heartwater

International Common Names

• English: cowdriosis; heartwater, Cowdria ruminantium, cowdriosis, in ruminants - exotic; heartwater, Ehrlichia ruminantium, in ruminants - exotic
• French: cowdriose

Local Common Names

• Guadeloupe: mal cadik
• Mali: tiéoudé
• Nigeria: kaboa
• South Africa: dronkgalsiekte; hartwater; nintas

Ehrlichia ruminantium

Heartwater (or cowdriosis) is a tickborne disease of sheep, goats, cattle and some wild ruminants caused by the rickettsia, Ehrlichia ruminantium (previously Cowdria ruminantium). It is a small pleomorphic organism (0.2-2.7 µm) and colonies named morula containing varying numbers are found in the cytoplasm of endothelial cells (Cowdry, 1926; Pienaar, 1970).

According to Neitz (1968), the first record of heartwater was probably made in South Africa by the Voortrekker pioneer Louis Trichard in 1838. In an entry in his diary on the 9th of March 1838, he mentions a fatal disease, ‘nintas’, amongst his sheep, approximately 3 weeks after a massive tick infestation. However, it was only in 1876, almost 50 years later, that the first official report describing heartwater as a generally known disease along the coast and borders of King William’s Town was presented before the Cattle and Sheep Disease Commission in Grahamstown, South Africa. According to Webb (1877), the disease was introduced into the eastern Cape region at about the same time that William Bowker found a bont tick (Amblyomma hebraeum) on a cow which was imported from northern KwaZulu-Natal (then Zululand) in approximately 1837. Due to confusion with other prevalent conditions of unknown aetiologies at that time, it is difficult to follow the introduction and spread of the disease in Africa. It is, for instance, still not clear whether heartwater is a disease indigenous to the African continent or whether it was imported at some stage, possibly from Madagascar. However, current knowledge suggests that it is a disease of the African mainland. Despite the fact that certain Amblyomma species occur on the Asian and American continents, there is no evidence that the disease exists there.

The first major breakthrough in understanding the disease came when Dixon (1898) and Edington (1898) proved that it could be produced experimentally by inoculating blood from diseased to susceptible animals. Although the causative organism could not be detected in the blood or tissue of diseased animals at the time, it was believed that heartwater was caused by a micro-organism (Hutcheon, 1900), possibly a virus (Spreull, 1904). At about the same time, Lounsbury (1900) confirmed the long-standing suspicion that the bont tick (A. hebraeum) was the vector in South Africa. However, it was not until 1925 that Cowdry (Cowdry, 1925a; Cowdry, 1925b) successfully demonstrated the organism in tissue of infected animals and ticks. Cowdry named the organism Rickettsia ruminantium but this was later changed to Cowdria ruminantium (Moshkovski, 1947) and finally to E. ruminantium (Dumler et al., 2001).

Traditional rickettsial taxonomy assigned Cowdria ruminantium as the sole member of the genus Cowdria in the tribe Ehrlichieae. This was one of three tribes within the family Rickettsiaceae in the order Rickettsiales which initially encompassed all intracellular bacteria but from which the Chlamydiae were later removed (Moulders, 1984). The obligate intracellular nature of E. ruminantium, coupled with morphological features suggestive of a Chlamydia-like life cycle led to confusion as to its position in the ehrlichial hierarchy (Uilenberg, 1983). After 16S ribosomal RNA and groESL gene comparisons, Dumler et al. (2001) defined that all members of the tribes Ehrlichieae and Wolbachieae should be transferred to the family Anaplasmataceae and the genus Ehrlichia was emended to include Ehrlichia ruminantium (formerly Cowdria ruminantium). The family Anaplasmataceae currently includes Ehrlichia, Anaplasma, Aegyptianella, Neorickettsia, Wolbachia, ‘Candidatus Neoehrlichia’ and ‘Candidatus Xenohaliotis’ (Thomas et al., 2016).

