A systematic, realist review of zooprophylaxis for malaria control

Despite renewed commitments and control efforts in recent years [1‐3] malaria continues to be a major contributor to global health burden, with approximately 165 million cases in 2013 [4]. Integrated vector management (IVM) has been promoted as a sustainable approach to combat malaria [5, 6] in the face of increasing insecticide resistance of malaria vectors, and environmental and health concerns [5, 7]. This strategy involves combining chemical and non-chemical interventions targeted to specific ecological settings in a way that maximizes efficacy while minimizing cost and negative environmental impacts [5]. IVM makes use of environmental modification, environmental manipulation, chemical control methods, and biological methods [5] (Table 1).

Strategic placement of livestock sheds or pens has also been proposed as a component of IVM to reduce contact between vectors and human hosts [8, 9]. The World Health Organization (WHO) began recommending this type of intervention in 1982 as a method to divert mosquitoes from human populations [10]. This purposeful use of livestock (i.e. as dead-end hosts) to divert mosquitoes away from humans is described as active zooprophylaxis. Passive zooprophylaxis occurs where normal presence of livestock draws mosquitoes away from humans [11]. Insecticide zooprophylaxis, more commonly described in tsetse fly control, involves the use of insecticide-treated cattle and has also been investigated for the control of malaria vectors [12‐15].

There remains considerable debate regarding the efficacy of zooprophylaxis [10, 11, 16‐20]. In addition to the literature supporting zooprophylaxis [21, 22], there is evidence that supports zoopotentiation; livestock presence may actually increase malaria transmission by creating additional blood meal sources, which, in turn, can increase vector lifespan and population density [10, 11, 16]. Due to the divergent nature of the literature and the complexity of the relationship between livestock and malaria prevalence, there has been a reluctance to employ zooprophylaxis in control programmes [8, 23, 24].

The goal of this paper was to characterize and critically assess the potential for zooprophylaxis to reduce malaria transmission, with specific attention paid to the contexts under which it may be an effective component of IVM. The strategic framework for IVM calls for evidence-based decision-making in the selection of appropriate interventions that acknowledge the local context, including vector ecology, epidemiology and socio-economic factors [5].

A modified systematic review methodology, employing realist approaches [25, 26] was applied to the self-identifying zooprophylaxis literature. This approach recognizes a priori that the scientific literature in this area is conflicting and in this case focuses on when, why, and in what contexts zooprophylaxis or zoopotentiation may occur. A meta-analysis, was not feasible due to the variety of study designs (including both observational and experimental designs) and outcome measures employed in this research area. ISI Web of knowledge, CAB Direct and PubMed databases were searched in December 2014 using the keywords ‘zooprophylaxis’ and ‘zoopotentiation’. While this invariably excluded studies of malaria risk factors that consider the presence of animals, but did not self-identify using the terms ‘zoopotentiation’ or ‘zooprophylaxis’, the search was limited to these explicit terms for two reasons: (1) to select a proxy sample of the key literature explicitly emphasizing and investigating zooprophylaxis, more likely to provide direct discussion, consideration of causal pathways of association and depth regarding the role of animals in malaria transmission; and, (2) to limit the number of results to a feasible and directly relevant sample for in-depth realist analysis. This search retrieved 75 documents after removal of duplicates. Only empirical, peer-reviewed articles that focused on either malaria infection in humans or mosquito behaviour associated with livestock presence were reviewed. Mathematical models of mosquito behaviour and review articles were excluded from the synthesis but their content was assessed to provide context for interpretation of results (Table 2). A total of 20 articles met final inclusion criteria and were retained for critical appraisal after full article review (Fig. 1). Forward and backward citation tracking were applied to the articles selected for critical appraisal with one additional relevant article identified.

