Diagnosis, Treatment and Management of Haemonchus contortus in Small Ruminants

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Diagnosis, Treatment and Management of Haemonchus contortus in Small Ruminants R.B. Besier*, 1, L.P. Kahnx, N.D. Sargison{, J.A. Van Wykjj *Department of Agriculture and Food Western Australia, Albany, WA, Australia x University of New England, Armidale, NSW, Australia { University of Edinburgh, Roslin, Midlothian, United Kingdom jj University of Pretoria, Hatfield, South Africa 1 Corresponding author: E-mail: [email protected]

Contents 1. Introduction 2. Diagnosis and Disease Monitoring 2.1 Clinical signs 2.2 The FAMACHA system for anaemia assessment 2.3 Postmortem examination 2.4 Laboratory diagnosis

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2.4.1 Faecal worm egg counts 2.4.2 Laboratory identification of eggs or larvae in faecal samples 2.4.3 Molecular techniques

2.5 Haematology 3. Anthelmintic Treatment 3.1 Anthelmintic groups 3.1.1 3.1.2 3.1.3 3.1.4 3.1.5 3.1.6 3.1.7 3.1.8

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Benzimidazoles Imidazothiazoles/tetrahydropyrimidines Organophosphates Macrocyclic lactones Salicylanilides and substituted phenols Amino-acetonitrile derivatives Spiroindoles Combination anthelmintics

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3.2 Anthelmintic-resistance management 3.2.1 3.2.2 3.2.3 3.2.4

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Minimizing resistance-selection treatment practices Refugia strategies to maintain anthelmintic-susceptible populations Anthelmintic choice Prevention of the introduction of resistant nematodes

4. Nonchemical Control 4.1 Grazing management 4.2 Nutritional management Advances in Parasitology, Volume 93 ISSN 0065-308X http://dx.doi.org/10.1016/bs.apar.2016.02.024

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4.3 Genetic selection against Haemonchus contortus 4.4 Biological control 4.5 Alternative anthelmintic compounds 4.6 Vaccines 5. Preventative Programmes 5.1 Haemonchosis risk assessment 5.2 Epidemiologically based preventative programmes 5.2.1 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6

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Wet tropical zones Subtropical zones Summer rainfall temperate zones Mediterranean climatic zones Cold temperate zones Arid zones

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5.3 Nonchemical strategies 5.4 Monitoring of Haemonchus contortus burdens 5.5 Anthelmintic choice and resistance management 6. Conclusions References

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Abstract Haemonchus contortus is a highly pathogenic, blood-feeding nematode of small ruminants, and a significant cause of mortalities worldwide. Haemonchosis is a particularly significant threat in tropical, subtropical and warm temperate regions, where warm and moist conditions favour the free-living stages, but periodic outbreaks occur more widely during periods of transient environmental favourability. The clinical diagnosis of haemonchosis is based mostly on the detection of anaemia in association with a characteristic epidemiological picture, and confirmed at postmortem by the finding of large numbers of H. contortus in the abomasum. The detection of impending haemonchosis relies chiefly on periodic monitoring for anaemia, including through the ‘FAMACHA’ conjunctival-colour index, or through faecal worm egg counts and other laboratory procedures. A range of anthelmintics for use against H. contortus is available, but in most endemic situations anthelmintic resistance significantly limits the available treatment options. Effective preventative programmes vary depending on environments and enterprise types, and according to the scale of the haemonchosis risk and the local epidemiology of infections, but should aim to prevent disease outbreaks while maintaining anthelmintic efficacy. Appropriate strategies include animal management programmes to avoid excessive H. contortus challenge, genetic and nutritional approaches to enhance resistance and resilience to infection, and the monitoring of H. contortus infection on an individual animal or flock basis. Specific strategies to manage anthelmintic resistance centre on the appropriate use of effective anthelmintics, and refugia-based treatment schedules. Alternative approaches, such as biological control, may also prove useful, and vaccination against H. contortus appears to have significant potential in control programmes.

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1. INTRODUCTION The effective prevention of haemonchosis is essential for the sustainable management of sheep and goats in regions where Haemonchus contortus is endemic, due especially to the threat of animal mortalities. Although the seasonal epidemiology of H. contortus infection in relation to weather patterns is well-established in the majority of climatic zones (O’Connor et al., 2006; chapter: The pathophysiology, ecology and epidemiology of Haemonchus contortus infections in small ruminants by Besier et al., 2016), the high biotic potential of H. contortus can lead to rapid population increases, and haemonchosis outbreaks frequently occur with little warning. Outside of the major risk zones, however, the ability of H. contortus to exploit short periods of favourable climatic conditions, and opportunities related to climate change in new environments, suggest that outbreaks of haemonchosis are increasingly likely in nonendemic regions. Fortunately, despite the potential severity of haemonchosis outbreaks, the presence of developing H. contortus burdens in small ruminants can be diagnosed relatively easily both clinically and by laboratory procedures, and easily confirmed by necropsy where deaths occur. This provides the basis for effective surveillance, treatment and preventative programmes, where the appropriate economic and labour resources are available. Unfortunately, in many situations, control measures are based either on intervention when outbreaks occur or on subjectively timed, ad hoc treatments, rather than on planned strategic or integrated programmes. Further, widespread anthelmintic resistance limits the effectiveness of both treatment and prevention, particularly given that control centres largely on the use of anthelmintics. The successful avoidance of haemonchosis relies on the early recognition of risk situations, the periodic monitoring of H. contortus burdens, and preventative programmes which include grazing management and nonchemical measures, in addition to anthelmintic treatments.

2. DIAGNOSIS AND DISEASE MONITORING An accurate diagnosis is essential when haemonchosis is suspected, given the potential for significant and ongoing animal mortalities without appropriate and timely treatment. It is also important to exclude haemonchosis when it is suspected not to be involved, as some of the clinical signs are not specific; in particular, sudden deaths of livestock in endemic zones

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may be erroneously attributed to H. contortus, whereas the actual primary cause is commonly related to other conditions, including trematodes or vector-transmitted protozoal infections. Under these circumstances, some treatments may be inappropriate to the actual condition, risking further losses until an accurate diagnosis is made. The signs and laboratory procedures used to detect clinical disease are also used to monitor for subclinical H. contortus infection or impending haemonchosis, and to indicate whether the rate of pasture contamination with H. contortus eggs is likely to lead to overt disease in the near future. Periodic monitoring of signs of anaemia in host animals, faecal worm egg counts (FWECs), and opportune postmortem examinations are an important part of integrated parasite management (IPM) programmes which aim to avoid both serious parasitism and excessive chemical treatments. The genetic selection of animals with a greater natural resistance to nematodes, a key component of IPM strategies, also relies on these diagnostic indicators. New laboratory tools based on molecular technologies will further improve both the diagnosis and management of H. contortus infections (chapter: The identification of Haemonchus species and diagnosis of haemonchosis by Zarlenga et al., 2016). In all situations, diagnostic protocols must take account of the epidemiological factors that influence the likelihood of a particular disease. In most locations, the seasonal occurrence of haemonchosis and the potential effects of specific weather events are well known, as are the classes of animal most at risk at particular times of the year. Animal management factors, including nutritional status, movements between pastures and the anthelmintic treatment history are also pertinent to the development of disease. In general, integrating clinical, laboratory and epidemiological information will rapidly confirm or otherwise a diagnosis of haemonchosis, without the necessity for prolonged or unnecessarily expensive investigations. Where a diagnosis remains equivocal, it can usually be confirmed or otherwise by observing the response to treatment with an effective anthelmintic.

2.1 Clinical signs The signs most characteristic of H. contortus infection relate almost entirely to the blood-feeding activities of adult and late larval stages (Bowman, 2014; Dunn, 1978; Levine, 1980; Taylor et al., 2007; Urquhart et al., 1996), and include deaths, anaemia, reduced exercise tolerance and subcutaneous oedema. In cases of overwhelming infection (‘hyperacute haemonchosis’), animals are found dead, with signs of severe anaemia in many of the

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survivors. In most cases, the epidemiological picture is characteristic, in terms of weather conditions that are especially conducive to the development of infective larvae and the susceptibility of the animals involved; this form of haemonchosis commonly involves juveniles (lambs or kids), and lactating ewes or does that are subject to the peri-parturient relaxation of resistance to nematode infection. Usually, haemonchosis occurs in an acute form, with varying rates of onset and mortality, depending mostly on the rate of intake of infective larvae of H. contortus. The most specific indication is anaemia, seen as pallor of the mucous membranes, especiallyeasily seen in the conjunctivae, and varying from the normal, red-pink colour to extreme white in terminal situations. Affected animals become progressively weaker with increasing blood loss, and are less inclined to move and may spend more time lying down than usual. On driving, some will collapse and may die, particularly if repeatedly forced to move. Without treatment, the hypoproteinaemia due to blood loss may lead to a general, ventral oedema in a proportion of animals. This is especially evident as submandibular oedema (‘bottle jaw’), although this is not pathognomonic for haemonchosis, as it also occurs on a flock or herd scale in chronic fasciolosis outbreaks and with extreme cachexia, and deaths may occur before oedema develops. The faeces are often firm and scant, and may be dark due to an occult blood content. Diarrhoea is not usual, although haemonchosis can occur concurrently with infections with other nematodes that cause this clinical sign. Pain is not visually evident, but a break in the wool of sheep occasionally occurs, with the shedding of strands of wool or even the entire fleece. If left untreated, deaths typically continue and the rate of losses increases over several days. However, a marked variation in susceptibility to haemonchosis among individuals is usual, reflecting both host resistance to H. contortus establishment and/or tolerance of its effects (presumably largely the capacity to replace lost blood, or an initial better blood status). Hence, it is not usual or inevitable that all individuals in a group affected by haemonchosis show the same extent of clinical signs or die if untreated (Roberts and Swan, 1982a). The proportion of animals within a flock or herd affected by different degrees of disease is largely genetically determined, and significantly mediated by their nutritional condition (chapter: The pathophysiology, ecology and epidemiology of Haemonchus contortus infections in small ruminants by Besier et al., 2016). The chronic form of haemonchosis is related to smaller but sustained burdens of H. contortus, seen as weight loss or poor weight gain, general

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illthrift and a degree of anaemia in some individuals (Dunn, 1978). This syndrome was first described from extensive grazing situations in Africa, where animals are often seasonally malnourished in highly seasonal environments (Allonby and Urquhart, 1975), and from pastoral situations in Australia (De Chaneet and Mayberry, 1978), especially if anthelmintic treatments are not routinely given. In such situations, haemonchosis becomes overt when blood loss cannot be sustained as the nutritional state declines, or when weather events incite an increased intake of infective larvae of H. contortus. It is also likely that a chronic form of haemonchosis occurs under intensive grazing conditions in less seasonal and higher rainfall zones, where occasional partially effective treatments fail to completely remove H. contortus burdens, but adequate nutrition ensures sufficient resilience to infection. In such situations, it is likely that H. contortus is one of the several nematode species contributing to suboptimal animal production.