Phylum: Proteobacteria

Class: Alphaproteobacteria

Order: Rickettsiales

Family: Anaplasmataceae

Genus: Ehrlichia

Species: Ehrlichia ruminantium

Economic impact and prevalence

Heartwater is one of the main tickborne diseases together with theileriosis and trypanosomosis in tropical countries. For the Southern Africa Development Community (Angola, Botswana, Malawi, Mozambique, South Africa, Swaziland, Tanzania and Zimbabwe) the losses are estimated around 47.6 millions of dollars per year. Important losses are due to mortality, diminution of productivity in farming systems and cost of treatment (use of antibiotics and acaricides). It is a major, and in some instances, the most important obstacle against introducing high producing animals into Africa with the aim of upgrading or replacing local stock (Uilenberg, 1982a). It is a major disease problem when local animals are moved from heartwater-free to heartwater endemic areas (Neitz, 1967). It remains a problem and a threat in endemic areas especially amongst small stock (Thomas and Mansvelt, 1957). The effect of dipping and environmental changes influences endemic stability, which is often difficult or impossible to manipulate (Bezuidenhout and Bigalke, 1987).

The development of molecular diagnostic tools allows a better estimation of the prevalence of heartwater thanks to detection both in organs from suspected dead ruminants and in ticks. In Burkina Faso, the E. ruminantium prevalence in ticks by nested PCR (pCS20 gene region) has been evaluated from 3% to 10% depending on the year of tick samplings (Dr Hassane Adakal, personal communication; Adakal et al., 2010a). Moreover, a study evaluating the efficiency of the inactivated vaccine in field conditions in Burkina Faso allowed identifying the impact of heartwater on susceptible ruminants. In this study, two successive trial assays on susceptible imported Sahelian sheep demonstrated that 51% and 53% of unvaccinated sheep died from heartwater (Adakal et al., 2010b). In The Gambia, the seroprevalence rate per site in small ruminants varied from 6.9% and 100% (five regions) (Faburay et al., 2005). The percentage of E. ruminantium infected Amblyomma ticks collected on 15 different sites, varied strongly from 1.6% to 15.1% depending on the site of sampling (Faburay et al., 2007a). These results showed a gradient risk of increasing heartwater from the east to the west of the Gambia. In the Caribbean region, only Guadeloupe and Antigua are infected with heartwater. In Guadeloupe, the E. ruminantium tick prevalence is higher (i.e. 19.1% in Marie Galante with 73.8% of herds infested) compared to Antigua 5.8% of E. ruminantium infected ticks with only 2.2% of herds infested (Vachiéry et al., 2008a). These islands still represent a reservoir for ticks and heartwater in the Caribbean. It is a threat to areas such as the American mainland due to migratory birds potentially carrying infected ticks from the Caribbean area where the disease is present. Moreover, potential vectors are present but do not harbour the disease (Uilenberg, 1982b; Uilenberg et al., 1984). It is also a threat to countries where the vectors may be introduced and become established (Wilson and Richard, 1984; Barré et al., 1987). In South Africa, heartwater is not a notifiable disease, therefore there is no detailed up to date data on the prevalence or economic impact, but it does have a noticeable impact on the economy. It will probably remain a disease of major importance until an effective and safe vaccine becomes available.

This disease is on the list of diseases notifiable to the World Organization for Animal Health (OIE). The distribution section contains data from OIE's WAHID database on disease occurrence. For further information on this disease from OIE, see the website: www.oie.int

blood and circulatory system diseases of large ruminants
blood and circulatory system diseases of small ruminants
nervous system diseases of large ruminants
nervous system diseases of small ruminants
respiratory diseases of large ruminants
respiratory diseases of small ruminants

Macroscopic pathology

Lesions in cattle, sheep and goats are similar, although quite variable in extent and some changes are more common in certain species than in others. Effusion of body cavities, (hydropericardium, hydrothorax, and, in some cases a degree of ascites) is a very common change in most fatal cases of heartwater. The transudate is usually transparent or slightly turbid, light yellow fluid that often coagulates on exposure to air. The volume of fluid ranges from 20 ml in goats, about 0.5 L in sheep to several litres in cattle (Steck, 1928). A hydropericardium, as indicated by the name ‘heartwater’, is a striking change in most animals that die of the disease and is usually more pronounced in sheep and goats than in cattle (Henning, 1956).

