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Cochrane Database of Systematic Reviews Protocol - Intervention

Control methods for Aedes albopictus and Aedes aegypti

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy of vector control measures against Ae. albopictus and Ae. aegypti in reducing the incidence of viral infections spread by these mosquito species.

Background

Two Aedes mosquito species, Aedes aegypti and Aedes albopictus, are responsible for transmission of several important viral infections, including yellow fever, dengue, chikungunya, and Zika virus. Yellow fever is currently endemic in 47 countries and is responsible for between 29,000 to 60,000 deaths annually (WHO 2016). Dengue‐related deaths are far fewer in number, but the estimated number of apparent cases globally was 58.4 million in 2013 (Stanaway 2016). This is a sharp increase from the estimate in 1990 of 8.3 million (Stanaway 2016). The total number of disability‐adjusted life years (DALYs) lost due to dengue was 1.14 million in 2013 alone (Stanaway 2016). Unlike the globally prevalent diseases mentioned above, both chikungunya and Zika virus infections usually occur in localized outbreaks. However, with increased international travel, they also can cause epidemics across borders (Burt 2017; Sakkas 2016; van Aalst 2017). The full spectrum of disease manifestations in people who are infected with Zika virus is not yet known and its association with microcephaly has recently raised concerns (Smith 2016a). Chikungunya, though rarely fatal, causes significant long‐term morbidity in the form of debilitating arthralgia (van Aalst 2017). In addition to the well‐known diseases mentioned above, these Aedes mosquito species are also the vectors of several other endemic viral infections such as West Nile fever, Mayaro virus infection, and Eastern equine encephalitis virus infection (Daep 2014; Long 2011; Romero 2003).

Many measures have been undertaken, some successfully, to prevent or minimize the number of infections spread by Aedes mosquitoes. Successful vaccination campaigns and legal requirements of countries for international travellers have largely contained the global spread of yellow fever (WHO 2016). For dengue fever, such a solution is long overdue. Currently a vaccine developed by Sanofi‐Pasteur (Dengvaxia) is approved for use in several South‐East Asian countries and it has shown moderate efficacy in children and adolescents (Godói 2017). Its efficacy in adults is not yet known (Godói 2017). Despite the preventive efforts in terms of vaccines, both dengue and yellow fever infections still occur in large numbers on a global scale. Hence other approaches to control the spread of the pathogen, such as vector control, are essential.

The utility of vector control is evident in the case of other infectious diseases, particularly falciparum malaria which had a 40% decline in clinical incidence within a 15‐year period due to successful Anopheles vector control methods in sub‐Saharan Africa (Bhatt 2015).

Description of the condition

The four main infections spread by Ae. albopictus and Ae. aegypti, dengue, yellow fever, chikungunya, and Zika virus, cause considerable morbidity, mortality, and healthcare expenditure in low‐ and middle‐income countries (LMICs).

The origin of Ae. aegypti is probably the African subcontinent. It subsequently spread throughout tropical, subtropical, and temperate climates. This species is currently found in Africa, South and Central America, parts of North America, the Middle East, Southeast Asia, and Oceania including Northern Australia (Powell 2013). It is mainly an urban mosquito that flies low and bites at dusk. These mosquitoes have a high vectorial capacity for dengue, chikungunya, Zika, and yellow fever (Anderson 2007; Manore 2017). Furthermore they have a propensity to breed in containers as well as small spaces, such as between large leaves and stems of vegetation. Ae. aegypti female mosquitoes feed preferentially on humans who are within enclosed spaces, such as houses (Scott 2010).

Ae. albopictus originated in Asia and subsequently spread globally, probably due to human migration, travel, and urbanization. It tolerates broader ranges of temperature and cool climates. This has enabled this mosquito species to survive in more temperate climates. The current distribution of Ae. albopictus mosquitoes is throughout Africa, Asia, South America, and in Pacific and Indian Ocean islands (Hawley 1988). Ae. albopictus is a daytime feeder that has a more cosmopolitan and semi‐urban presence and prefers environments with vegetation (Smith 2016b). Ae. albopictus also breeds in artificial containers and prefers to feed indoors.