2.2 The FAMACHA system for anaemia assessment The visible signs of anaemia have been exploited as a simple and rapid diagnostic indicator through the development of the FAMACHA system in South Africa, which involves the assessment of the colour of the conjunctival membranes (Van Wyk and Bath, 2002). For this, animals are restrained, and the eyes are examined and scored against a standardized set of five colours ranging from red-pink (normal) to white (terminal anaemia) (FAMACHA refers to ‘FAfa MAlan CHArt’; Malan et al., 2001). The FAMACHA system provides an assessment of relative anaemia (of any cause), and was specifically developed for the identification of animals requiring treatment on an individual basis, to reduce the selection pressure for anthelmintic resistance imposed by the usual (and frequent) treatment of all animals in the group. However, the classifications can also be used as the basis for whole-flock or herd anthelmintic treatments, when a proportion of animals fall below a threshold value. This approach requires frequent assessments to ensure the early detection and treatment of animals with subclinical haemonchosis, with a recommended schedule of inspections at 7e10 day intervals, once anaemia is detected in a small monitor group (Van Wyk and Bath, 2002). A significant labour input is required, which is most feasible when animal numbers are small or sufficient labour is available, and the system has achieved wide adoption for both sheep and goats in situations where these conditions can be met. In addition to a dramatic reduction in the proportion of anthelmintic treatments given, ‘repeat offender’ animals can be identified and culled, as there is a high heritability

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of FAMACHA score for both sheep (Riley and Van Wyk, 2009) and goats (Mathieu et al., 2007).

2.3 Postmortem examination Outbreaks of haemonchosis are often first recognized when mortalities occur, and postmortem examinations enable rapid confirmation. H. contortus burdens are readily visible on the abomasal surface as 2 cm-long worms with a ‘barber’s pole’ appearance where the red gut (from host-derived haemoglobin) spirals around the white ovaries of female worms. The large burdens (many thousands) of worms considered typical of acute haemonchosis leaves little doubt about the diagnosis. The mucosa is oedematous and appears covered with worms, with petechiae and often frank blood-seepage evident. Depending on the number of worms and the stage of infection, there are varying degrees of pallor of the carcass and of ascites, and the blood may be watery and fail to congeal. In more chronic forms of haemonchosis, the carcass may appear cachectic, with only a few hundred worms, and a diagnosis requires greater support in relation to the epidemiological circumstances and complementary laboratory assessments. The number of H. contortus present is rarely quantified by a total worm count, as the presence of many worms in association with the clinical signs and epidemiological picture are diagnostic. However, the worm numbers quoted from original observations of different stages of haemonchosis (Dargie and Allonby, 1975) suggest that, in the hyperacute form, massive numbers, >30,000 H. contortus may be present; 2000e20,000 worms in the acute form, and 100e1000 in chronic haemonchosis. As noted previously, the considerable variation in effects on individuals within a flock relates especially to genetic differences in host susceptibility to infection (and hence intensity of infection, or burden sizes), and the capacity to replace lost blood, as well to the time that an infection is present, and in less acute forms, the nutritional status of host animals.

2.4 Laboratory diagnosis 2.4.1 Faecal worm egg counts FWECs can be helpful to support the diagnosis of haemonchosis when no necropsy is conducted, or the epidemiological picture or clinical signs are atypical. Usually, FWECs are used as a monitoring tool to indicate the relative threat of disease or the extent of pasture contamination with H. contortus eggs. For nematode species generally, the FWEC is not a precise or sensitive measure of infection, due to the variable relationship between the number

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of worms in the gastrointestinal tract of the host and the number of eggs in the faeces, and the typically large variation in worm burdens among different animals in a group (Barger, 1985; Whitlock et al., 1972). In addition, the FWEC does not account for the presence of immature (nonegg laying, but potentially blood-feeding) worms, and is further influenced by the density of faeces due to variations in the water content (Le Jambre et al., 2007). Nonetheless, FWEC has advantages of low cost and simplicity of technique, and is an effective diagnostic indicator, provided that sufficient animals from a group are sampled, the laboratory procedures are appropriate (including for the identification of eggs) and allowances are made for other variables. Fortunately, the diagnostic value of FWEC is greater for H. contortus than for other trichostrongyles, because there is a relatively strong relationship between the biomass and the worm egg output (Coadwell and Ward, 1982), and between the total H. contortus count and FWEC in sheep (Roberts and Swan, 1981) and goats (Rinaldi et al., 2009). Le Jambre (1995) also found a high correlation between biomass and the number of adult H. contortus, and also with the degree of blood loss and FWEC. Of major practical importance, FWEC is most reliable when haemonchosis is imminent or present, due to extremely high counts. In comparison with most ruminant nematodes, H. contortus is a prolific egg-producer (Gordon, 1948), and the high FWECs typically seen in acute haemonchosis usually allow this disease to be distinguished from other helminthoses. For H. contortus, FWECs associated with significant but not immediately dangerous burdens typically number in the thousands of eggs per gram (epg). Levine (1980, p. 204) quotes sources that suggest 3000 epg to indicate ‘light’ infections for individual adult sheep, compared with 30,000 epg for ‘severe’ infections, and Taylor et al. (2007, p. 160) indicate that ‘moderate’ burdens may relate to FWECs of between 2000 and 20,000 epg. These figures are ten-times higher than FWECs relating to Trichostrongylus and Teladorsagia burdens of similar significance, which rarely reach such high values, and are then typically accompanied by the primary sign of diarrhoea. High FWECs in the absence of the latter sign are hence a strong indication of the presence of H. contortus. The interpretation of nematode FWECs is usually based on the mean for a flock or herd, particularly if processed by a composite (bulked) laboratory method; this value is obviously far lower than the highest extreme counts, but the latter must be taken into consideration. There is no point in withholding treatment on the basis of a moderate mean FWEC if some individuals are likely to be at significant risk, and where (as usual) it is not possible to individually identify them.

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FWECs are less definitive when intended to indicate the presence of H. contortus before significant burdens develop, or the degree of pasture contamination with H. contortus eggs, particularly if no differentiation of counts to genus or species is available. In such situations, considerably lower FWECs become significant, and to prevent excessive pasture contamination, treatment may be recommended at mean values of as low as 1000 epg (www.wormboss.com.au). Sufficient animals from the flock or herd must be sampled for confidence that the mean result reflects the group situation. Although trichostrongylid egg counts within groups of grazing animals usually follow an aggregated (skewed) pattern, typically as the statistically negative binomial distribution (Barger, 1985; Torgerson et al., 2005), field studies indicate that FWECs for H. contortus are moderately repeatable between individuals, indicating that the same animals tend to have a consistently high or low ranking of counts within the group (Barger and Dash, 1987; Doligalska et al., 1997; Van Wyk and Riley, 2009). A key question is the number of samples necessary to account for the typical within-flock variation in FWECs. Other sources of variation also affect the mean count result, including variability inherent to the technique and operator proficiency, each of which follow different statistical distributions (Van Burgel et al., 2014), and usually results in wide confidence intervals around the ‘true’ mean count. The variation expected for egg distribution within faecal suspensions (as a Poisson distribution) can be predicted, and inappropriate variation reduced by increasing the sample number, and to a degree by more sensitive detection methods (Torgerson et al., 2012). The minimum sample size of 10 from a flock, which has become established (Brundson, 1970; Nicholls and Obendorf, 1994), is considered reasonable for the majority of situations, and is supported by modelling of sample sizes for use in a composite technique (Morgan et al., 2005). However, this statement is made with the important qualification that more samples may be required if there is significant aggregation (overdispersion) within the group. Obviously, the degree of within-flock variation cannot be easily estimated from a small sample, but it is particularly common for H. contortus, where individual animals with high burdens may have massively higher FWECs than the mean of the group; to this extent, a sample number larger than 10 is generally warranted when a ‘sensitive’ indication of H. contortus burden or an estimate of H. contortus egg output is required. The most commonly used techniques in the laboratory remain variations on the McMaster procedure (Bowman, 2014; Urquhart et al., 1996; Vadlejch et al., 2011; Whitlock, 1948), where helminth eggs are counted

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by faecal salt flotation. The within-laboratory sensitivity can be increased by counting more chambers or larger amounts of faeces, although considerably more sensitive techniques, such as FLOTAC (Rinaldi et al., 2011) and an earlier cuvette method (Christie and Jackson, 1982), have been developed. If the cost of FWEC techniques is a limitation to wide adoption for routine nematode monitoring, this can be reduced by the use of a composite (bulked) counting technique. This entails counting a smaller number of chambers, but there is no loss of precision of the mean count in comparison with that from individual counts (Baldock et al., 1990; Morgan et al., 2005; Nicholls and Obendorf, 1994), allowing the sampling and testing of a larger number of animals at a reduced cost. Regardless of the technique used, its apparent simplicity should not be overestimated, as evaluations have shown considerable potential for operator-error when conducted in a laboratory setting (Van Burgel et al., 2014) and by less-trained operators (McCoy et al., 2005). In summary, FWECs are an essential part of the diagnostic toolkit, as the samples are simple to obtain and relatively inexpensive to process. Very high FWECs in some individuals can provide rapid confirmation of cases of acute haemonchosis, and may provide early indication of impending outbreaks, without resorting to species identification. Less extreme FWEC results may indicate the potential for excessive pasture contamination to lead to disease in the future. When results are not clearly indicative of H. contortus, larger sample numbers or more precise laboratory methods may be used to increase sensitivity. Further testing is frequently necessary to indicate the genus or species present before a diagnostic interpretation is possible. 2.4.2 Laboratory identification of eggs or larvae in faecal samples Confirmation of the identity of nematode eggs is a routine component of a laboratory diagnosis, and a number of techniques exist for the species or genus identification of the egg or larval stages present in faecal samples. The identification of H. contortus is especially relevant in situations where the size of the estimated burden will determine the necessity or otherwise for treatment, and because narrow spectrum anthelmintics are available specifically for blood-feeding helminths. Since the 1990s, research has focussed on the development of rapid and precise molecular tests for the quantitative indicators of individual species present in faecal samples (Zarlenga et al., 2016). As the eggs of most ruminant trichostrongyles cannot be reliably differentiated based on size or morphology alone (Christie and Jackson, 1982), their identification has depended on the use of conventional laboratory

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culture of eggs in faecal samples to the infective larval stage, and the identification of the larvae on the basis of the dimensions and morphology of various structures (e.g., Bowman, 2014; Urquhart et al., 1996). However, despite the relative simplicity of the approach, it suffers from numerous disadvantages (reviewed by Roeber and Kahn, 2014). These include the requirement for culturing of faeces for about one week; the skill required to differentiate among some genera on the basis of larval-sheath tail length; and that some genera cannot be reliably distinguished according to the longused standard identification key (Dikmans and Andrews, 1933). Various revisions of the identification criteria have increased the accuracy, and at least one detailed guide to increase the speed and accuracy of differentiation has been published (Van Wyk and Mayhew, 2013; van Wyk et al., 2004). As a further source of potential error, different nematode species vary in their response to faecal culture conditions, which may affect the size of infective larvae (Rossanigo and Gruner, 1996) and the proportion of different species from cultures (Dobson et al., 1992; McKenna, 1998). For the specific and rapid identification of H. contortus eggs in a mixedgenus faecal sample, many of these limitations are overcome by the lectinbinding assay. For this procedure, nematode eggs are isolated from a faecal suspension, and incubated briefly with a fluorescent dye conjugated to a lectin (peanut agglutinin) which has a specific affinity for H. contortus eggs (Palmer and McCombe, 1996). Eggs with a fluorescent margin are counted and the proportion of H. contortus eggs estimated. Compared with larval culture, the lectin-based assay has a high degree of specificity for Haemonchus species (Jurasek et al., 2010; Palmer and McCombe, 1996), requires no special skill for identification and can be completed within 2e3 h, provided that a fluorescent microscope is available. Lectins specific for other ovine nematodes have been found (Colditz et al., 2002), potentially extending the technique to other parasitic nematodes, although lectin binding appears of limited value for the identification of infective larvae or adult worms (Hillrichs et al., 2012). However, in most instances the prime requirement of species identification is to indicate the presence and proportion of H. contortus eggs following the quantification of strongylid eggs in a faecal sample. 2.4.3 Molecular techniques Advances in molecular technologies are now reaching practicality, with the validation of PCR techniques for species identification, and the developing commercialization of this and other new approaches for use in diagnostic