Oedema of the lungs is a regular finding and appears to be more severe in most animals that die peracutely from the disease (Pypekamp and Prozesky, 1987). The interlobular septa of the lungs, mediastinum and associated lymph nodes are oedematous and serous frothy fluid oozes from the cut surface of the lung. The trachea and bronchi often contain serofibrinous exudates, and their mucosae are congested, with petechiae and ecchymoses.

Splenomegaly is present although less strikingly in sheep and goats. The cut surface is dark red in colour and has a pulpy consistency. In animals that die peracutely, it is often impossible to make a diagnosis on macroscopical lesions alone; splenomegaly, epi- and endocardial haemorrhages are sometimes the only significant changes (Alexander, 1931). Hepatic lesions are less striking with only a mild hepatomegaly present and the gallbladder slightly distended.

Congestion and/or oedema of the mucosa of the abomasum are regularly seen in cattle, but are less common in sheep and goats. Enterorrhagia (small and large intestine) is present in a small percentage of domestic ruminants, particularly Jersey cattle.

The lymph nodes are moderately swollen in most animals. The cut surface is moist and petechiae are often present, especially in the retropharyngeal, submaxillary, cervical, bronchial and mediastinal lymph nodes (Alexander, 1931). Petechiae are frequently visible on mucous membranes of tissues including those of the urinary bladder, vagina, epi- and endocardium and conjunctiva.

The nervous symptoms observed in affected animals are usually attributed to oedema of the brain, although it is often difficult and sometimes impossible to detect swelling of the brain macroscopically. Occasionally, the entire brain, but particularly the gyri of the cerebellum may be strikingly swollen and severe oedema of the brain may even result in a partial prolapse (herniation) of the cerebellum through the foramen magnum. Most animals that die of heartwater show congestion and oedema of the meninges. There is an accumulation of excessive fluid in the subarachnoid space and thickening of the choroid plexus, which has a dull greyish appearance. In some animals, petechiae and ecchymoses and sometimes sugillations are evident in the midbrain, brain stem and cerebellum (Pienaar et al., 1966).

Histopathology

Comprehensive studies on the histopathological changes of heartwater were made by Steck (1928), Alexander (1931) and Pienaar et al. (1966).

Lungs: An alveolar and interstitial oedema occurs in most animals but is not always discernible histopathologically.

Kidneys: Nephrosis of varying degree is a common change in domestic ruminants that die of heartwater. The observations of Steck (1928) of a multifocal lymphocytic interstitial nephritis occurring in cattle, sheep and goats could not be confirmed in subsequent studies (Uilenberg, 1983).

Brain: Lesions in the brain of cattle, sheep and goats were described by Pienaar et al. (1966) and are characterized by changes compatible with oedema, such as widened perivascular spaces which sometimes contain oedematous fluid or protein droplets; swollen, often necrotic, astrocytes; swollen axons, and multifocal microcavitations and haemorrhages affecting mainly the midbrain, brain stem, cerebral white matter and cerebral peduncles. A perivascular accumulation of cells, mainly macrophages and a few neutrophils, and occasionally a vasculitis, were observed in all the bovines and in only about 50% of the sheep. A diffuse meningitis, mainly macrophages, was present in a few bovines only. In the majority of animals, a fibrinous choroiditis occurred and occasionally mutifocal glial nodules, mainly confined to the neutrophil around small blood vessels, were apparent in sheep and cattle. Brain lesions in recumbent animals often comprise different degrees of status spongiosus and in severe cases, the white matter of the entire brain may be affected.

Other organs: in most animals that die of heartwater the hepatic changes are inconspicuous; the lymph nodes are congested and oedematous; and congestion is the only splenic change.

Variable numbers of E. ruminantium colonies are discernable in the cytoplasm of endothelial cells, particularly those of the brain and lungs. Cowdry (1926) and Steck (1928) frequently also observed colonies in the endothelial cells of glomerular capillaries. As a general rule, however, these colonies are difficult to find in haematoxylin- and eosin-stained sections.

Several species of game are susceptible to heartwater but reports on the pathological changes in game that died of heartwater are limited and in most cases, lesions are very similar to that described in domestic animals (Young and Basson, 1973; Prozesky, 1987).