Description of the intervention

Mosquito‐borne viral infections can be prevented by boosting host immunity (vaccines) or controlling the vector. Different forms of vector control has been implemented against Aedes spp. with varying success. The principal intervention categories are as follows.

  • Chemical interventions: insecticides, chemical larviciding.

  • Habitat management.

  • Non‐chemical larviciding: larvivorous fish, oil coating, and mass trapping of larvae.

  • Population replacement methods.

  • Genetic techniques.

Insecticides that belong to the chemical classes of pyrethroids, carbamates, organophosphates, and organochlorines can be used for chemical control of mosquitoes (van den Berg 2012). However, organophosphates and pyrethroids (for example, permethrin, deltamethrin, cyfluthrin) are mainly used against Aedes spp. mosquitoes. Insecticides can be used against adult mosquitoes and larvae in forms of space treatment, indoor residual spraying, insecticide‐treated bed nets, and as larvicides (Smith 2016b). These insecticides act on various stages of the mosquito life cycle, such as larval and adult forms. Chemical larviciding is predominantly with Bacillus thuringiensis israelensis (Bti), which is a grampositive, spore‐forming bacterium that is pathogenic to mosquitoes (Goldberg 1977).

Habitat (source) management attempts to reduce mosquito breeding sites by removing potential breeding sites (Gubler 1996). Many countries that face regular epidemics try to enforce these measures by public education or by punitive methods through the legal systems (for example, fines or imprisonments) (Mendes 2014).

Non‐chemical methods of larviciding includes oil coating, mass trapping of larvae, and the use of larvivorous fish (Hurst 2012; Seng 2008). Population control methods, such as the use of Wolbachia spp. as well as genetic manipulation of mosquito populations (for example, introduction of sterile males) are emerging methods of vector control (Alphey 2013; Kean 2015).

How the intervention might work

Insecticides have been used extensively for vector control and have shown to be effective. Dichlorodiphenyltrichloroethane (DDT) was successfully used to eradicate Ae. aegypti from 19 countries between 1947 and early 1960s (Smith 2016b). Eventually DDT resistance emerged and this compound was phased out in mosquito control measures.

Pyrethroids are neurotoxins that prolong the opening of voltage‐gated sodium ion channels of the mosquito (Lund 1981). Historically, pyrethroids were successful in controlling mosquito populations but resistance due to a) mutations in the voltage‐gated sodium ion channel and b) increased detoxification by the mosquito cytochrome p450 monooxygenase system have limited their use (Smith 2016b).

Organophosphates, such as fenthion and malathion, are also neurotoxins that work by irreversibly blocking insect acetylcholinesterase. However, resistance of the Aedes mosquito to commonly used organophosphates has been reported (Polson 2010). The two principal groups of organochlorine insecticides are the DDT‐type compounds and the chlorinated alicyclics. DDT‐type compounds exert their action by preventing deactivation of the sodium channel after depolarization of neurons in the peripheral nervous system, while the chlorinated alicyclics act by inhibition of neurons secreting gamma‐aminobutyric acid (GABAergic neurons) (Coats 1990).

Chemical larviciding involves the use of Bti bacteria. Bti exerts its lethal effects by producing toxic proteins, which are subsequently ingested by the larvae of the target organism (Lacey 2007). These toxins are activated in the gut of the larvae and cause extensive disruption of cell membranes of the organism causing cell death. These toxic proteins demonstrate significant species specificity and do not exert toxic effects on non‐target organisms (Saik 1990).

Habitat management works by reducing mosquito breeding grounds. Countries use a combination of methods, such as grassroots community involvement, coordination of public health systems, health education, and punitive measures in vector control (Mendes 2014). However, by nature, Aedes mosquitoes prefer both urban and semi‐urban areas. In urban areas, breeding places are difficult to eliminate due to overcrowding, pollution, suboptimal waste water drainage, and inappropriate garbage and waste disposal. In semi‐urban areas, there are plenty of natural water collection sites that are also difficult to eliminate.

