13 Fertility Control in Dogs

Simple deterministic model considerations indicate the frailty of current serological screening and culling as the core of control campaigns against zoonotic VL. Thus, knowing fluctuating seroprevalence rates, estimates for serology coverage and failure rates, and the temporal aspect of surveys and the course of canine infection, it is apparent that current methods of serological surveillance and culling alone will still allow canine VL to be sustained and expand (Miles, unpublished observations), as clearly demonstrated by computer modelling of reduction and resurgence of prevalence by Courtenay et al. (2002). In view of these various factors complicating implementation of culling it is not surprising that field trials, which may have inherent design weakness and multiple confounders, have had mixed and partially conflicting results (Nunes et al., 2008, 2010; Quinnell and Courtney, 2009; Romero and Boelaert, 2010). As indicated above, the future success of dog culling as a control strategy will depend on a highly sensitive rapid diagnostic test for field use (Maia and Campino, 2008) and immediate removal of infected dogs, which are not replaced by new susceptible animals, in combination with health education and strong community support. Furthermore, dog culling as a control strategy cannot ignore the immense importance and value that some communities may attach to their domestic and working dogs, with consequent understandable reluctance of such communities to accept full implementation of an optimal culling programme. Control of sandflies with insecticides: an essential element of VL control Sandflies may be extremely abundant in endemic regions of canine VL. In the absence of resistance, sandflies are exquisitely sensitive to insecticides. DDT is effective, as are the synthetic pyrethroids (deltamethrin, permethrin, cypermethrin, and others), which have low toxicity and high residual activity. In localities where malaria and VL are sympatric, spraying against mosquito vectors of malaria can have a dramatic effect on abundance of sandflies and the prevalence of VL. Insecticides are used residually against sandflies, and applied to domestic and peridomestic resting sites. Occasionally, ultralow-volume spraying into the air (fogging) can help to stem epidemic outbreaks of VL. However, this blanket approach only reaches adult sandflies at the time of spraying. For long-term effect, ultra-low-volume spraying must be applied repeatedly, with high coverage of the affected area, and at seasonal peaks of sandfly abundance. Insecticideimpregnated bed nets offer protection against sandflies during sleeping periods at night. Barrier curtains treated with insecticides can restrict access of sandflies to houses. Topical insecticide treatment of dogs (below) may also reduce sandfly numbers. Comparative impact of treating human VL, culling dogs, and vector control Few studies have attempted to assess the relative values of the treatment of clinical cases, the removal of infected dogs, and spraying against sandflies as components of a VL control campaign. Such studies are fraught with difficulty due to complexities of design, multiple potential confounders, and equivocal outputs. Withholding treatment for overt clinical human VL, which is usually fatal if not treated, is clearly not an ethical option as part of comparisons of interventions. Comparative studies in which treatment of human VL is specifically withheld to assess its epidemiological impact are thus not available. Deane and Deane (1962) thought that outbreaks of human VL in Brazil depended on the abundance of the vector Lu. longipalpis, but believed that small sandfly populations could maintain endemic canine VL. Alencar (1961) assessed the impact of sandfly control with insecticides in a comparative study of interventions against human VL. With two groups of communities, he found that the incidence of human VL decreased only when insecticides were used in addition to the treatment of human cases and the removal . of seropositive dogs. This supported Deane and Deane’s view of the significance of sandfly abundance and the importance of vector control. Studies of the impact of serological screening and removal of seropositive dogs are few and limited. The total removal of the dog population has been reported to be an effective control measure in China (Ashford, 1999). Ashford et al. (1998) were able to show a decrease in both the incidence of human VL and seropositivity rates in dogs when 69% of seropositive dogs were removed promptly by using the FAST-ELISA for serology. Failure of compliance did not allow removal of all the seropositive dogs. Akhavan (1996) considered whether control of VL based on the three strategies of treatment of cases, culling of seropositive dogs, and spraying against sandflies, had been effective in north-eastern Brazil. He assumed that epidemics with increasing levels of incidence occurred every 10 years. The total cost of control campaigns was estimated at US$95,000,000. It was further estimated that 68,000 DALYs had been gained, at a cost of US$139 for each DALY recovered. The control campaign in northeastern Brazil has been difficult to sustain continuously. Nevertheless, Akhavan concluded that the campaign had been costeffective. It is not clear, however, what contribution to the campaign is attributable to