Transmission electron microscopy studies of the lung lesions in sheep and goats reveal the presence of minor cytopathic changes in endothelial cells. Apart from mild swelling of mitochondria and endoplasmic reticulum, no other changes occur in most parasitized alveolar endothelial cells. Non-parasitized endothelial cells are sometimes swollen, or even necrotic, and are separated from their basement membranes. Oedema of blood vessel walls is infrequently seen (Prozesky and Plessis, 1985a, b).

In all suspected cases, a diagnosis of heartwater must be confirmed by the demonstration of Ehrlichia organisms in Giemsa-stained preparations made from the hippocampus.

The pathogenesis of the disease is still poorly understood, but the following hypothesis has been proposed.

The Amblyomma tick spp. attaches firmly on the host skin with their relatively big mouth parts (hyposome) that penetrate the skin damaging the tissue and small blood vessels. To secure them firmly on the host, they excrete proteinaceous cement that helps secure the hyposome of the tick at the bite site (Anderson and Magnarelli, 2008). The cement fills the gaps between the host skin and the hyposome of the tick to prevent the blood leaking during feeding while the tick also excretes anticoagulant that prevents blood clotting (Thomas et al., 2016; Denisov et al., 2021).

After infection of the host with E. ruminantium, initial replication of the organisms appears to take place in reticuloendothelial cells and macrophages in the regional lymph nodes. From here, the organisms are disseminated via the blood stream to invade endothelial cells of blood vessels in various organs where further multiplication occurs (Plessis, 1970). Endothelial cell parasitization coincides with the onset of fever. There is an increased vascular permeability allowing the seepage of plasma proteins which result in transudation through the serous membranes with resultant tissue oedema (Brown and Skowronek, 1990) and effusion into body cavities. This causes the drastic fall in blood volume before death (Clark, 1962). Oedema of the brain is responsible for the nervous signs, hydropericardium contributes to cardiac dysfunction during the terminal stages of the disease and progressive pulmonary oedema and hydrothorax result in asphyxiation (Uilenberg, 1971; Owen et al., 1973). Amstel et al. (1988a, b) found normal arterial carbon dioxide tension in calves with experimentally induced heartwater, with a tendency towards alkalosis, an increased pulmonary dead space and fluctuations in venous admixture. In the terminal stages of the disease, there was a marked decrease in stroke volume and cardiac output.

The pathogenesis of vascular permeability remains speculative as the intracytoplasmic development of the organisms seems to have little detectable cytopathic effect upon the endothelial cells (Pienaar, 1970), and there is also no apparent correlation between the number of parasitized cells in the pulmonary blood vessels and the severity of the pulmonary oedema (Jackson and Neitz, 1932; Prozesky and Plessis, 1985a). It has been proposed that an endotoxin (Amstel et al., 1988a) and increased cerebrospinal fluid pressure (Brown and Skowronek, 1990) play a role in the development of lung oedema.

The course of the disease can vary from a peracute form marked by sudden death with little or no clinical signs, to a chronic form, characterized by a transitory fever, followed by natural recovery. Small ruminants (sheep and goats, particularly Angora goats) appear to be most susceptible. A similar course, to a varying degree, is also seen in cattle.

In general, the prognosis is especially poor for imported or exotic cattle and small ruminants. Peracute and acute forms are usually fatal. Few ruminants survive once nervous symptoms have appeared. Case mortalities vary from 5% to virtually 100% depending on the strain of E. ruminantium involved, the locality, season and host breed.

Factors relating to the tick vector, causative organism and vertebrate host are important in the epidemiology of heartwater. These include genetic diversity and strain differences of E. ruminantium, availability of wild animal reservoir hosts or vectors for the organisms, infection rate in ticks, age and genetic resistance of domestic ruminant populations, seasonal changes influencing tick abundance and activity, and the intensity of tick control (Uilenberg, 1983).