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laboratories (chapter: The identification of Haemonchus species and diagnosis of haemonchosis by Zarlenga et al., 2016). The basic premise is that species can be individually identified and differentiated using genetic markers in the nuclear ribosomal DNA (first and second internal transcribed spacers, ITS-1 and ITS-2) for a range of strongylid nematodes (eg, Gasser, 2006; Gasser et al., 1993, 2008; Roeber et al., 2013; Wimmer et al., 2004), because of a low level of intraspecific variation and a significantly higher variation among species (Gasser, 2006). These markers have been exploited to detect and identify a number of species simultaneously through various PCR techniques, based on the amplification of DNA from nematode eggs in faeces (Bott et al., 2009; Demeler et al., 2103; Learmount et al., 2009; Roeber et al., 2012), directly from faecal DNA (McNally et al., 2013), or from individual nematode larvae (Bissett et al., 2014). The potential to quantify worm burdens through real-time PCR has also been demonstrated, with the prospect of replacing both the FWEC and species identification procedures, providing present challenges can be met (Bott et al., 2009; Harmon et al., 2007; H€ oglund et al., 2013; Learmount et al., 2009; McNally et al., 2013; Melville et al., 2014). The introduction of high-throughput molecular methods has the potential to revolutionize the application of nematode diagnostics, and automated PCR systems are now becoming available for ruminant parasitology laboratories (Roeber and Kahn, 2014; Roeber et al., 2012, 2015). Their routine use to complement traditional methods will increase as cost-efficiencies increase, given the advantages of more rapid sample processing and an increased accuracy of species identification. The prospect of quantitative nematode detection, and possibly the molecular detection of anthelmintic resistance and ‘point-of-care’ diagnostic systems, such as loop-mediated isothermal amplification (LAMP) assays (Melville et al., 2014), would provide major, additional benefits. Advances in the understanding of the genomic structure of H. contortus will aid the development of new diagnostic tools and treatment technologies (chapter: Functional genomics tools for Haemonchus contortus and lessons from other helminths by Britton et al., 2016; chapter: Understanding Haemonchus contortus better through genomics and transcriptomics by Gasser et al., 2016; chapter: Haemonchus contortus: genome structure, organization and comparative genomics by Laing et al., 2016).

2.5 Haematology Although anaemia is the key pathogenic process leading to haemonchosis, and blood loss is closely linked to the H. contortus burden (Le Jambre,

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1995), it is rarely practical or efficient to utilize haematology to confirm a diagnosis or to indicate impending disease. Critical values associated with terminal haemonchosis are evident from field and pen observations: a fall in haematocrit (packed cell volume) to <15% for an individual animal is generally fatal, unless immediate treatment is given (Albers et al., 1989; Dargie and Allonby, 1975), and despite treatment, recovery is unlikely at values of <10e12%. Using the perhaps more consistent index of haemoglobin concentration, Roberts and Swan (1982b) considered values of <8.5 g/100 mL to be indicative of heavy H. contortus burdens. The relationship between excreted blood in the faeces from infected hosts and burdens of haematophagic parasites offers the potential for pen-side tests. A simple test for the detection of faecal occult blood in H. contortuseinfected sheep, based on a scale of colour changes on a commercially available dipstick in relation to the concentration of blood, has shown some promise (Colditz and Le Jambre, 2008). In practice, however, the test has proven insufficiently precise to detect low and moderate worm burdens, and as for any simple haematological test, it is not specific regarding the cause of faecal blood content. Nevertheless, with improved technologies, it may prove feasible to develop this concept as a relatively simple laboratory or field assay, without the complications of host effects on FWEC.

3. ANTHELMINTIC TREATMENT The necessity for effective anthelmintics for the treatment and prevention of haemonchosis is hard to overestimate, given the potential for animal mortalities if left unchecked. Although anthelmintics should always be used in conjunction with nonchemical strategies as part of an IPM approach, the potential for rapid increases in H. contortus populations requires effective treatment at appropriate times. The choice of which anthelmintic and when they should be used is a question of balance between the necessity for treatment or prevention, the cost in terms of economics and the labour effort required, and the potential for the development of anthelmintic resistance. Fortunately, there are several anthelmintic groups (ie, classes with distinct mechanisms of effect on target helminths) available for blood-feeding parasites. Without considering older compounds no longer widely used, at least six single-active anthelmintic groups are produced for use against H. contortus, and a number of others marketed as combinations, although the range

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available at any one time varies among countries. Less fortunately, there is no guarantee that all chemicals will be uniformly effective in any one region, due to the widespread occurrence of anthelmintic resistance. The requirement for frequent treatment, perceived or real, has resulted in heavy exposure of H. contortus to anthelmintics, and in some situations, few effective options remain. As there can be wide variation in the severity of resistance among geographical regions and properties within a region, an awareness of the likely effectiveness of the different groups is necessary for an optimal anthelmintic choice. A summary of the global anthelmintic-resistance situation is provided in Kaplan and Vidyashankar (2012).

3.1 Anthelmintic groups Specific reference to anthelmintics and resistance is made here only for presently available compounds and as they apply to treatment and preventative programmes. Numerous texts and journal publications provide details of the mode of action, pharmacokinetics and efficacy spectrum of the major anthelmintics (eg, Martin, 1997; McKellar and Jackson, 2004), and Chapter “Anthelmintic resistance in Haemonchus contortus: history, mechanisms and diagnosis” by Kotze and Prichard (2016) provides a review of the cellular mechanisms of anthelmintic resistance. 3.1.1 Benzimidazoles The first modern broad-spectrum anthelmintic, thiabendazole, was released for commercial use in the early 1960s, and shown to be safe, easy to administer and highly effective (>95%) against a wide range of major ruminant parasites (including nematodes, some trematodes and arthropods) (Gordon, 1961), and against the immature parasitic stages of some species. Other benzimidazoles followed, some of which are no longer in general use (parbendazole, cambendazole and oxibendazole), with the current range (albendazole, fenbendazole, oxfendazole, mebendazole) available from the late 1970s (McKellar and Jackson, 2004). The pro-benzimidazoles, thiophanate and netobomin, are also available in some countries. Members of this group act on nematodes at the cellular level, mainly by inhibiting the polymerization of microtubules, eventually causing cell death (Lacey, 1988; Martin, 1997). Due to the time of their availability and frequent use, resistance in nematodes to the benzimidazoles has been widespread globally for many years; used alone, the group is rarely still effective against the dominant strongylid species in a particular region (Kaplan and Vidyashankar, 2012). In most areas

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endemic for H. contortus, resistance is especially severe, and the benzimidazoles retain a significant role only when used in combination with other drugs. 3.1.2 Imidazothiazoles/tetrahydropyrimidines The two families within this group share a common mode of action, as nicotinic agonists, against acetylcholine receptors (Martin, 1997; Robertson and Martin, 1993). This group represented the second modern broad-spectrum anthelmintics to be introduced (in the late 1960s), with a wide range of activity against helminths. Levamisole is the most widely used of the group in small ruminants, although morantel is still available in some countries for use in sheep. Although resistance is very common in many nematode genera, field testing results indicate that H. contortus has remained generally susceptible to levamisole for a longer period than to the other major drugs (eg, Playford et al., 2014). However, this is no longer the case in the main endemic regions, and resistance must be expected to increase, although levamisole typically remains effective against H. contortus in regions where it is of lesser importance. 3.1.3 Organophosphates An older anthelmintic group, the oral organophosphate anthelmintics, continues to be used in countries where it is still available (Campbell et al., 1978), and includes naphthalophos, triclorfon and (as a combination product) pyraclyfos. As with all organophosphates, they act by inhibiting acetylcholinesterase activity (Martin, 1997), and are hence potentially toxic to mammals as well as to target parasites, and caution is necessary for their administration and handling. H. contortus is comparatively more sensitive to these compounds than to most other ruminant nematodes (Fiel et al., 2011), and very few cases of resistance have been reported; however, it is less active against several other important nematodes, and especially the larval stages of some species. Although this group is not universally available, it can have a useful, narrow-spectrum role, particularly when resistance to other groups is common. 3.1.4 Macrocyclic lactones The release of ivermectin in the early 1980s introduced a new era of effectiveness against most species and all stages of nematodes (but not cestodes or trematodes) and also against some ectoparasites (Campbell et al., 1983). Although different actives within the macrocyclic lactone (ML) group

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share a major mode of action, the disruption of nervous transmission by potentiating glutamate-gated chloride channels (Martin and Pennington, 1988; Martin, 1997), pharmacologic differences exist among avermectins, milbemycin and moxidectin, with implications for the relative potency and mechanisms of resistance selection (Lloberas et al., 2013; Prichard et al., 2012). In field efficacy tests using recommended dose rates, moxidectin has been shown to be more effective than other MLs once resistance to this group appears, including against T. circumcincta (see Leathwick et al., 2000) and H. contortus, with abamectin more effective than ivermectin (Lloberas et al., 2013; Playford et al., 2014; Wooster et al., 2008). Resistance to ivermectin is widespread in H. contortus populations in endemic zones, and is increasing in prevalence to moxidectin (Kaplan and Vidyashankar, 2012; Prichard et al., 2012). The persistent effect of moxidectin (as both the oral and long-acting injectable formulations) against H. contortus offers potential control benefits, but is also reduced or eliminated when ML resistance develops. Other MLs, such as doramectin, mostly used in cattle, are also available in some countries, primarily for use as endectocides. 3.1.5 Salicylanilides and substituted phenols This group comprises a number of compounds which act by inhibiting energy metabolism (uncoupling of oxidative phosphorylation; Martin, 1997), with those active against nematodes including closantel, rafoxanide, and (by injection) disophenol and nitroxynil (other chemicals in this group are more useful for cestodes and trematodes). As narrow-spectrum anthelmintics with activity specifically against blood-feeding helminths, they are of particular importance for the control of H. contortus, especially as some, such as closantel and disophenol, have a prolonged activity of some weeks after administration (Hall et al., 1981). However, the latter effect may also have predisposed this group to resistance in H. contortus (Rolfe, 1990; Van Wyk, 2001), which is first seen as a reduction in the persistent effect. Resistance to closantel is now common in endemic regions where it was intensively used (eg, Playford et al., 2014), but is generally uncommon in lower-risk situations where the frequent use of a long-acting anthelmintic specifically for H. contortus control has not been warranted. 3.1.6 Amino-acetonitrile derivatives The sole member of this group, monepantel, was introduced in the late 2000s, as the first new anthelmintic type for some 30 years (Kaminsky et al., 2008). It has a unique mode of action against nicotinic acetylcholine