the culling of seropositive dogs. More recent combination control trials in Brazil are summarized by Romero and Boelaert (2010): one trial showed reduction in incidence of human VL associated with a combination of insecticide spraying and dog culling (de Oliveira et al., 2003), one indicated a partial association (Costa et al., 2007), and a third showed a similar trend but was not significant (de Souza et al., cited in Romero and Boelaert, 2010). Vaccination and immunotherapy: some progress The development of vaccines against human VL has been a research objective for decades, impelled by knowledge that introduction of infective L. major to induce a lesion at a hidden cutaneous site (leishmanization) can protect against subsequent infection and potential facial disfigurement. Nevertheless, there are no attenuated, killed, or recombinant vaccines for human VL, although intensive research efforts continue. Two vaccines have been developed and commercialized for canine VL; their futures are dependent on conclusive demonstration of capacity to prevent severe clinical disease in dogs, and to stop transmission from vaccinated dogs that might acquire subclinical infections. In addition, it is essential that the serological response of vaccinated animals can be distinguished from that of dogs acquiring natural infection, because failure to separate them is a complication of effective surveillance. Leishmune® (Fort Dodge Animal Health, Brazil) is an FML- (fucose-mannose ligand antigenic fraction, of L. donovani) saponin vaccine for canine VL. In Brazilian field trials, the efficacy of Leishmune® was reported to be indicated by FML-seroconversion, skin test positivity, protection against clinical canine VL, blocking of transmission, and associated reduction of incidence of human VL in some but not all localities where vaccination was a supplementary intervention in control programmes (Borja-Cabrera et al., 2008; Palatnik-de-Sousa et al., 2009). Leishimmune® is also reported to have some immunotherapeutic potential (BorjaCabrera et al., 2010) and the immunological response has been characterized in vitro (de Lima et al., 2010). FML-seroconversion did not cross-react significantly with standard ELISA for serological surveillance (de Amorim et al., 2010). Similarly, another candidate, prime boost vaccine DNA/ MVA, did not induce rK39 seroconversion (Carson et al., 2009). In a smaller field trial a L. infantum antigen with muramyldipeptide as adjuvant (LiESAp) was reported as having 92% efficacy, with 1/165 clinical cases in vaccinees versus 12/165 in controls (Lemesre et al., 2007). Several other second-generation vaccines are also under development, with varying degrees of success, including Leish-111f+MPL-SE vaccine which may have some immunotherapeutic potential (Trigo et al., 2010). Topical application of insecticides to dogs: a useful adjunct to control of VL A promising approach to control of canine VL is to use pyrethroids in new ways, such as by dipping hosts or spotting-on insecticides to diminish sandfly attack and to kill biting sandflies (Xiong et al., 1995). Similar systems are effective against other insect vectors, for example in the form of ear tags on cattle. An emulsifiable concentrate of deltramethrin was effective for 5–6 months after application (Courtenay et al., 2009). One approach is the use of pyrethroid-impregnated protective bands for dogs, which slowly release insecticide that spreads over the host. Experimental trials have shown efficacy, and field trials have indicated potential to reduce incidence of canine VL. However, collars are vulnerable to shedding and can only be regarded as a supplementary adjunct to control programmes that deploy the principal means of diagnosis, surveillance, and more orthodox vector control (Killick-Kendrick et al., 1997; Killick-Kendrick 1999; Lucientes, 1999; Aoun et al., 2008; WHO, 2011a). Integration of disease control: not to be overlooked Coordination of control activities across organizations responsible for human and veterinary health or the management of VL is imperative, and various models have been proposed (Arias et al., 1996; WHO, 2011a). Primary health care workers in the community, as well as veterinary surgeons, need to be able to recognize the clinical symptoms of canine VL and to know how to report the presence of canine VL through local health channels. Veterinary surgeons and zoonosis centres or similar organizations need to be equipped to make serological and parasitological diagnoses, and require clear guidelines on how to manage canine VL. Effective liaison between veterinary health authorities and human health authorities is essential, even if human VL has not yet been reported in the locality. This is because sporadic infant cases may go unrecognized, and be fatal. Informed higher-level public health authorities will need to decide whether epidemiological survey for human and canine VL is justified, and if further cases are found whether to begin a coordinated and integrated control campaign. Where rabies surveillance and control campaigns are envisaged or in place, or where there are overlapping interventions against other insect vectors such as mosquitoes, it is essential to communicate across the control programmes and share resources whenever it makes logistic and economic sense. Health education and community support: fundamental to success