Although there is a lack of information on the development of E. ruminantium, there is some evidence that the parasite undergoes a sequential development in both the vertebrate and invertebrate hosts (Plessis, 1982; Kocan et al., 1987a). The organism replicates mainly by binary fission, and possibly by endosporulation (Pienaar, 1970). It appears that the reticulate bodies are predominately proliferative, while the elementary bodies represent the infective stage (Jongejan et al., 1990). Transmission electron microscope studies of in vitro-cultivated organisms demonstrated the presence of intracellular reticulate bodies 2 to 4 days after infection and intermediate bodies 4 to 5 days after infection. Large numbers of elementary bodies are seen after rupture of endothelial cells 5 to 6 days after infection (Jongejan et al., 1990; Jongejan, 1991).

The host Amblyomma spp. ticks become infected during the larval and nymphal stages when they feed on infected domestic and wild ruminants, and possibly also on certain game birds and reptiles while E. ruminantium is circulating in the blood of these hosts. Nymphae and adult ticks transmit E. ruminantium to susceptible hosts without losing the infection. Intrastadial transmission has been demonstrated (Andrew and Norval, 1989). The development cycle of the organism in the tick and the infectivity of successive stages of the tick are poorly understood. It is thought that after an infected blood meal, initial replication of the organism takes place in the intestinal epithelium of the tick and that the salivary glands eventually become parasitized (Kocan et al., 1987b). Transmission of the parasite to the vertebrate host probably takes place either by regurgitation of their gut contents or through the saliva of the tick while feeding. The minimum period required for transmission of the parasite after tick attachment is between 27-38 h in nymphs and 21-75 h in adults (Bezuidenhout, 1988).

The main vectors of heartwater are Amblyomma variegatum and A. hebraeum, although a number of other Amblyomma spp. have been shown experimentally to be able to transmit the organism. A. maculatum, occurring in the USA is also capable of transmitting the disease (Uilenberg, 1982b). Not all are equally good vectors, and their importance in the transmission of heartwater depends not only on their vector competence, but also on their distribution and association with domestic stock (Uilenberg, 1983). Furthermore, the activity and abundance of the ticks is influenced by temperature and humidity (Petney et al., 1987). Ticks can acquire the infection from the host from about the time of the febrile reaction for up to 361 days, or even longer (Andrew and Norval, 1989) and probably retain their infectivity for life (Neitz, 1968; Ilemobade, 1976). Infection rates in ticks vary, from 0-44.9% for males, 20-36.1% for females and 0-13.4% for nymphs, depending on the season and the locality in which they are collected (Plessis, 1985; Plessis and Malan, 1987b; Norval et al., 1990).

The existence of antigenically different strains of E. ruminantium with varying virulence has been demonstrated. There is also variable cross-protection between these different varieties (Jongejan et al., 1988; Plessis et al., 1989). The introduction of animals which are immune to a particular variant of E. ruminantium into an endemic area where a different variety occurs may therefore result in recombination of the strains of heartwater. This leads to a new strain that can be more or less virulent.

Various factors such as species, breed, age, degree of natural resistance and immune status play a role in determining whether asymptomatic or overt disease will develop in a susceptible host after infection. Young calves, lambs and kids possess a non-specific resistance which is independent of the immune status of the dam and is of short duration: the first 4-6 weeks of life in calves and only the first week in lambs and kids (Neitz and Alexander, 1941; Alexander et al., 1946; Uilenberg, 1981; Plessis et al., 1987). The susceptibilities of different breeds of cattle and sheep vary. Some sheep breeds, such as the Blackhead Persian, possess a certain degree of natural resistance (Alexander, 1931; Uilenberg, 1983). Angora goats are highly susceptible to heartwater and their immunity is of short duration (Plessis et al., 1983). Genetic resistance, which is due to a recessive sex-linked gene, has been demonstrated in Creole goats in Guadeloupe (Matheron et al., 1987).

Wild ruminants such as the blesbok (Damaliscus dorcas phillipsi), South African buffalo and black wildebeest, as well as helmeted guinea fowl, leopard tortoise (Geochelone pardalis [Stigmochelys pardalis]), A. marmoreum and scrub hare have been shown to harbour E. ruminantium subclinically for long periods and may therefore play a role as source of infection for ticks (Petney and Horak, 1988).