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receptors, and a wide spectrum of activity, similar to that of the MLs (Hosking et al., 2010). Some instances of resistance to monepantel have been reported, including to H. contortus (see Mederos et al., 2014; Van den Brom et al., 2015). 3.1.7 Spiroindoles The introduction to the anthelmintic armoury is the first member of the spiroindole group, derquantel (2-desoxoparaherquamide) (Little et al., 2011), described as nicotinic cholinergic antagonists. It is produced for commercial use only in combination with abamectin, as derqantel is itself not fully effective against all nematodes, especially the larval stages of T. circumcincta. The combination compound has been shown in numerous trials to have high efficacy against a range of sheep nematodes of varying resistance status (Little et al., 2010), although a lower efficacy has been reported if abamectin is particularly ineffective (Sager et al., 2012). 3.1.8 Combination anthelmintics In addition to single-active anthelmintics, a wide range of combination anthelmintics are produced, although combination products are not accepted in all countries. In addition to the newly introduced derquanteleabamectin combination, various mixtures of benzimidazoles, levamisole, MLs, closantel and organophosphates have been available. The prime purpose is to ensure efficacy against helminths resistant to one or more of the components of a combination, but the additional benefit of reducing the rate of selection for anthelmintic resistance, as recognized some time ago (Anderson et al., 1988; Barnes et al., 1995), is now the basis for recommendations for the routine use of combinations (Bartram et al., 2012; Leathwick et al., 2009; Le Jambre et al., 2010). As expected, resistance to anthelmintic combinations is far less common than to individual components, but instances of resistance occur even to combinations of three or more actives (Mariadass et al., 2006; Playford et al., 2014), and H. contortus populations separately resistant to several different groups have been detected (Cezar et al., 2010; Chandrawathani et al., 2004a; Van Wyk et al., 1997a). Plainly, the control of multipleresistant worms will be difficult should they become a significant part of the total population, and procedures to prevent this from occurring are an essential part of sustainable management programmes.

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3.2 Anthelmintic-resistance management Following the recognition of the major causal factors for anthelmintic resistance (Prichard et al., 1980; Waller, 1986), strategies to minimize the further development and impact of such resistance have been incorporated into recommended parasite management strategies. The wide recognition of the key role of the refugia concept in explaining the development of anthelmintic resistance has provided a general basis for sustainable control programmes in different environments and different ruminant hosts (Leathwick and Besier, 2014). The theoretical basis of the development of resistance and the underlying cellular mechanisms is the subject of a more detailed review in Chapter “Anthelmintic resistance in Haemonchus contortus: history, mechanisms and diagnosis” by Kotze and Prichard (2016), and the discussion here is confined to principles for resistance management at the field level. 3.2.1 Minimizing resistance-selection treatment practices 3.2.1.1 Underdosing with anthelmintics

The potential for resistance to develop as a consequence of inadequate anthelmintic doses has long been recognized (Prichard et al., 1980; Smith et al., 1999). This issue appears to have been surprisingly common due both to a lack of awareness of the importance of ensuring appropriate doses and an underestimation of animal weights (Besier and Hopkins, 1988). However, although underdosing may have been a factor in the development of resistance to the older anthelmintic groups, the advice to ensure appropriate dosing appears to have largely been adopted in intensive, commercial grazing situations, at least, such that underdosing should no longer play a significant role. An exception may be where substandard products are marketed and low doses are unwittingly administered (Van Wyk et al., 1997b; Waller et al., 1996), and local awareness of the risk is the only defence. An interesting situation exists where anthelmintics have not been trialled in animal species that require treatment, but where the market is not perceived to justify commercial registration. It appears that, in comparison to sheep, higher doses are required to reach or maintain the necessary blood levels of some anthelmintic groups, and this could explain reports of apparent suboptimal efficacy in goats (Edwards et al., 2007; Jackson et al., 2012), South American camelids (Gillespie et al., 2010; Gonzalez-Canga et al., 2012; Jabbar et al., 2013) and deer (MacIntosh et al., 1985; Mylrea et al., 1991). For both the effective treatment of these species and prevention of the development of resistance that may spread more widely, it is

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unfortunate that appropriate dose rates have not been established and widely promoted for less-commercial livestock species. 3.2.1.2 Excessive treatment frequency

Also long recognized as a major causal factor for anthelmintic resistance is a high frequency of treatment (Prichard et al., 1980), which is a particular risk when haemonchosis is a major risk. In environments or seasons especially favourable for the development of the infective larvae on the pasture, treatments at short intervals e often regardless of the actual immediate threat e have been the basis of control programmes in many instances. The inevitable occurrence of high levels of resistance to a wide range of anthelmintics underlines the lack of sustainability of control regimes based largely on chemical treatments. While anthelmintic treatments will always be required, rational approaches to minimizing their frequency utilize the IPM principles of manipulating the exposure of susceptible host populations to the significant intake of infective larvae, including by using pasture management; avoiding routine treatments by monitoring flocks and herds or individuals within them; and incorporating nonchemical control approaches such as nutrition and genetics. In particular, the different requirement for the treatment of classes of stock at various stages of susceptibility should be recognized: young lambs or kids require more anthelmintic support than adults until an effective acquired immunity to nematodes has developed, and specific management may be required for lactating females during peri-parturient relaxation of resistance to helminth infection (Houdijk, 2008). Individual-animal treatment strategies (see Section 3.2.2) further reduce the intensity of treatment, despite the presence of potentially significant H. contortus challenge. 3.2.2 Refugia strategies to maintain anthelmintic-susceptible populations The refugia concept has been identified as a fundamental principle in resistance management, to ensure that the selection advantage to resistant worms immediately following an anthelmintic treatment does not result in a permanent increase in their proportion in the total population. Strategies developed for a particular environment aim to ensure the survival of sufficient worms in refugia from anthelmintics to dilute any resistant worms surviving anthelmintic treatment, generally through the establishment of infective larvae from a non(or less)-resistant source (Besier, 2008; Jackson and Waller, 2008; Kenyon and Jackson, 2012; Leathwick et al., 2009; Van Wyk, 2001).

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Although a high frequency of treatment is a major causal factor, in many situations, it is not the sole or most important factor in the development of resistance. The selective effect of any treatment regime depends largely on the scale of dilution of resistant nematodes with newly acquired infective larvae, and a relatively small number of treatments in a ‘low refugia’ situation (such as a move after treatment on to helminth-free pastures) may provide significant selection pressure (Leathwick and Besier, 2014). Given the potentially adverse consequences of excessive parasitism, where larger worm populations than otherwise may survive through a refugia-based strategy, a balance is needed between the effectiveness of resistance management and the efficiency of worm control. This potential conflict is of particular concern in intensively managed enterprises that require highly effective worm control, and especially so in the major H. contortus zones where there is a low margin for error in preventing excessive population increases. The planning of refugia-based strategies requires judgements regarding several factors: the disease risk posed by resident nematode burdens; the initial resistance status; the likely intake of infective larvae (numbers and resistance status); and the resistance selection potential of anthelmintic treatments and animal management. Refugia management regimes typically involve either objectively based schedules for whole-flock/herd treatment (‘targeted treatment’) or the introduction of selective treatment strategies (‘targeted selective treatment’ e TST), by which some animals are left untreated when treatments are given (Besier, 2012; Kenyon et al., 2009). A targeted treatment approach requires decisions on the need for treatment for each flock or herd, rather than as routine treatments to all groups at the same time; this ensures that some worm populations of relatively lower resistance status (either in animals or as infective larvae on the pasture) are present on a particular farm or grazed area. When H. contortus is the predominant species, targeted treatment can be based on visual assessments for anaemia (FAMACHA) on a representative sample of animals, or by similarly representative FWECs, with whole-group treatment once threshold levels are indicated. These programmes are most effective when combined with preplanned pasture movements based on local epidemiological patterns for H. contortus, to minimize the need for anthelmintic treatments in comparison to continuous grazing strategies (eg, Bailey et al., 2009). This approach also reduces the requirement for continual monitoring of animals, which can involve significant time and cost, and is generally prohibitive in intensively managed situations. However, for all targeted treatment approaches, it is important

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that treated flocks eventually graze the pasture occupied by those not treated at the same time, to allow the uptake of infective larvae of a less-resistant background. ‘TST strategies provide refugia for nonselected populations within a flock or herd through individual-animal assessments, on the basis of various indicators appropriate to the parasites involved (eg, Besier, 2012; Kenyon and Jackson, 2012). For H. contortus, the most effective and efficient indicators assess the degree of anaemia, exemplified in the FAMACHA system (Van Wyk and Bath, 2002). As noted in Section 2.2, the procedure entails the periodic, individual examination of the conjunctival membranes, with colour categories providing an indication of anaemia. FAMACHA has been demonstrated to allow a major reduction in the need for treatment of individual sheep (Malan et al., 2001) and goats (Burke et al., 2007; Sotomaor et al., 2012), provided that assessments are made by trained operators (Maia et al., 2014) at an appropriate frequency (Reynecke et al., 2011a), and are used in situations where haemonchosis is the dominant nematode species (Moors and Gauly, 2009). Due to the requirement for frequent inspection of all animals during the main periods of haemonchosis threat, FAMACHA is most applicable where labour costs are low, flocks or herds are relatively small, and/or animal value is high. This approach has gained acceptance in a wide range of tropical, subtropical and summer rainfall regions, including in high input-cost enterprises where anthelmintic resistance has reached extreme levels, and has a particular role in resource-poor communities where the cost of whole-group treatments and the use of other diagnostic aids is not feasible (Vatta et al., 2001). TST strategies requiring intensive inputs are less practicable where labour is expensive and flocks are large, and, therefore, in intensive commercial situations, a targeted treatment programme based on flock or herd decisions rather than for individual animals is usually more applicable. Although TST based on the periodic assessment of changes in live-weight (Greer et al., 2009) or body condition score (Besier et al., 2010; Cornelius et al., 2014) has been demonstrated to be feasible where Teladorsagia and Trichostrongylus are the main nematode genera, this is not appropriate for H. contortus. 3.2.3 Anthelmintic choice Although high anthelmintic efficacy is essential for effective treatment if haemonchosis has occurred or is imminent, it is also important to minimize the survival of resistant H. contortus even when worm burdens and the disease risk are low. The effectiveness of a refugia strategy is dependent on the

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dilution necessary to ensure that resistant worms remain in the minority, and the larger the number of resistant survivors of treatment, the less efficient is the dilution effect (Leathwick et al., 2009). There is no doubt that many livestock owners routinely use partially effective anthelmintics, which may remove sufficient nematodes to achieve a clinical result, but exacerbate the resistance situation by allowing resistant worms to survive. The failure to achieve an adequate effect is of particular consequence in regard to H. contortus, due to both the risk of animal mortalities and the diminishing range of anthelmintic options in many haemonchosis-endemic regions. 3.2.3.1 Detection of resistance

In the majority of cases, livestock owners are not aware of the anthelmintic resistance situation on their properties. Although a variety of in vitro resistance detection tests have been developed (chapter: Anthelmintic Resistance in Haemonchus contortus: History, Mechanisms and Diagnosis by Kotze and Prichard, 2016), at present none are available commercially as multianthelmintic, multispecies systems. The faecal egg count reduction test remains the only currently available method of simultaneously assessing the efficacy of a range of anthelmintics against a range of species, but the time and effort required appears to be a barrier to its wide adoption. Consequently, as well as an absence of information about individual farms, in almost all situations, there is a paucity of data for regional predictions of likely anthelmintic efficacy patterns. Although the use of the faecal egg count reduction test (FECRT) should continue at present to be advocated as a routine management component, the development of practicable laboratory tests, ideally with a molecular basis, is a major research priority for livestock parasite management. 3.2.3.2 Narrow or broad-spectrum?