Health education and mobilization of community resources are fundamental but somewhat neglected areas of control of VL. Knowledge, attitude, and practices (KAP) studies are a useful means of understanding the extent of information on transmission and control of VL that are available to public health professionals, patients, and communities. There are often abundant and diverse levels of harnessing community support for control programmes, and increasing options for communication and health education such as radio, TV, computer, and mobile phone technologies which are dispersed to locations that previously had poor accessibility. Poor socioeconomic conditions associated with propagation of VL may not be altered easily, but other predisposing factors such as environmental degradation and chaotic husbandry of dogs and other domestic animals can be addressed (Marzochi et al., 2009). Community activities can include clinical surveillance and follow-up of treated patients, environmental surveillance, environmental improvement, and assistance with vector and reservoir control, and can be a driving force for behavioural change. zero cost to patients in poor communities, including coverage of ancillary costs of treatment such as secondary chemotherapy or travel to treatment centres. • Serological surveillance of dog populations to detect the presence of canine VL as a predictor of human VL, and to encourage risk reduction and better management of domestic and stray dogs. • Systematic enhancement of health education, communication, community support, and integration of activities by organizations with responsibilities for disease control. • Environmental management and vector control to reduce breeding and abundance of sandflies, where possible implemented by community support. For anthroponotic VL due to L. donovani (responsible for such large epidemic outbreaks on the Indian subcontinent and in the Sudan), case finding, diagnosis, treatment, health education, communication, and community support apply, but not the surveillance and management of dog populations. Among such impoverished, displaced, and highly vulnerable populations there will be limited capacity for community support, and an imperative need to improve nutritional status and to consider multiple complicating factors of such epidemic outbreaks. Conclusions Treatment for canine VL is clearly unsatisfactory. The last-resort method in Europe of prolonged or lifelong allopurinol administration cannot be advocated for widespread use elsewhere, or as a control strategy, especially in view of the risk of sustaining endemicity. There is an urgent need for a cheap, highly effective drug for the treatment of canine VL. The drug should be simple to administer either orally or by few doses given by inoculation. There is a strong case for encouraging veterinary companies to take a research interest in this objective, with its concomitant impact on control of human VL. Clearly, better drugs for treatment of human VL are still desirable. Epidemiological screening for L. infantuminfected dogs should not be abandoned. Nevertheless, considerable improvements are essential if this method is to be effective. In particular, a reliable, specific, highly sensitive, rapid diagnostic test suitable for field use is essential. Such a test may be beyond reach, although new antigens and new formats are still being sought. Some thought could also be devoted to strategies for increasing dog examination rates and compliance with public health recommendations. Were a new treatment suitable for mass therapy to be found, this could virtually eliminate difficulties with compliance. Vaccination is a promising new development, remains a research priority, and requires further proof of efficacy in field trials. Incorporation of Leishmania antigens into the vaccine strain of rabies virus could be explored as a delivery system to provide simultaneous rabies and Leishmania vaccine coverage. In Europe, 50% of human L. infantum infections are associated with HIV coinfection (Alvar et al., 1996; WHO, 2011a), and most of these cases will receive prolonged antileishmanial therapy. In endemic areas in developing countries, some HIV/L. infantum coinfections in the community might provide a new reservoir of infection for sandflies, if not adequately treated, especially in areas where HIV and VL are increasingly sympatric. This may possibly shift the pattern of epidemiology of VL due to L. infantum to be less reliant on the dog as the primary reservoir host. As described above, attention is repeatedly drawn to sandfly abundance as one of the most important factors in transmission of VL. Thousands of sandflies may be caught in a CDC trap during a single night: improved traps incorporating host or sandfly pheromone attractants are worthy of investigation as a method of reducing domestic sandfly infestations. Economic analysis, comparing cost of prevention against the financial loss due to disease, can provide a strong argument for control campaigns against leishmaniasis. A concerted effort is required to improve awareness of canine and human VL among communities and health professionals, and to give impetus to available and proven local and national strategies for control. In launching control programmes, whether at community or national level, these should

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