Non‐chemical methods, such as oil coating and vector trapping, interrupt the life cycle of the vector, thus limiting propagation. In larval traps, which are decoy breeding surfaces, the collected larvae can be destroyed by physical (for example, drying) or other means (chemicals). The utility of oil coating in larval control is limited for Aedes spp. mosquitoes. Larvivorous fish, such as Gambusia affinis, have been known to ingest mosquito larvae and pupae and lower the density of immature vector forms in water bodies. They are successfully used to control larvae of the Anopheles mosquito (Pyke 2005).

Wolbachia spp. are used as a population control method for the Aedes mosquito. Wolbachia is an intracellular, maternally‐inherited, endosymbiotic bacteria found in insects. Wolbachia causes reproductive modifications, such as cytoplasmic incompatability, which results in the generation of unviable offspring when an uninfected female mates with a Wolbachia‐infected male (Zabalou 2004). There is also evidence that It limits dengue and chikungunya viral replication within the vector (Moreira 2009).

Genetic manipulation encompasses several modalities for vector control. The sterile insect technique involves creation and release of sterile males into the environment, reducing the reproductive potential of the target wild population thus eventually reducing the population size. Sterility is induced traditionally by radiation and lately by genetic manipulation. These methods cause death of mosquito offspring following mating. Modifications of this system such as Release of Insects carrying a Dominant Lethal (RIDL) are also in use (Alphey 2013). Genetic strategies for generation of refractory insects include the expression of specific antibodies, peptides, or manipulating cell signalling. For example, RNA manipulation techniques are currently under investigation to reduce arbovirus replication within vectors (Alphey 2013).

Why it is important to do this review

As mentioned above, viral infections spread by Aedes spp. cause significant morbidity and mortality globally. Despite having an effective vaccine for yellow fever, the annual estimated mortality of yellow fever still exceeds 30,000 people (WHO 2016). Although not as deadly as yellow fever, the morbidity caused by dengue infection is also high, with an estimated 60 million infections per annum (Stanaway 2016). The annual incidence of dengue has more than doubled per decade since reliable statistics became available from the latter part of the 20th century (Stanaway 2016). These statistics are only for symptomatic cases and do not include the asymptomatic cases that can also serve as reservoirs for infection at the community level.

While vaccinations (when available) help to reduce the impact of infections, this alone is not enough to stem the existing burden of disease as shown in the case of yellow fever. For dengue, the efficacy of the new vaccine remains to be clarified. For many other viral infections for which Aedes spp. serve as a vector, vaccines are unavailable. Hence it is essential to evaluate the value of vector control measures as a means of reducing disease morbidity and mortality. This evaluation should be in the form of a systematic review to weigh the evidence more objectively for each of the many options available. The efficacy of vaccines can be tested relatively easily due to the low number of choices available and clear outcome measures. However, given the heterogeneity of vector control measures and the difficulty of measuring the impact, a systematic review on vector control is a challenging task. Nevertheless, evidence from such an analysis will be a useful adjunct to decision‐making and for assessing cost effectiveness by public health authorities combating these diseases.

Objectives

To assess the efficacy of vector control measures against Ae. albopictus and Ae. aegypti in reducing the incidence of viral infections spread by these mosquito species.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs), cluster‐RCTs, and quasi‐RCTs. Also, we will include non‐randomized studies that have a concurrent comparison group and are adjusted for baseline characteristics and confounders. Controlled before‐and‐after (CBA) studies with more than one intervention and control sites, and interrupted time series (ITS) trials with at least three data points before and after the intervention will also be included.

Types of participants

Adults and children living in Ae. aegypti and Ae. albopictus endemic areas.

Types of interventions

Intervention

Communities and villages that receive any of the following vector control measures that specifically targeting Ae. albopictus and Ae. aegypti.

  • Chemical interventions: insecticides, chemical larviciding.

  • Habitat management.

  • Non‐chemical larviciding: larvivorous fish, oil coating, and mass trapping of larvae.