It is fortunate that as the most pathogenic of the common livestock nematodes, narrow-spectrum options with significant effects only against haematophagous species are available (eg, salacylanilides and organophosphates). The chief advantage in their use (in addition to the persistent effect of some) is to reduce the exposure of other species to the broad-spectrum groups, and some effort and cost is often justified to confirm that H. contortus is the preponderant species at a particular time, and that a narrow-spectrum anthelmintic is therefore appropriate. As for the broad-spectrum compounds, resistance to some narrow-spectrum anthelmintics is common in some regions, such as those where the salacylanilides have been used

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extensively; in these situations, it is essential to assess the resistance status. Nevertheless, the relatively wide range of treatment options for H. contortus reduces the pressure for resistance to develop against broad-spectrum anthelmintics in both this and other species. 3.2.3.3 Long-acting anthelmintics

Formulations providing long-term ‘protection’ against nematodes through persistent activity against ingested infective larvae have a particular attraction for the control of H. contortus, given its pathogenicity and propensity for rapid population increases. Products include those with persistent activity for some weeks as a property of the normal formulation (the salacylanilides, closantel and disophenol, and the ML, moxidectin), and some that are specifically formulated as long-acting injections (MLs) or slow-release capsule formulations (avermectins and BZs, including as combinations), with activity for w3 months. However, the ‘protective’ benefits (and economics) must be weighed against the relatively greater potential for resistance development in comparison to short-acting formulations. The chief resistance risk relates to the prolonged periods in which worms of susceptible genotypes are excluded in comparison to resistant ones, due to the effect against infective larvae (‘tail’ selection), as well as to the survival of resistant adult worms (‘head’ selection) (Dobson et al., 1996; Le Jambre et al., 1999). Field studies in New Zealand confirm the more rapid selection for resistance in a number of species, including H. contortus, from a slow-release formulation in comparison to multiple short-acting treatments (Leathwick et al., 2006). The first manifestation of resistance to persistent products is a reduction in the protective period (Rolfe, 1990; Van Wyk et al., 1982), although this is usually not suspected until reduced efficacy against adult worms is evident in an anthelmintic-resistance test, or more seriously, as a cause of clinical disease. While long-acting formulations can play a beneficial role in high haemonchosis-risk situations, especially when used in a planned epidemiologically based programme (Dash, 1986), active steps must be taken to manage the resistance-selection potential. These include ensuring that the adequate dilution of resistant worms by refugia strategies, and if necessary, the removal of resistant surviving worms with anthelmintics of alternative groups when the persistent activity ceases. Without careful management, the continued use of long-acting products against populations already resistant to the anthelmintic groups involved must be expected to accelerate resistance development (Barnes et al., 2001), and, hence, increasingly compromise the aims of prolonged control. A high treatment efficacy (in relation to

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the resistance status) is an obvious requirement for the choice of a particular, long-acting product. 3.2.3.4 Combination anthelmintics

The beneficial effect of combining anthelmintics has long been utilized to extend the useful lives of individual components once resistance limits their efficacies. A range of products containing between two and four active ingredients are available in some countries, although the registration of preformulated combinations is not always permitted (Geary et al., 2012). The superior efficacy of combinations is readily seen in a comparison of anthelmintic-resistance figures for combination products and their individual components (McKenna, 2010; Playford et al., 2014). Of equivalent importance is their role in delaying the rate of resistance development (Bartram et al., 2012; Dobson et al., 2011; Geary et al., 2012; Leathwick and Besier, 2014). To maximize this effect, it may be preferable that newly introduced anthelmintics are used in combination, as the combination advantage in delaying resistance has been shown to decrease as resistance to the individual actives increases (Leathwick et al., 2012). As noted previously, a major qualification to the routine use of combination anthelmintics is the potential to exacerbate resistance to all components, hence denying the individual use of several groups. This is a significant risk, and combinations should always be used in the context of refugia and effective IPM strategies, rather than considered simply as a simple addition to the range of treatment options. 3.2.4 Prevention of the introduction of resistant nematodes Routine measures to prevent the introduction of new forms of resistance onto a farm through the transfer of animals appear intuitively logical. Even in regions where resistance is highly prevalent, there is a wide variation among farms in the severity and range of groups involved, reflecting interactions between treatment practices and environmental and animal management factors. The efficacy of anthelmintic groups that remain effective can therefore be reduced by the inadvertent introduction of a population with a greater degree of resistance. The presence of ivermectin resistance has been linked to the failure to give ‘quarantine’ treatments to animals when transferred (Suter et al., 2004) and to the introduction of relatively larger numbers of untreated stock (Hughes et al., 2007; Lawrence et al., 2006) in surveys in Australia and New Zealand, respectively.

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Given that the efficacy of anthelmintics against the nematode population harboured by introduced animals is generally unknown, present recommendations are that they should be treated with a combination of several anthelmintics, then placed on pastures likely to carry substantial populations of infective larvae, to dilute any survivors of this treatment. Surprisingly, surveys in a number of countries suggest that the adoption of a quarantine treatment strategy is relatively poor (Lawrence et al., 2007; Morgan et al., 2012; Suter et al., 2004). As one of the more simple elements of anthelmintic-resistance management programmes, this strategy clearly merits more emphasis by advisers to livestock owners.

4. NONCHEMICAL CONTROL While a reliance on anthelmintics as the basis of helminth control is not sustainable, the reluctance by many livestock owners in H. contortuse endemic zones to reduce the high frequency of treatment is understandable, unless alternatives are confirmed to be effective. A number of IPM approaches have been shown to successfully reduce the need for anthelmintic use, by either reducing the exposure to H. contortus challenge or by increasing the resistance or resilience of the host. While some individual IPM elements, such as grazing management, are often used on an opportunistic basis and therefore have a limited effect, objectively planned programmes incorporating a number of IPM components, in association with appropriate monitoring of H. contortus burdens, offer the prospect of a sustained reduction in both anthelmintic use and the risk of haemonchosis outbreaks.

4.1 Grazing management Grazing schedules based on local epidemiological information aim to minimize both the intake of H. contortus infective larvae by susceptible animals and the excessive contamination of pasture with H. contortus eggs, and hence reduce the haemonchosis risk in the immediate and long terms. Ecological and epidemiological data for a wide range of H. contortuseendemic zones indicate the periods for which grazing animals must be excluded from pasture to minimize the intake of infective larvae (chapter: The pathophysiology, ecology and epidemiology of Haemonchus contortus infections in small ruminants by Besier et al., 2016). Grazing studies confirm the effectiveness of larval-avoidance strategies, although, as expected, the time required varies considerably between environments, from a few weeks in the wet tropics

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(Fiji e Banks et al., 1990; Martinique e Mahieu and Aumont, 2009) to some months in a summer rainfall region temperate environment (northern New South Wales e Bailey et al., 2009; Southcott and Barger, 1975). However, the failure of many animal owners to utilize pasture management does not necessarily relate to a lack of awareness of its potential for H. contortus control. A major limitation is the practicality of spelling pastures for the necessary length of time, as animal movements are largely determined by nutritional availability. In intensive grazing situations, especially, the available pasture must be utilized for agronomic and economic reasons, and pasture regrowth typically occurs more rapidly than the die-off of infective larvae, although high-input, short-interval rotational systems may be feasible (Colvin et al., 2008). A particularly effective solution is the alternation of sheep or goats with cattle (Southcott and Barger, 1975), which have limited susceptibility to H. contortus, although young cattle may acquire minor burdens of H. contortus. Within a rotational grazing strategy, short periods of grazing by cattle may allow some utilization of pastures, while H. contortus larval populations diminish, and thus increase the feasibility of a pasturespelling strategy for sheep or goats. If grazing management opportunities are limited, the most rational approach may be to consider the relative susceptibility of various animal classes to H. contortus, and plan to ensure that they receive priority allocation to prepared low-risk pastures (Morley and Donald, 1980).

4.2 Nutritional management The ability of animals in good nutritional condition to resist infection with nematodes and to withstand their effects has long been recognized (Coop and Holmes, 1996), with positive responses to nutritional supplementation demonstrated for both resistance and resilience to H. contortus (see Steel, 2003). Tolerance of H. contortus infection is significantly reduced in sheep maintained on low-protein rations compared with animals receiving supplements (Abbott et al., 1986; Nnadi et al., 2009; Wallace et al., 1996), even though improved nutrition may not necessarily result in lower H. contortus burdens (Abbott et al., 1986; Wallace et al., 1996). In situations of chronic haemonchosis, overt disease may be precipitated by a reduction in nutritional quality, and a loss of milk production may occur in sheep with chronic H. contortus burdens (Nnadi et al., 2009; Thomas and Ali, 1983). As would be expected, the benefits of supplementation in enhancing the resistance and resilience of sheep against H. contortus infection have been shown to be greatest in the breeds or individual animals most susceptible

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to helminthosis (Abbott et al., 1985), and during periods of suboptimal nutrition or general weight loss (Kahn et al., 2003). The relationship shown between a higher body condition score (or fat score) and an enhanced protective immunity to H. contortus (see Macarthur et al., 2013) suggests that this relatively simple index can be used to indicate nutritional adequacy for worm control purposes. The necessity for effective nutritional management to ensure adequate helminth control is a cornerstone of all worm control recommendations, particularly when planned on the basis of nematode epidemiology (Houdijk et al., 2012), and when combined with other control strategies (Torres-Acosta et al., 2012).

