Meta-analysis of studies on chemical, physical and biological agents in the control of Aedes aegypti

Aedes aegypti is a species of international concern because it can transmit to humans three important arboviral diseases: yellow fever, dengue and chikungunya, which have spread to all continents. The main one of these is still dengue, whose incidence has increased 30 fold in the past 50 years, with increasing geographic expansion to new countries. In the last 10 years it has also expanded to smaller towns and rural areas [1].

In Brazil, A. aegypti is found distributed throughout the country, with a circulation record of three serotypes of the dengue virus (DENV) [2], a situation that increases the risk of severe forms of the disease, the lethality rate and the number of deaths [3].

The prevention of dengue depends on the control of its vector to interrupt the chain of transmission and, probably, this strategy will continue to be the main one, even when an effective vaccine against the virus is implemented [4], together with other strategies, such as the blockage of viral transmission by the bacteria Wolbachia in infected mosquitoes [5].

In general, vector control can be carried out, using a chemical, physical, biological, or an integrated approach, and the components of this system include entomological surveillance, source reduction (or environmental management), biological control, chemical control, with the use of insecticides and repellents; traps and insecticide resistance management [6].

In Brazil, since 1947, the year diphenyltrichloroethane (DDT) was introduced to Public Health campaigns, synthetic insecticides were adopted as a form of priority vector control [7]. However, the epidemics that are repeated year after year in various urban centers indicate that there are flaws in the control, allowing the vector to continue expanding [8].

A Systematic Review Study with Meta-Analysis was carried out, which aimed to combine studies on a given topic without bias, and group the individual data for each one [9].

The searches were done through the Capes Portal of journals (Portal de periódicos da Capes) which located articles in the databases, Scopus, Medline, SciVerse Science Direct, OneFile, Science Citation Index Expanded, Pubmed Central, PLoS, SpringerLink, Directory of Open Access Journals, Dialnet, SciELO, and SciELO Brazil.

Journal articles on control strategies that did not include field testing, and exclusively on entomological surveillance were excluded.

Data were statistically analyzed using the program Bio-Stat 5.0, which allowed meta-analysis of the studies using the p-value application (pw, combined), since the level of significance was the only result comparable and common to 22 of 26 articles analyzed. The p-value for each study was converted into a Naperian logarithm, and applying, in the end, a chi-square test for obtaining the combined value (w = pooled).

To control publication bias the following steps were adopted: 1. The definition of the formulated question should be clear, direct and objective. 2. The selection of the articles used in the study should be made according to the relevance of the articles and to their relation to the formulated question. 3. The selection of the relevant articles should be in accordance with the inclusion and exclusion criteria. 4. The data compilation should be done by the reading and categorization of the relevant articles. 5. Careful assessment should be made on the relevance of the topic that is being discussed in the selected articles with the formulated question in the study. 6. Careful association should be made among the results of studies, using as a parameter, the relevance of the selected articles with the addressed theme in the research and its scientific evidence. 7. Thematic variation should be made among the studies selected stressing the validity of their evidence in order to answer the formulated question. 8. Assessment must be made of how much of the data from the selected articles may be generalized in order to be used as statistics sources for the methodological design and for the systematic review.

The control of A. aegypti is a complex task, because the permanence of this vector on the human environment is associated with local eco-bio-social factors. Among these factors, the lack of infrastructure in urban centers and the difficulties in securing water supplies and regular garbage collection represented a major challenge. When not overcome, this confines the city to a permanent state of vulnerability, conditioning the population to offer mosquitoes highly productive breeding grounds, such as drums and water storage tanks, coupled with large quantities of artificial breeding grounds, such as plastic bottles, cans and other receptacles [36].

Of all the strategies analyzed those applied in an integrated form represented the most effective control. The World Health Organization (WHO) recommends Integrated Vector Management (IVM) as an ideal control program. It is defined as “a rational decision-making process for the optimal use of resources for vector control. The approach seeks to improve the efficacy, cost-effectiveness, ecological soundness and sustainability of disease-vector control” [37].

