control: vector control, chemotherapy, and immunity. Effective control can be achieved by eliminating or markedly reducing contact with the tick vector either by grazing sheep and cattle on tick-free pastures in lowland areas or by use of acaricides. In sheep practice, this commonly involves keeping ewes and lambs in a fenced, relatively tick-free pasture until the lambs are ~6 wk old. Lambs also benefit from improved nutrition of the ewes. Dipping lambs within 1–2 wk of birth is not commonly practiced because of difficulties of gathering the 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-wk interval or use of pour-on preparations or smears applied 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 may 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 wk of life can be protective for as long as 3 wk and helps reduce secondary infections such as tick pyemia, pasteurellosis, and colibacillosis. It may also improve growth rate.
Several aspects of immunity remain controversial, but it is generally accepted that sheep and cattle are immune to challenge after recovery from one or two bouts of clinical disease caused by tickborne fever. The immunity may last for several months but wanes rapidly if the animals are removed from tick-infested areas. Secondary infections are usually milder as residual immunity persists. There is a variable degree of cross-protection among strains of A phagocytophilum. 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 allows multiplication of the organism and therefore stimulation of immune responses without uncontrolled clinical 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.