4.3 Genetic selection against Haemonchus contortus The potential for the genetic selection of animals with a superior resistance (Wollaston and Baker, 1996) or resilience (tolerance) (Bisset and Morris, 1996) to nematode infections, and, hence, reduced requirement for anthelmintic control, has been recognized for many years. Genetic strategies for H. contortus have largely centred on resistance, as a reduction in worm burdens decreases both the haemonchosis risk and pasture worm egg contamination. The relatively high heritability offers significant potential for genetic selection strategies (Nieuwoudt et al., 2012; Riley and Van Wyk, 2009, 2011; Woolaston and Baker, 1996), and although some investigations with Merino sheep indicate that selection for low H. contortus FWECs may result in marginally lower animal production (Kelly et al., 2013; Wollaston and Baker, 1996), it has also been demonstrated that sheep that survive heavy H. contortus challenge have lower FWECs and higher haematocrits and body weights (Kelly et al., 2013). Taken together, it appears that selection based on either FWEC or body weight when under significant H. contortus challenge will identify sheep that are both resistant and resilient, and hence most suited to haemonchosis-endemic situations, although possibly with a minor compromise in wool production (Kelly et al., 2013). The greater natural resistance to H. contortus of hair-breed sheep compared with European breeds was well described from observations on Red Masai sheep in Kenya (Preston and Allonby, 1979), and has since been confirmed for both sheep and goats in numerous reports from a wide range of environments (eg, Amarante et al., 1999; Aumont et al., 2003; Bowdridge et al., 2013; Burke and Miller, 2002; Chiejina et al., 2010; Courtney et al., 1985; Gamble and Zajac, 1992; Gruner et al., 1986; Shakya et al., 2011). Presumably breed variation reflects the diverse evolutionary environments, and is

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consistent with demonstrated differences in immunological responses (Amarante et al., 2005; Bowdridge et al., 2013; Shakya et al., 2011). A key factor influencing the uptake of genetic strategies by livestock owners is the practicality and accuracy of selection markers for worm resistance. At present, selection is generally based on an FWEC index, and significant genetic progress towards increased flock resistance has been achieved where this has been pursued over some years. The high correlation demonstrated between FAMACHA values for anaemia assessment and haematocrit (Riley and Van Wyk, 2009, 2011) indicates this is also a practical selection procedure, particularly when applied under significant H. contortus challenge. Under these circumstances, a moderate correlation of FAMACHA scores with resilience traits (body weight and weight gain) was seen, and Kelly et al. (2013) also found a modest correlation of haematocrit with resilience traits. The potential for more precise and easily utilized genetic markers has been the subject of much investigation (Krawczyk and Slota, 2009), including quantitative trait loci (QTLs) (De la Chevrotiere et al., 2012; Marshall et al., 2013), algorithms based on haematological parameters (Andronicos et al., 2014), immunological indicators (Amarante et al., 2005; Shaw et al., 2012) and molecular markers (Castillo et al., 2011; Kathiravan et al., 2014; McRae et al., 2014). Direct genomic assessment is likely to prove challenging, given the multiplicity of processes contributing to the immunological recognition and response mechanisms, but at least one genomic test that explains a proportion of the resistance variation between individuals is available commercially (‘Wormstar’, Zoetis Genetics), and further molecular technology research may provide tools to realize the potential for genomic selection strategies. There is no evidence for adaptation by nematodes to selection-conferred resistance in sheep (Kemper et al., 2009; Woolston et al., 1992), and genetic approaches are therefore considered a key element of sustainable control strategies. Realistically, objective selection for resistance to H contortus is likely to be most applicable in large commercial flocks, particularly in sire-breeding enterprises, but FAMACHA assessment have also been advocated for smaller and less-intensive situations (Riley and Van Wyk, 2009).

4.4 Biological control The potential for biological control technologies to supplement the use of anthelmintics has led to a considerable volume of research over some decades, especially into the possible roles for nematophagous fungi and bioactive pasture plants. The effect of naturally occurring fungi which inhabit the

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soil and pasture, and form hyphae which trap and destroy nematode larvae, has been exploited by dosing sheep with fungal spores, so that these pass into the faeces, where they develop and predate infective larvae (Waller and Larsen, 1993). A number of fungal species have activity against the larvae of ruminant nematode parasites, with investigations chiefly involving Duddingtonia flagrans, although the search for additional candidate species continues (Kelly et al., 2009). It is envisaged that by continuous feeding of the predacious fungi to grazing animals (not only ruminants) in feed supplements over periods of weeks or months, an epidemiological effect will be achieved due to the reduction in their larval intake. Some promising, though variable, results have been shown in small-scale grazing studies in different environment with sheep (eg, Chandrawathani et al., 2004b; Fontenot et al., 2003; Waller et al., 2001) and goats (Maingi et al., 2006), including against H. contortus, but it appears that this approach is yet to be translated into routine control programmes for ruminants. A large number of pasture plant species are known to contain bioactive chemicals, especially the condensed tannin phenolic compounds, which are associated with reduced nematode burdens and improved animal production performance (reviewed by Hoste et al., 2006; chapter: Interactions Between Nutrition and Infections with Haemonchus contortus and Related Gastrointestinal Nematodes in Small Ruminants by Hoste et al. (2016)). These compounds, especially the condensed tannins, bind to proteins and prevent their degradation in the rumen, and can hence have a positive nutritive value, although in excessive concentrations or when protein intake is low, they can also have detrimental nutritional effects (reviewed by Waghorn, 2008). There is some contention regarding the mode of anthelmintic action of condensed tannins: whether this is a direct pharmaceutical-like effect of various polyphenolic compounds on nematode at various life-cycle stages (Hoste et al., 2012) or an indirect effect through an improved host immune response due to the protein-binding properties of tannins (Athanasiadou et al., 2005; Hoste et al., 2006; Waghorn, 2008). Generally, positive but variable effects against worm infections have been demonstrated in pen feeding and grazing studies for a number of candidate species (eg, Athanasiadou et al., 2005; Heckendorn et al., 2006; Min et al., 2004; Moreno et al., 2012; Niezen et al., 1998; Paolini et al., 2003), including Lotus pedunculatus (lotus), Hedysarium coronarium (sulla), Onobrychis viciifolia (sainfoin), Cichorium intybus (chicory) and Lolium perenne/Trifolium repens (grass/clover); useful results have also been reported for Sericea lespedeza, whether grazed or fed as hay or pellets (Burke et al., 2012, 2014; Shaik et al., 2006). However, major

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challenges remain due to the considerable variability in both animal production and anthelmintic effects, which have been attributed to varying concentrations of active compounds, plant growth stages and nutritional values, as well as the poor palatability and antinutritive effect associated with tannins, and, for some species, significant agronomic constraints. However, the evident potential clearly warrants further investigations, especially when the worm control and nutritional benefits are combined.

4.5 Alternative anthelmintic compounds Observations of the use of traditional plant-based remedies against parasitic disease have underpinned a considerable body of research into alternative anthelmintics, initially for economic reasons, and, as a response to increasing anthelmintic resistance. In many cases, the putative beneficial effects of ethnoveterinary preparations, as extracts or whole plant material, are anecdotal and are not supported when objectively investigated, but a number does appear to have some potential (eg, Athanasiadou et al., 2007; Githiori et al., 2006). Some widely used traditional remedies have been shown to be inactive against H. contortus (eg, garlic and papaya; Burke et al., 2009a), while for others the results are positive (eg, extracts of Artemisia; Irum et al., 2015), or conflicting (eg, Azadirachta indica; Chagas et al., 2008; Chandrawathani et al., 2006; Costa et al., 2006). In some instances, positive effects from in vitro laboratory investigations of plant extracts have not translated to useful activity in animals. Natural compounds found to have activity would require the development of practical deployment systems, particularly regarding the frequency of administration (most are less effective than anthelmintics), and format (as plant material or an extract). The known effect of the element copper against nematodes, used in various forms as an anthelmintic until the development of modern synthetic compounds, has been the subject of numerous investigations as an alternative treatment when used as a copper oxide wire particle bolus product (COWP). Encouraging anthelmintic effects with COWPs have been demonstrated, especially against H. contortus (eg, Bang et al., 1990; Burke and Miller, 2006; Knox, 2002; Spickett et al., 2012; Vatta et al., 2009), although clarification is needed as to whether this effect is largely against adult worm burdens or whether there is also a persistent effect against infective larvae (Galindo-Barboza et al., 2011; Vatta et al., 2012). However, as it appears that there is no significant toxicity risk when COWPs are used at the recommended dose (Burke and Miller, 2006; Vatta et al., 2012), there could be a role for this form of therapy to augment conventional anthelmintics,

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particularly when used in conjunction with other forms of nonanthelmintic control (Burke et al., 2005, 2012; De Montellano et al., 2007). The search for alternatives to synthetic anthelmintics raises the query: how effective must they be to justify development as widely applicable control methods? In contrast to anthelmintic-based control, no single biological control approach is generally expected to provide total efficacy, and they will be best used in conjunction with other natural approaches or existing strategies (Terrill et al., 2012; Torres-Acosta and Hoste, 2008). However, within these limits, the individual methodologies require objective evaluation, including across different environments and animal management systems, before acceptance for wide recommendation (Ketzis et al., 2006).

4.6 Vaccines The prospect of vaccination against helminth parasites as an alternative to the reliance on anthelmintics has underpinned a great deal of research over many years, but until 2014 the only vaccine available for ruminant nematodes has been for bovine lungworm. An effective vaccine would have a particular role for the control of H. contortus, as continuous protection against the development of damaging burdens would minimize the risk of animal mortalities, and mitigate the severity of anthelmintic resistance. Due to the epidemiological effect of limiting or preventing the establishment of infective larvae, the efficacy criteria for vaccines differ from those of short-acting anthelmintics; simulation modelling by Barnes et al. (1995) has suggested that for Trichostrongylus colubriformis, a vaccine would be highly effective provided that it was 80% effective in 80% of animals. The potential to produce an effective vaccine against H. contortus has been evident for many years, using ‘hidden antigens’ extracted from worm intestinal membranes (reviewed by chapter: Immunity to Haemonchus contortus and vaccine development by Nisbet et al., 2016). Significant reductions in worm burden and worm egg counts of vaccinated sheep have been demonstrated with this approach in numerous pen experiments in the UK (eg, Munn et al., 1993; Smith, 1993). However, although the immunological basis has since been extensively investigated and protective antigens characterized (Knox, 2013), it has not proved possible to reproduce the protective effects in sheep when individual proteins were produced in recombinant expression systems (reviewed by Cachat et al., 2010; Knox, 2013; and Newton and Meeusen, 2003; chapter: Immunity to Haemonchus contortus and vaccine development by Nisbet et al., 2016). Useful reductions in H. contortus egg counts have been shown using prototype recombinant vaccine in

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lambs (Fawzi et al., 2015) and goats (Yan et al., 2013), but the prospects for their development to a commercial stage are not clear. While vaccine production by recombinant technology has been unsuccessful, trials in sheep have confirmed the efficacy in the field of a vaccine produced at the Moredun Research Institute in Edinburgh from the ‘native antigens’ H11 and H-gal-GP, extracted from adult H. contortus. Vaccination with a combination of antigens in a trial in South Africa showed worm egg count reductions of >80%, with simultaneous reductions in anaemia and sheep deaths (Smith et al., 2001), and a field trial in New South Wales of a vaccine against H. contortus based on these antigens showed comparable results, despite clinical haemonchosis in untreated control group lambs (Le Jambre et al., 2008). Both trials confirmed that repeated vaccination at intervals of some weeks was necessary to maintain season-long protection, and also that, as with pen trials, plasma antibody levels followed parasitological and haematological indices relatively closely. These investigations have led to the development by the Moredun Research Institute of ‘Barbervax’, a native antigen-based vaccine against Haemonchus species. The vaccine is produced in Albany, Western Australia, in collaboration with the Department of Agriculture and Food Western Australia (Besier and Smith, 2014). Following extensive testing, the vaccine was released for commercial use in New South Wales in late 2014 (www. barbervax.com.au). Initial field results appear promising (Besier et al., 2015), and a trial in Brazil of a vaccine of a similar formulation indicated significant protection against H. contortus in lambs when given at 3week intervals, although it was less effective in ewes under especially severe challenge (Bassetto et al., 2014). Nevertheless, whether or not further development includes production by recombinant technology, it appears that the feasibility of vaccination against H. contortus on a commercial basis has now been demonstrated. In summary, the potential for vaccination to provide effective protection and hence to significantly reduce the requirement for anthelmintics is now evident. From the Australian experience, it appears that in regions where the haemonchosis risk is particularly severe, many sheep owners understand the need to minimize the development of anthelmintic resistance, and would be prepared to follow a vaccination schedule requiring multiple doses. Extension of vaccination to other sheep classes would be expected to provide an increased epidemiological benefit through the farm-wide reduction of pasture contamination with H. contortus eggs, and consequent reduction in larval challenge. Although commercial vaccine production by recombinant

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technology may facilitate its availability, and a less-intensive vaccination schedule would reduce the effort required, it appears that this approach is now feasible as an effective alternative or adjunct to anthelmintic-based preventative programmes.