In the studies analyzed, only one described a control strategy similar to the IVM program as proposed by the WHO, incorporating four elements: (1) a combined vertical and horizontal approach that depends on community understanding; (2) prioritized control, according to the larval productivity of major habitat types; (3) use of a predacious biological control agent; delivered by (4) community activities of health volunteers, schools, and the public [18].

A multicenter study done in Asia was conducted between 2006 and 2011 in urban and peri-urban areas of six countries, and where it was considered an eco-bio-social approach, generated evidence relevant to the adoption of controls based on the principles of IVM. The results suggest that for a more sustainable control there should be involvement of several partners, including the local community; the interventions should be directed at a significant reduction of infestation in breeding areas; adoption of new non-insecticidal tools such as lids or container covers and predators of the vector [4].

Corroborating the above authors, a meta-analysis of interventions for vector control of dengue in developing countries, the current authors found that the integrated management was the most effective in reducing HI, BI and infestations in containers [38]. However, in contrast, another review [39] pointed out biological interventions as the most successful and sustainable, according to Mulla’s percent reductions (100–(Control 1⁄Treated · Treated 2 ⁄Control 2) · 100).

In this review, successful strategies by biological control agents was also observed, but it is difficult to pinpoint the most effective agent because the studies lacked standardized predictor variables, for example, species, number of specimens and frequency of replacement of containers, physical-chemical quality of the water and time monitoring. However, one can see that among the fish, Betta showed a superior performance to Poecilia [13‐15], mainly against resistance. Studies performed in Brazil, employing fish/containers, and reposition of fish was programmed according to the visits of health agents, once every 2 months, in the majority of cases. After 6 months the presence of fish in the containers had been reduced to 13.5 % [13, 14], due, probably, to the long interval between visits and inefficient reposition.

In the studies with Poecilia, the amount of fish/container was greater (2–3/container, in Cambodia and 10–15/container in India) and reposition could be performed when necessary. Thus, after one year, the fish were still present in 56.9 and 86 % of the containers, respectively [15, 16].

For the adoption of biological control interventions, local cultural, social and environmental characteristics should be considered, because the success of the strategy is affected by such factors as: population adherence, types of water storage containers, water quality and species adaptation to climatic conditions.

The reviews of Ballenger-Browning and Elder [39] pointed out the advantages and limitations of biological control. It was found that bacteria and copepods were well tolerated by the community, lethal only to the target vector, and not contaminating the environment as insecticides do. To corroborate thisstatement, there is as an example of a successful strategy employed in Vietnam, where endemic species of copepods and fish were selected, from natural and artificial national reservoirs [17].

The main disadvantages are associated with the intense work to maintain the organisms in the containers that depend on the above environmental factors, in addition to the emptying of reservoirs, escape or death of the organisms [39]. It should be emphasized that communities are usually against using fish in their drinking containers.

In the case of fish, one of the most influential environmental problems on performance of a species is its resistance to temperature and to the physicochemical characteristics of the water, especially to chlorine. Studies in Brazil evaluating the resistance of Betta to these factors revealed that, under laboratory conditions, the fish survived without any discomfort at a chlorine concentration of 1.0 mg/L and 75 % of them survived at a concentration of 1.50 mg/L [40]. Under field conditions, over 97 % of them survived for a period of 45 to 60 days [13].

Regarding tolerance to the larvicides used in the routine program, Betta showed greater resistance compared to the larvae-eating fish species Trichogaster trichopterus and Poecilia reticulata [41].

Studies comparing the action of Bti, a larvicidal produced from the bacteria Bacillus thuringiensis with Betta and chemical larvicides showed a less effective action of this product [13, 20]. We also realized that the commercial brand of Bti had a strong influence on the larvicidal effect, with Bactivec® being more effective than Vectobac® [19]. Bti showed good results in association with ovitraps, with incremental action, making the collecting network safer for the human being and more lethal to the mosquitoes [20, 33]. Just like any other form of biological control, the use of Bti in ovitraps also requires more frequent maintenance, due to its low persistence.

The longevity of an intervention is of utmost importance to public health, especially those that prioritize the use of insecticides, because those that were short-lived generate a series of negative economic, social and operational effects, such as increased human exposure to these products, increasedwaste disposal impacts on the environment and selection for more resistant mosquitoes.