Ehrlichia ruminantium strains have been isolated from ticks other than Amblyomma; the Kümm strain from Hyalomma tick in 1971, and the Omatjenne strain from a non-endemic area in 1990. The original Kümm strain has since been shown to contain two separate strains: Kümm 1 and Kümm 2 (Zweygarth et al., 2002). In an epidemiological study by Steyn and Pretorius (2020) using the pCS20 gene region sequence, it was shown that the Kumm 2 and Omatjenne strains cluster together with a new strain called Riverside. However, genome sequencing of these strains revealed that the Riverside strain differed from the other two strains (Liebenberg et al., 2020). Interestingly, the Kümm 1 strain clusters together with the West African strains (Steyn and Pretorius, 2020). The Omatjenne strain has since been detected in endemic and non-endemic areas in South Africa in cattle, sheep and goats. The Ehrlichia Omatjenne strain must not be confused with the Anaplasma Omatjenne strain that have the same origin (Namibia).

Genome sequencing:

The complete genome sequence of E. ruminantium, the South African Welgevonden strain, was published in 2005 (Collins et al., 2005). This was soon followed by the genome sequences of the daughter strain of Welgevonden maintained in Guadeloupe since 1988, and the Gardel strain from Guadeloupe (Frutos et al., 2006). As sequencing technologies have advanced, whole genome sequencing of more strains became attainable. Consequently, several complete and draft genomes became available more recently (Nakao et al., 2016; Liebenberg et al., 2020). Currently, 23 genome sequences are available on the microbial genome database at the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/), representing isolates from southern Africa, as well as West Africa.

Most authorities regard heartwater in southern Africa as an economically important disease. Uilenberg (1983) ranked it second only to East Coast fever and tsetse-transmitted trypanosomosis. Neitz (1968) stated that in endemic areas, mortalities due to heartwater were three times as high as those due to babesiosis and anaplasmosis. However, there have been no definitive studies designed to quantify this importance. Under the auspices of the UF/USAID/SADC heartwater research project, a study was undertaken to evaluate the economic impact of heartwater in Zimbabwe. The total annual losses were estimated at US $5.6 million (Mukhebi et al., 1999). Annual economic losses per animal in the commercial production system in Zimbabwe were 25 times higher than losses in the communal system. The greatest components of economic loss were acaricide costs (76%), followed by milk loss (18%) and treatment cost (5%). However, no other reliable figures are available on the economic impact of heartwater in the region. Heartwater is not a notifiable disease in South Africa. As result of cases being unreported, there is no official data recording the impact statistically, however, it does have a great impact on the economy.

The fact that E. ruminantium can be grown in human endothelial cells (Totté et al., 1993) has led to speculation that cowdriosis might be a zoonosis. But to date, no evidence from the field supports this (Kelly et al., 1992).

Drug Treatment

A variety of drugs have been used with varying success against E. ruminantium (Amstel and Oberem, 1987). Treatment of heartwater during the early febrile stages presents very few problems and recovery can be expected when tetracyclines are used at 10 mg/10 kg body weight dose rates. The successful treatment of field cases of heartwater remains a problem because of the advanced stage of the disease in which the animal is usually presented and because of ineffective supportive therapy. Drugs active in reducing oedema (Shakespeare et al., 1998), stabilization of membranes and blocking effect of vasoactive compounds released with cellular death could be considered (Amstel and Oberem, 1987).

Chemoprophylaxis

This is a procedure by which a series of tetracycline injections is used to protect susceptible animals against heartwater when they are introduced into an endemic area (Purnell, 1987). In goats, it is advocated that short-acting tetracyclines be administered at a dosage rate of 3 mg/kg body weight on 10, 20, 30, 45 and 60 days after introduction and the animals should not be dipped until after 60 days (Gruss, 1981). Similarly, injections of long-acting tetracycline formulations (10-20 mg/kg body weight) given on days 7, 14 and 21, or even on only two occasions (days 7 and 14) in cattle are sufficient to protect them from contracting heartwater, while at the same time allowing them to develop a natural immunity (Purnell, 1987). The success of this regime is dependent on all the animals becoming naturally infected during the time that they are protected by the drug. With fluctuating infection rates in ticks under different ecological conditions this approach may fail. This method can also lead to antibiotic resistance. Many farmers in the endemic regions of South Africa farming Angora goats use tetracycline on a daily basis to treat Angora goats that appear sick (Allsopp, 2009).