5. PREVENTATIVE PROGRAMMES Planned preventative programmes are integral to the efficient control of all significant parasites, and vary widely between environments in relation to the scale and seasonality of the haemonchosis risk. Optimal helminth control programmes employ sufficient effort and resources to maintain animal health and prevent production loss, but avoid the excessive anthelmintic exposure that leads to anthelmintic resistance. The most sustainable and effective programmes integrate animal management, anthelmintic treatment and nonchemical strategies, and are most efficiently structured on the basis of several basic elements.

5.1 Haemonchosis risk assessment The degree of effort appropriate for H. contortus monitoring and treatment in different situations varies among regions, and relates mostly to whether there is a seasonally significant risk or a sporadic occurrence when local conditions are favourable. In general, the potential risk can be gauged by an awareness of the annual pattern of availability of infective larvae to grazing livestock in a particular location (reviewed by O’Connor et al., 2006; chapter: The pathophysiology, ecology and epidemiology of Haemonchus contortus infections in small ruminants by Besier et al., 2016), although in many environments the seasonal favourability varies considerably between and within years. Longterm implications for the H. contortus threat are also relevant where there are indications that permanent climate change may occur. Although livestock owners are usually cognizant of the general threat level in their region, there is often considerable variation among farms and flocks within a district due to differences in animal management and husbandry routines, the use of nonchemical strategies (particularly genetic and nutritional), and policies for anthelmintic use. Animals of different species, breed, age and class vary in their susceptibility and resilience to infection. Establishing the scale and annual pattern of risk for particular environments and individual flocks is the basis of developing appropriate responses (Reynecke et al., 2011b); to this extent, ‘one size does not fit all’.

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5.2 Epidemiologically based preventative programmes ‘The epidemiology of helminth infections integrates the biology of the parasite with that of the host as an expression of parasite abundance in relation to environmental effects, as the basis for planning preventative measures’ (Barger, 1997). Programmes based on the local epidemiology indicate the optimal (or minimal) requirement for anthelmintic treatments and their timing, as well as opportunities to utilize animal management and other approaches (Sargison, 2012). In contrast, in regions endemic for haemonchosis, ad hoc treatment policies whereby treatments are only given when clinical disease occurs or heavy worm burdens are detected obviously risk animal mortalities. Alternatively, suppressive regimes based on regular and frequent anthelmintic treatment regimens incite and exacerbate anthelmintic resistance (Table 1). Annual treatment and management programmes for H. contortus have several aims: • The removal of H. contortus burdens before they reach pathogenic levels. • The avoidance of the excessive intake of infective larvae from pastures. • Prevention of significant pasture contamination with H. contortus eggs. • The management of specific risks, such as increased H. contortus burdens due to the peri-parturient relaxation of resistance in lactating females, the unique susceptibility to infection of young animals, and the potential for hypobiotic worms to contribute to excessive worm populations. Except in regions of climatic extremes, such as the wet tropics and arid or frigid temperate zones, there is usually a clearly defined seasonal pattern to H. contortus population development, and to the animal husbandry routines that can be exploited to provide effective control without the excessive use of anthelmintics. Typically, this involves the identification of periods during the year when either helminth burdens should be monitored, or alternatively, routine preventative action taken (anthelmintic treatments or pasture movements) on the basis of objective observations and past experience. 5.2.1 Wet tropical zones Haemonchosis is a continual threat in these zones due to the high temperatures and year-round rainfall (Dorny et al., 1995; Ikeme et al., 1987; Waller, 1997), although the relatively short period of survival of infective larvae provides the basis for rotational pasture strategies. Control strategies appropriate for different enterprise types vary: in traditional small-holder situations, where there is typically little use of modern anthelmintics, ‘cut and carry’ systems have been advocated. In larger commercial flocks, where the

Wet tropical regions

Hot and moist climatic conditions favour the development of H. contortus infective larvae throughout most of the year, with only a transient reduction in larval intake during occasional periods of drier conditions. Small ruminants at pasture must be considered at continual risk of haemonchosis, but the short period of survival of infective larvae under these conditions offers opportunities for rotational gazing systems.

Subtropical regions

The distinctly seasonal climate confines the H. contortus risk to annual wet seasons, but during these periods hot conditions favour the rapid development of infective larvae, and haemonchosis is a major threat. Opportunities for control strategies are provided by the seasonal nature of the high-risk periods, although their duration and timing varies, and hypobiosis of the fourthstage larvae also occurs variably within this zone. The likelihood of overt haemonchosis also varies seasonally with the quality of the nutrition available to grazing animals, and is lowest in locally adapted (H. contortusresistant) breeds.

Continual monitoring of H. contortus burdens (FWEC) or their effects (anaemia, such as through FAMACHA) is essential. Management tactics to prevent the overwhelming intake of larva include short-term pasture rotations, or where feasible, ‘cut and carry’ feeding systems to avoid the grazing of pastures occupied by H. contortuseinfected ruminants. Where feasible, treatments should be confined to individually identified animals at risk, as the frequent use of anthelmintics has led to widespread resistance in H. contortus where mass treatments have been given routinely. H. contortus is the major helminth parasite of small ruminants in this zone and monitoring for infections is essential, although the intensity required varies seasonally according to the annual pattern of risk. The FAMACHA system is especially appropriate in the small-holder situations that predominate in this zone, and together with animal management strategies based on the seasonal variation in infective larvae availability, this provides a sound basis for rational anthelmintic use.

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Table 1 The relative risk of occurrence of haemonchosis and management strategies appropriate in different climatic zones (see Section 5.2) Climatic zone Haemonchosis risk Management strategies

The development of H. contortus larvae is highly seasonal, but haemonchosis is typically a significant threat for some months each year, from early summer onwards. However, the favourability for infective H. contortus larvae typically varies considerably during this period in relation to rainfall, and winter conditions are often too cold for the development of larvae. In some locations, larvae may fail to survive through winter (especially where temperatures are moderated by high altitudes), but in some regions hypobiosis allows the over-winter survival of H. contortus populations.

Mediterranean climates

The development of H. contortus infective larvae is typically limited to short periods of the year, chiefly during the autumn and spring months when sufficiently warm temperatures and rainfall coincide. However, the likelihood of haemonchosis outbreaks greatly from a seasonally endemic risk to a sporadic occurrence with outbreaks mostly in years with atypical weather conditions. In regions with particularly dry summers, H. contortus is only occasionally detected and disease is rare or absent.

Haemonchosis is usually the dominant parasitic risk to sheep and goats in this zone. In large intensively grazed flocks, pasture management strategies are commonly used to minimize the intake of infective H. contortus larvae, especially where cold winters extend the period when few larvae are present. These strategies require monitoring of H. contortus burdens, typically with FWECs, particularly throughout the summer risk period. In smaller flocks or where labour resources permit, monitoring by FAMACHA is also appropriate, commencing when seasonal conditions favour H. contortus larval development. Anthelmintic resistance is an especially severe problem in large commercial flocks in this zone, and tactics should aim to limit treatments to individual animals or particular flocks. Genetic selection for nematode resistance is also an effective strategy in intensively managed flocks. The importance of H. contortus in this zone varies from negligible to moderate, and its management is usually secondary to that required for other nematodes (chiefly Teladorsagia and Trichostrongylus). In areas where haemonchosis occurs commonly, the times of year and classes of livestock at most risk are usually well established, providing the basis for appropriate preemptive treatments or management strategies. Where outbreaks occur only occasionally, FWEC monitoring usually provides an effective indication of an impending risk.

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Table 1 The relative risk of occurrence of haemonchosis and management strategies appropriate in different climatic zones (see Section 5.2)dcont'd Climatic zone Haemonchosis risk Management strategies

Cold winter conditions restrict the development of infective larvae of H. contortus to relatively short summer periods, and in general haemonchosis is of only occasional concern in this zone. However, H. contortus populations commonly survive through winter as hypobiotic larvae, and the emergence of large numbers in spring leads to regular annual outbreaks of haemonchosis in regions where summer temperatures are sufficiently high. Since the 2010s, increasing reports of haemonchosis in locations where it has previously been rare have led to speculation that this reflects climatic changes that could increase the extent of the endemic zone.

Arid regions

The critical requirement for moisture severely limits H. contortus development, although minor populations may remain endemic due to hypobiosis if seasonal rainfall occurs, or because anthelmintics are rarely required (for any nematode species). Occasionally, cases of haemonchosis occur following unusually prolonged conditions that are favourable for larval development. In common with all climates with periods of hot or warm weather, irrigated pastures carry a potential risk of haemonchosis unless managed to prevent this.

Specific measures to control H. contortus are rarely necessary, and management programs directed at other nematodes are usually adequate. Where summer outbreaks occur, treatments at the end of winter (within a sustainable anthelmintic-use strategy) will reduce the haemonchosis risk, and monitoring of FWECs (with routine species identification) will indicate whether H. contortus is increasing in significance. In the environments most hostile for H. contortus (frigid and arctic zones), local eradication may be feasible, although both the economic justification and the potential for the required anthelmintic treatments to lead to resistance (including to nontarget species) would need to be considered. Routine control measures are rarely required, but an awareness of conditions favourable for larval development is appropriate in regions where there is the potential for occasional haemonchosis outbreaks. Eradication may be technically feasible but would rarely be justified. Where H. contortus exists on irrigated pasture, periodic monitoring will indicate the development of significant populations.