  • Population replacement methods.

  • Genetic techniques.

We will include any combinations of the above methods, and health education programmes combined with specific intervention(s).

Control

Existing interventions or no intervention. Existing interventions can be one or a combination of methods listed above that is already in place at the start of the study and applied similarly for control and cases. When there are different combinations of existing interventions that are compared against the new intervention, we will assess them as separate comparisons.

Types of outcome measures

Primary outcomes

  • Number of cases of vector‐borne diseases caused by Ae. albopictus.

  • Number of cases of vector‐borne diseases caused by Ae. aegypti.

Secondary outcomes
Human

  • Mortality from vector‐borne diseases caused by Ae. albopictus in the target area.

  • Mortality from vector‐borne diseases caused by Ae. aegypti in the target area.

For mortality, we will include case‐specific death rates. We will include passive and active case detection where reported. However, we will only combine studies that report similar outcomes in the meta‐analysis. We will count re‐infections as new infections.

Mosquito

  • Containers infested with larvae/pupae; for example, the number of positive containers per 100 houses (Breteau Index) (WHO 2011).

  • When a study does not report the Breteau index, we will use the following measures: house index (houses positive for larvae or pupae, or both), container index (containers specifically designed for water storage infested with larvae/pupae) (WHO 2011).

Adverse effects

  • Any reported adverse outcome or unintended consequences on people or the environment.

Search methods for identification of studies

We will identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). There will be no time limit for the search.

Electronic searches

We will search the following databases using the search terms and strategy described in Appendix 1: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Science Citation Index‐Expanded, Conference proceedings citation index (Web of Science); CAB Abstracts (Web of Science; CINAHL (EBSCOHost); and LILACS (BIREME). We will also search the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for trials in progress, using "Aedes control" as the search terms.

Searching other resources

Conference proceedings

We will search relevant proceedings of the American Society of Tropical Medicine and Hygiene Annual Meeting from 1990 onwards for trial information.

Researchers

We will contact researchers working in the field and the WHO for unpublished and ongoing trials.

Reference lists

We will check the reference lists of existing reviews and of all trials identified by the above methods.

Data collection and analysis

Selection of studies

Two review authors (PW and CR) will independently screen all trials identified by the search strategy and obtain the full‐text reports of potentially relevant studies. We will independently apply the inclusion criteria to the full‐text reports using an eligibility form and will scrutinize publications to ensure each study is included in the Cochrane Review only once. If necessary, we will contact the study authors for clarification. We will resolve any disagreement by consensus in consultation with SR and SDF. We will list all studies excluded after full‐text assessment in a ʽCharacteristics of excluded studies' table. We will illustrate the study selection process in a PRISMA study diagram.

Data extraction and management

Two review authors (PW and CR) will extract data from the selected trials and independently record outcomes in consultation with SR and SDF. We will develop and use a data extraction and assessment form suited for the needs of this review according to Cochrane guidance (Higgins 2011). We will use Review Manager 5 (RevMan 5) for data analysis and storage (RevMan 2014), and create ʽSummary of findings' tables with GRADEpro Guideline Development Tool (GDT) software (GRADEpro 2015). In each of the selected trials, we will identify key information such as demographic and behavioural characteristics of selected populations, existing vector control interventions, trial design, measures taken to minimize bias, interventions offered in different trial arms, duration and frequency of follow‐up, adverse events, and reported outcomes. We will also note the limitations in each of the included studies.

For cluster‐RCTs that adjust for clustering in the analysis, we will extract the measures of effect including the risk ratio, odds ratio, or mean difference.

For cluster‐RCTs that do not adjust for clustering in the analysis, we will use the following approaches.

  • For dichotomous outcomes, the number of patients experiencing each outcome and the number of patients in each treatment group.

  • For count outcomes, the number of outcomes in the treatment and control groups, and the total person time at risk in each group or the rate ratio with a measure of variance.

  • For continuous outcomes, the mean and standard deviation for the treatment and control group.