Evaluations of programs that used only insecticides indicated that few succeeded for more than a year, except in Thailand in the ‘70. The best performance was achieved using the organophosphate fenitrothion at ULV, which lowered the BI to 90.7 % after 17 months [27]. As this is an intervention made for over 40 years, many factors may have influenced this result, e.g. the absence of resistance of Aedes to organophosphates, which is currently present in various parts of the world.

In the latest programs, triflumuron, a growth regulator belonging to the benzoylurea group showed the best performance, inhibiting the emergence of adult mosquitoes for up to 12 weeks. However, the field test was conducted with a small sample (5 replica buckets of 2 L each) [28]. Permethrin and pyriproxyfen (ULV and fumigation) were effective, except that after three weeks, vector infestation indexes, observed before the intervention, were restored [26].

Special applications (spraying) at ULV continued to be indicated for emergency situations [38], but several studies showed that the success of these interventions is associated with community involvement [39].

Studies show that the use of insecticides for some years is being criticized, especially regarding spatial application, partially explained by its negative impacts on environmental and human health, in addition to widespread insecticide resistance in the vector. This resulted in a change in policy for the use of insecticides, which led to the prioritization of focal treatment and impregnation of materials used as physical barriers (curtains, container covers, bednets, etc.). These protection measures generate an additional benefit, because they can also protect residents against the vectors of other diseases, such as malaria, leishmaniasis and Chagas’s disease [38, 42].

In these cases, it is observed that the use of insecticides impregnated in some materials obtained more success than when used alone. On curtains for example, deltamethrin caused mortality of adults for as long as 18 months [22] and in container covers treated with permethrin, the treatment persisted for more than 5 months [10].

In this review, we noticed that in several studies, even in the absence of analysis of the effect of community involvement, the implementation of some measures was shown to be directly dependent on community participation, e.g. elimination of breeding places, maintenance and care of fish [13‐16, 29], curtains [21, 22], lids and covers [10, 32, 34].

In three studies, the effectiveness of community involvement was assessed in the form of an educational campaign, associated with or compared to other interventions [16, 24, 35]. The measure evaluated alone did not show significant results, but when associated, it contributed to the reduction of vector infestation or enhanced the effectiveness of other interventions. This corroborates the findings of other authors when they suggest that social mobilization is essential for the sustainability of control methods [39].

Some countries have experienced the empowerment of the community in vector control and obtained satisfactory results, with the programs of greatest impact, being those implemented in Vietnam, which reported the expansion of a community-based strategy from 6 to 46 communities, resulting in the elimination of the vector in 40 of the communities, and in Cuba, where for 2 years the BI remained 53 % lower as compared to areas without intervention [43, 44].

Of the integrated control strategies, two are noticeable. The first one implemented in Argentina, based on the adoption of three different classes of insecticides, two being larvicides, one biological and one chemical (Bti and temephos, respectively), complemented with environmental management and the application of adulticides in ULV (pyrethroids) showed a result that was the most impactful in reducing the incidence of dengue for a more extended period of time (60 months) [11]. The second one, implemented in Vietnam, stood out because it promoted vector control in a sustainable way and for an extended time, using the available natural resources, i.e. endemic mosquitoes larvae predators in aquatic collections and community participation, either civil, scholar or health agents. Because the copepods were known by the population, the adhering to the program facilitated both their implementation and maintenance [18].

Assessing the effectiveness of a control program has to consider the indicators of success of the strategy within the eco-bio-social context. Otherwise, the simple reproducibility of a program that was successful in one location may not provide the same results in another. This may explain the discrepancy observed in some articles on the use of similar control measures, but with different results.

Considering the results of this meta-analysis as parameters to evaluate the performance of biological, chemical and integrated control strategies, we observed that the chemical controls alone showed the worst performance, while the integrated strategy showed the best.

The most successful integrated strategies used different approaches to attack A. aegypti. Considering the main ones, one used insecticides, another, natural predators, but both had components in common: the community involvement, not only as receivers of information, but as active agents of vector control, and environmental management, thereby recognizing the influence of eco-bio-social determinants in the virus-vector-human epidemiological chain. These components, probably ensured the sustainability of programs, and on the basis of the results achieved, we suggest the adoption of integrated control of A. aegypti including these factors.