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heavy reliance on anthelmintics has produced severe resistance (Cezar et al., 2010; Chandrawathani et al., 2004a), nonanthelmintic control will include pasture rotations (Barger et al., 1994; Mathieu and Aumont, 2009). The FAMACHA system for indicating impending disease in both flocks and individuals has particular potential in such high-risk situations (Mahieu et al., 2007). 5.2.2 Subtropical zones The haemonchosis risk is generally more sharply seasonal than in the true tropics due to annual dry periods, although both the length of dry seasons and the total rainfall, and the importance of hypobiosis, vary greatly throughout the zone (see review by Bolajoko and Morgan, 2012). Rotational grazing is a key preventative strategy to minimize animal losses or excessive anthelmintic treatment, though appropriate regimes vary widely between locations and seasons. As in all high-risk environments, FAMACHA has a particular role for indicating H. contortus risk, especially as although the effectiveness of frequent anthelmintic use has been demonstrated (Fabiyi, 1987), the dominant management system involves small flocks kept in traditional village situations. 5.2.3 Summer rainfall temperate zones H. contortus development is also seasonal in these climatic zones, and depending on the rainfall pattern, is often the dominant livestock health risk for periods of several months each year. This is a zone where large flocks of intensively managed sheep are grazed, and the previously general practice of frequent anthelmintic treatment has led to especially severe anthelmintic resistance (Dash, 1986; Van Wyk et al., 1997b). In common with other high-risk situations, effective H. contortus preventative strategies include pasture management to avoid excessive infective larvae intake, typically by rotational grazing strategies whereby sheep follow cattle (Bailey et al., 2009; Southcott and Barger, 1975) or pasture rotations at seasonally variable intervals (Colvin et al., 2008). Where winter periods are sufficiently cold, the periods for which H. contortus fails to develop on pasture can extend the benefits of rotational grazing (Bailey et al., 2009). The use of FWEC monitoring (Section 2.4.1) has a particular role in supporting grazing strategies, and has become a routine management tool by sheep owners in some situations, especially in Australia (www.wormboss.co.au). In South Africa, where the particular threat of haemonchosis led to the development of the FAMACHA system, the availability of adequate labour

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resources has led to its application in large flocks and also by small holders in communal grazing situations (Vatta et al., 2001). In the less seasonal southern USA, where sufficiently warm temperatures and adequate rainfall prevail year round, the haemonchosis risk requires continual management, and control programmes advocated for sheep and goats include rotational strategies (Burke et al., 2009b), FAMACHA assessments (Burke et al., 2007) and a variety of nonchemical approaches (Terrill et al., 2012). 5.2.4 Mediterranean climatic zones In highly seasonal climates where rainfall is limited during the warmer months, there are large variations in the risk among locations and among years, but management regimes effective against haemonchosis are generally less intensive than in summer rainfall zones. In Mediterranean climates, the hot and dry summer conditions and relatively cool winters typically confine H. contortus development to short periods of the year (Besier and Dunsmore, 1993), reducing the severity and duration of the threat. Preemptive treatments prior to high-risk periods, identified through local experience and FWEC monitoring, and confined to specific animal classes at risk, can prevent the development of significant populations with little anthelmintic-resistance risk. In many cases, programmes aimed mostly at other nematodes also control H. contortus, and specific anthelmintic treatment is only occasionally required. 5.2.5 Cold temperate zones In higher latitudes, H. contortus is of relatively lesser importance, due to shorter and cooler summers and more severe winters, and hypobiosis has been demonstrated as the major over-winter survival mechanism, in studies such as in Canada (Gibbs, 1986; Mederos et al., 2010), Sweden (Waller et al., 2004) and South Dakota (Grosz et al., 2013). Measures directed primarily at more cold-adapted species are generally also effective against H. contortus, although its potential for rapid population increases following turn-out can lead to clinical haemonchosis. The vulnerability of the dependence by H. contortus on hypobiosis has suggested the prospect of the eradication by treating livestock while housed during winter (Waller et al., 2006), although the low degree of external refugia in this situation has significant potential for the development of anthelmintic resistance (Grosz et al., 2013). The outbreaks of haemonchosis in atypical environments raise the query regarding changes in climatic conditions (Eysker

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et al., 2005; Sargison et al., 2007), and the need to reevaluate H. contortus control (Morgan and van Dijk, 2012). 5.2.6 Arid zones The presence of H. contortus in arid and semidesert areas is testimony to its survival capacity (mostly through hypobiosis) and potential for rapid population increases. Rare haemonchosis outbreaks are chiefly due to the occasional coincidence of favourable conditions, and it is possible that in some situations H. contortus could be effectively eradicated on a local basis. Eradication could be especially useful where there was a potential for haemonchosis in irrigated pasture situations, although the justification of any such attempt would require evaluation in terms of both the technical feasibility and the potential to develop severe anthelmintic resistance (Le Jambre, 2006).

5.3 Nonchemical strategies IPM strategies are integral to sustainable preventative programmes in the major H. contortuseendemic zones, as experience indicates that control based chiefly on anthelmintic treatments will almost always be inadequate or unsustainable. As noted above, the available nonchemical approaches are not as immediately effective as anthelmintics in removing helminth burdens, but the ‘basket of best options’ approach (Krecek and Waller, 2006) has an additive effect, and in combination allows a significant reduction in anthelmintic use (Barger, 1997; Jackson and Miller, 2006; Torres-Acosta and Hoste, 2008; Waller, 2006). In general, the requirement for effort, planning and resources is greatest where the haemonchosis risk is especially great, especially in intensive production operations where maximal animal health is essential. Grazing management and pasture rotations to minimize H. contortus larval intake, along with structured monitoring schedules, are an essential element of sustainable programmes in tropical and summer rainfall temperate zone. The major IPM elements, breeding for superior resistance and/or resilience to haemonchosis and ensuring adequate nutrition, have been demonstrated to have particular application for the management of the risk and effects of H. contortus. Worm-resistant animals excrete fewer nematode eggs, hence providing the epidemiological benefit of reduced exposure to infective larvae, which is permanent within genetically selected flocks. The very significant between-breed differences in H. contortus tolerance are routinely, if not always consciously, utilized in many zones where

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haemonchosis is a limiting factor on animal enterprises, although under intensive commercial conditions there may be a limited role for breeds not selected for high production efficiency. Optimal nutrition is a general recommendation to maximize animal production, and undernutrition is of greatest significance as a factor in haemonchosis outbreaks in small-holder situations. A number of alternative nonchemical approaches have potential, and are advocated as a suite of strategies (Terrill et al., 2012; Torres-Acosta et al., 2012), although at present their roles in commercial situations are yet to be realized. However, the demonstration that vaccination against H. contortus is a feasible option (see Section 4.6) may provide an additional option to reducing dependence on anthelmintic control.

5.4 Monitoring of Haemonchus contortus burdens The legendary capacity for rapid increases in H. contortus populations requires a stringent monitoring schedule during high-risk periods, whether by FWEC or FAMACHA, and an objective indication of H. contortus burdens allows a reduction in the frequency of treatment. This is most efficiently included as part of a planned management programme, as the immediate risk, and hence value of monitoring activities, varies in relation to the time of anthelmintic treatments or pasture changes. In general, in all except tropical environments, monitoring specifically for H. contortus needs to be conducted only during high-risk periods: for example, whole-flock FAMACHA inspection need not commence until anaemia is evident from checks of a small subsample, although as with all monitoring programmes, the FAMACHA data must be interpreted in relation to prevailing epidemiological factors (Van Wyk and Reynecke, 2011). Where H. contortus is only occasionally significant, monitoring may most efficiently be limited to periods of unusual weather conditions, and in many cases its presence will only be evident after tests for species identification. In endemic situations, however, the costs and effort of monitoring are easily recouped through the avoidance of animal losses by the timely recognition of risk, and the maintenance of anthelmintic efficacy by minimizing exposure.

5.5 Anthelmintic choice and resistance management As previously noted (Section 3.2), a number of factors influence the optimal choice of anthelmintic, and on many intensively grazed properties, a number of different anthelmintic groups and formulations may be used in any one year. While H. contortus is the chief worm control target, the use of narrow-spectrum products at appropriate times is an obvious approach to

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combat the development of resistance against other anthelmintic groups, with benefits for the control of both H. contortus and other species. Where suitable refugia tactics are feasible to manage the anthelmintic-resistance risk, long-acting anthelmintics may be appropriate for particularly susceptible flocks. In many situations, the anthelmintic options are limited due to the poor efficacy of most available groups or particular formulations. Unfortunately, in the majority of livestock situations, there is little information regarding the efficacy of various options, and the continued use of failing products will reduce their effectiveness. A move to combination anthelmintics, usually to ensure adequate efficacy, will have the additional benefit of delaying the onset of resistance, provided they are used within a refugia context. The recommendation to conduct anthelmintic-resistance tests is especially pertinent where H. contortus is a major threat. As detailed previously , providing adequate refugia for worms of lowresistance status is arguably the most important element of resistancemanagement strategies. These strategies are integral to sustainable control programmes, and in conjunction with monitoring of H. contortus burdens, will not entail a reduction in animal production. Specific resistance management tactics, including periodic testing for anthelmintic resistance and the use of quarantine treatments for introduced animals, have long been central elements of sustainable control recommendations. The implementation of strategies to rationalize the use of anthelmintics has had variable success on a worldwide scale. A balance is required between the appropriate and excessive use of sustainable programmes, given the potential for either inadequate parasite control or the development of resistance (Bath, 2006). Programmes to achieve this are often slow to gain adoption, especially those requiring a commitment of time and cost, or where the underlying concepts appear complex (Besier, 2012; Van Wyk et al., 2006). Objectively planned communication strategies are essential for the adoption of effective and sustainable control programmes (Kahn and Woodgate, 2012; Woodgate and Love, 2012), requiring the close cooperation of the scientific and advisory sectors.

6. CONCLUSIONS Recognition of the risk of haemonchosis and the need for effective prevention is essential to avoid serious mortalities in sheep and goats in

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H. contortuseendemic zones. Haemonchosis also poses a periodic seasonal risk in environments that are more marginal for H. contortus, and significant losses may occur without appropriate monitoring and treatment programmes. However, despite the propensity of H. contortus for rapid population increases under even transiently favourable conditions, a range of diagnosis and treatment options assist in its management. Outbreaks of acute haemonchosis are relatively easily diagnosed, as large numbers of H. contortus are characteristic, and smaller but also lethal burdens seen in animals with chronic haemonchosis are generally associated with typical epidemiological and nutritional conditions. The clinical sign of anaemia is a simple indication of the pathogenic effects in individual animals, and the FAMACHA conjunctival colour index of anaemia provides a practical monitoring system which can be applied at regular intervals. Where individual animal inspections are not practicable, the relatively close correlation between H. contortus burdens and FWECs provides an effective flock or herd monitoring tool, augmented, where necessary, by a number of techniques for the specific identification of H. contortus in mixed-nematode populations. Although a wide range of anthelmintic groups is potentially available for use against H. contortus, in practice, widespread anthelmintic resistance limits their effectiveness. Strategies to minimize the development of resistance must be an integral component of H. contortus control programmes, and these include measures to optimize the frequency of anthelmintic treatments, and the application of refugia policies to ensure the retention of worms of relatively lower-resistance status. Although a number of nonchemical parasite control approaches have been considered, those most feasible and effective include pasture management to manage H. contortus larval intake, the provision of adequate nutrition, and the genetic selection of host animals for superior worm resistance and resilience. The development of a vaccine against H. contortus provides an additional control possibility, but further work is needed before other biological control possibilities become a reality. The development of more practical and costeffective tests for anthelmintic resistance, nematode burdens and host worm resistance would significantly assist with H. contortus control, and are important research objectives. The preventative programmes appropriate for different environments vary according to the scale of the haemonchosis risk and the local epidemiology of H. contortus infections and haemonchosis outbreaks. In the major endemic zones, control has relied heavily on anthelmintics, with consequent widespread and severe resistance. Sustainable approaches require the

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effective detection of developing H. contortus burdens and the avoidance of excessive larval intake through pasture changes, with the application of refugia-based strategies on either an individual animal or a flock basis. In environments where haemonchosis occurs more sporadically, monitoring is particularly important to allow preemptive treatments during potential risk periods, including where hypobiosis leads to seasonal outbreaks. In all situations, appropriate anthelmintic choice and the use of IPM principles are fundamental to the effective management of H. contortus, although their perceived complexity requires a significant communication effort to achieve wide implementation.

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