In addition, we will extract an estimate of the average cluster size and the intra‐cluster correlation coefficient (ICC). If an included study does not report the ICC value we will estimate it from other studies with similar cluster sizes and features. However, we will perform sensitivity analysis to evaluate the impact of the above estimation on the results of the meta‐analysis.

Assessment of risk of bias in included studies

Two review authors (PW and CR) will independently assess the risk of bias for each included study using a ʽRisk of bias' assessment form and the Cochrane ʽRisk of bias' tool. This covers five domains of bias: allocation (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other potential sources of bias. We will resolve any discrepancies between the results of the ʽRisk of bias' analysis through discussion and in consensus with the other review authors. If data are unclear or not reported, we will write to the study authors for clarification.

We will summarize the risk of bias for individual studies in a ʽRisk of bias' table.

We will assess cluster‐RCTs for bias based on the following additional domains.

  • Recruitment bias.

  • Baseline imbalance.

  • Loss of clusters.

  • Incorrect analysis.

  • Comparability with individually randomized trials.

Measures of treatment effect

We will group the included studies by intervention or by combinations of interventions that are commonly used together.

We will express the effect of intervention within studies as relative risk ratio for dichotomous outcomes, rate ratios for count outcomes, and as mean differences for continuous outcomes. We will set the level of statistical significance at P < 0.05. For all results, we will calculate the 95% confidence intervals (CIs). We will perform meta‐analyses if sufficient data are available.

Unit of analysis issues

We will adjust the effect estimates from studies that allocate intervention groups to clusters without adjusting the analysis for clustering by inflating the standard error using the design effect (based on average cluster size and the ICC value).

Dealing with missing data

If there are missing data, we will contact the study authors and request this information.

Assessment of heterogeneity

We will assess the included trials for heterogeneity by all authors with regard to study design, interventions, participant selection and outcome reporting prior to selecting suitable studies to combine in a meta‐analysis. When studies are combined in a meta‐analysis, heterogeneity will be assessed using the I² statistic (Higgins 2011), which examines the percentage of total variation across studies that are due to heterogeneity rather than chance. If the I² statistic value is greater than 50%, we will perform the meta‐analysis using a random‐effects model and we will examine the CIs in the forest plot for overlap.

Assessment of reporting biases

If there is a sufficient number of studies for each primary outcome (greater than 10 trials), we will construct funnel plots to look for evidence of publication bias.

Data synthesis

Two review authors (CR and PW) will analyse the data using RevMan 5 (RevMan 2014). Two review authors (SR and SDF) will independently double check and perform re‐calculations. We will use a fixed‐effect model for combining cluster‐RCTs that adjust for clustering effect (we will use a random‐effects model in instances of heterogeneity). We will not perform meta‐analyses in instances of significant heterogeneity.

Given the broad range of studies that are expected to fit in to the inclusion criteria, we will categorize the RCTs as follows; a) chemical methods, b) physical methods, c) habitat management and d) biological methods including genetic manipulation. Under each category, we will further categorize trials as those directed against adult mosquitoes and those that target immature forms such as larvae.

We anticipate first presenting the data across interventions on the secondary entomological outcomes, and will then examine data on disease‐related outcomes.

Subgroup analysis and investigation of heterogeneity

In the event that we detect heterogeneity in meta‐analysis, we will perform subgroup analyses (participants, outcome measures) to investigate possible explanations for these observations.

  • Chemical interventions: existing resistance, coverage, and methods used (for example, impregnated bednets, spraying).

  • Habitat management: existing endemicity (high, medium, low), type of habitat (natural versus man‐made), method used.

  • Non‐chemical larviciding: species of larvivorous fish species used, coverage, and distribution.

  • Genetic techniques: type of alleles, proteins targeted, size of population manipulation (for example, number of sterile mosquitoes introduced).

Sensitivity analysis

We will perform a sensitivity analysis by excluding studies at high risk of bias and cluster‐RCTs that did not adjust for clustering. We will also perform a best‐case/worse‐case scenario in case of missing data.