Data extraction from each article included author, date of publication, study location, livestock exposure, malaria risk outcome measures, study design, and study limitations. Published results reporting significant associations at the 95% confidence level were classified as supporting a significant zooprophylaxis or zoopotentiation effect. Critical appraisal [27] resulted in the exclusion of 14 articles. Reasons for exclusion (Additional file 1) were related to data analysis such as a lack of evidence of statistical significance [28, 29], and pooling of data preventing conclusions from being made on the effect of livestock on malaria risk [30]. Others were excluded based on study design issues, such as the absence of a comparison group [31] and small sample sizes [32]. The pertinent results and conclusions of each study were analysed with regard to the associations between livestock and malaria risk.

This systematic realist review points to three key findings regarding the context under which zooprophylaxis may be utilized as a component of IVM. First, zooprophylaxis is most likely to be effective when the mosquito species present do not have a strong preference for human hosts. Second, in order to take advantage of mosquito preference for animals, animals must be kept out of human sleeping quarters at night. There is evidence that even in the context of mosquito species with preference for animal hosts, close proximity to humans at night may result in zoopotentiation. Third, where bed nets are used, mosquitoes are more likely to feed on animal hosts as an alternative.

Proximity of livestock to humans at night has been identified as an important factor in zooprophylaxis [45]. What remains unclear is the appropriate distance at which livestock should be kept in order to promote zooprophylaxis or prevent zoopotentiation. It is also unknown whether this distance differs between regions, species and contexts. Incidence rates of Plasmodium vivax were reduced in Sri Lankan households where cattle sheds were located within 70 m of the home when wealth, bed nets and other protective measures were considered; however, this effect was weak (RR 0.70, 95% CI 0.47–1.03) [46]. Current evidence supports the exclusion of animals from human dwellings at night, particularly where mosquito species are zoophilic. Improved estimation and precision around appropriate livestock proximities would benefit from the inclusion of livestock species, their number and location, and use of bed nets or other malaria prophylaxis in future studies.

Mosquito species characteristics were also identified as a key predictor of zooprophylaxis and zoopotentiation. Highly anthropophilic species were generally unaffected by the presence or absence of livestock whereas zoophilic and opportunistic species may be deterred from humans in the presence of alternative hosts. This is consistent with a model by Saul predicting that for vectors with a low human biting index, an increase in animal host density can significantly decrease disease transmission, while the same did not hold for weakly zoophilic species [18]. Similarly, Franco et al. predict that in the presence of moderately zoophilic vectors, such as An. arabiensis, the introduction of livestock would increase malaria transmission except in two cases: (1) where vector carrying capacity has already been reached in the system and the addition of livestock hosts does not increase vector density; and, (2) where livestock density and availability are so great as to counteract the effect of increased vector density associated with the introduction of livestock [47].

With regard to the impact of bed nets, since the rate of disease transmission is dependent upon host species interaction, any intervention that decreases contact between host and vector will decrease the risk of infection [5]. This has been corroborated by mathematical transmission models which find that while increased cattle density can decrease malaria transmission when sufficient animals are present and are housed separately, the most successful reduction transmission occurs when personal protective measures are also employed [18, 39]. Where accessibility of humans relative to animals is decreased, it is predicted that malaria prevalence and number of bites will decrease [18, 47]. Time of biting and human behaviour may also have an impact on the effectiveness of bed nets. If people are outdoors during peak biting times, bed nets will not provide protection against mosquito bites [21].

Socio-economic factors may be important unmeasured confounders in studies of zooprophylaxis. Risk factors for malaria are related to poverty through limited access to preventative measures such as bed nets, screened windows, closed roofing, and adequate health care [48]. Livestock ownership is also associated with increased socio-economic status, especially among the rural poor [49‐51]. It has been suggested that in addition to zooprophylactic effects, livestock may be a confounder for reduced malaria risk as those who own livestock may also be able to afford preventative and treatment measures [10] or have better overall health and nutritional status [51, 52]. Households keeping animals indoors at night may represent those who are financially restricted from providing alternative livestock shelters, further complicating the inter-relationships between wealth and animal ownership in malaria transmission.