Results of searches.

8822 initial hits were identified on the seven databases (Fig 1: Prisma flowchart). Title and abstract screening focused on 263 potentially relevant articles, with 223 duplicates. With the large number of duplicates, most studies were identified on PubMed and equally on Google Scholar. 40 articles were fully assessed. After application of full inclusion and exclusion criteria, 19 articles were further excluded, mostly since the focus was not VL and its vectors. 21 studies were fully included, with 17 studies assessing effectiveness of IRS (five cRCTs, one RCT, 10 intervention studies in Asia, one intervention study in Latin America) and further three modelling studies and one survey. The last two groups were included, although not directly assessing effectiveness, but informing about the estimated or perceived effects of IRS.

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Fig 1. PRISMA flowchart for searches and inclusion of articles for Systematic Review on the use of indoor residual spraying for visceral leishmaniasis control [13].

https://doi.org/10.1371/journal.pntd.0010391.g001

Description of included studies.

Time and geographical clustering of included studies. Of the 17 included effectiveness studies and four further studies, the vast majority (20/21) were conducted in the geographical context of the Regional Initiative, or even embedded in the Regional Initiative, with only one study [14] from Brazil (Tables 1 and S1). Furthermore, of the five cRCTs, four focused on Bangladesh [4,15,16] of which one was conducted in Bangladesh, India and Nepal [17] and one further study in Nepal only [18]. The only RCT was equally conducted in Nepal [19]. As for the 10 intervention studies in the geographical area of the Regional Initiative, most studies were implemented in India, only Chowdhury (2018) is from Bangladesh and Chowdhury (2011/2) from India and Nepal [20,21].

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Table 1. Summary IRS result table.

https://doi.org/10.1371/journal.pntd.0010391.t001

Similarly, when analysing the time frame of the studies, the studies of the Regional Initiative cluster between 2009 and 2020, with two studies from the 1990s in the region [22,23], but before the Regional Initiative. The study from Brazil was conducted in 2011 (Barata).

Also, the modelling studies and the included survey, are geographically in the Regional Initiative [24–27], and conducted in the 2010s.

Clustering of authors and groups of authors. Most studies, including the modelling studies [24,26,27] (India) and the included survey [25] were either directly conducted with a group of authors affiliated to WHO/TDR, or have been involved with this group and the Regional Initiative (Tables 1 and S1). For the geographical area of the Regional Initiative only the two studies from the 1990s [22,23] were not conducted by the group of authors and/or affiliated to this group. Funding has been provided often by WHO/TDR directly, but also by other funding agencies, such as the Bill and Melinda Gates Foundation, European Union funded programmes, and the Indian Council for Medical Research.

Methods used by the included studies. Of the 17 included studies assessing effectiveness of IRS, the five cRCTs [4,15,16,17,18] and the RCT [19] clearly specify the methodology used, and in detail. However, no internationally recognised standard for the methodology is specified—such as the “extension to cluster randomised trials of the Consort 2010 statement” [28]. Similarly, the 11 intervention studies are not specifying any standard used, and vary in study design, with Intervention-Control designs, Intervention-Intervention designs, and Before-and-After designs.

Furthermore, overall methods in the studies vary as well, since multiple study arms are applied, mixing different methods. As an example, Chowdhury [21] mixes six methodological tools, with formal interviews with district VL officers responsible for the VL control programme, structured observations of the spraying teams-assay-based monitoring of the bio- availability of insecticides, quantification of insecticide concentrations on sprayed walls, tube bioassays for susceptibility of local Phlebotomus argentipes–and monitoring of sandfly densities. Some studies, Huda [4] for example, mix different vector control interventions in one study arm, with the use of IRS and Temephos.

The survey included [25] and the modelling studies [24–27] specify their respective methods, however no standards for methods are used. Also, the focus of each of these studies is different. Hasker [25] is embedded in an ongoing VL cohort study and establishes risk factors for developing VL as a disease, including IRS. Gupta [24] estimates incidence decreases with spatiotemporal models, in relation to an “intensified control strategy”, including the use of IRS. Hasker [26] aims to establish the most appropriate “buffer zone” for perifocal application of IRS, and Stauch [27] estimates transmission thresholds in relation to application of interventions, including IRS.

Sample sizes and follow up periods of the included studies. In general, sample sizes vary considerably between the studies:

Since most cRCTs and RCT have multiple study arms, samples sizes vary also between the study arms (Tables 1 and S1). Huda [4] for example operates in a total of 8143 households (HHs) with 36,869 people. However, the study follows up on VL cases, identifying different levels of VL transmission, and intervening with study arms of “House-to-house active search for cases with VL and PKDL, implementation of IRS with deltamethrin and deployment of larvicide Temephos”, or “fever camps plus installation of durable wall lining impregnated with deltamethrin” or “fever camps plus impregnation of existing bednets with a slow-release insecticide tablet”. Also Cone bioassay tests are performed. The HH sandfly density measurement however is performed in 36 HHs only, in each study arm.

The number of surveyed HHs per cluster is highest with 24 clusters with 120 HHs each [17]. The RCT has 264 intervention and 92 control HHs [19].

The intervention studies also have massive sample sizes for the overall study and a smaller subset of HHs surveyed for entomological assessment, for example Chowdhury [21] operates in districts in India and Nepal, with 116056, 111076 and 5153 HHs respectively, however the entomological assessment was implemented in 40 HHs in each intervention and 10 HHs in the control. Different are the early intervention studies from 1994 [23] and 1996 [22], with smaller intervention and control sites, with for example 77HHs for the intervention and 55 HHs for the control [22].

Follow up periods and measurement vary also considerably, with earlier intervention studies typically measuring a baseline and a follow up measurement one month post IRS [23].

The cRCTs and the RCT have multiple measurements, mostly a baseline and four to five follow up measurements post IRS, up to 12 months (e.g. Huda [4]). However, Chowdhury [15] measures up to 22 months post IRS with nine follow up measurements.

The modelling studies and the survey follow different methodologies and no entomological measurements have been implemented [24–27].

Outcome measures and sampling methods of the included studies. Outcome measures varied according to the objectives of the included studies, and study arms (Tables 1 and S1). For entomological indicators the most commonly used indicator is the total number of Phlebotomus argentipes caught, sometimes total number of sandflies caught. Very few studies further distinguish into female and male Phlebotomus argentipes, and even fewer analyse counts of gravid Phlebotomus argentipes females or fed Phlebotomus argentipes females. Percentage reductions between intervention and control sites are mostly calculated.

Sandfly captures are consistently performed with CDC light traps, older studies, such as Das [18] also use manual mouth aspirator methods and compare the methods. Even older studies, such as Kaul [23] and Mukhopadhyay [22] are relying only on manual aspirator methods.

As for human disease indicators, these are only very seldom measured, and the indicators vary: Huda [4] performs house to house searches for fever cases of more than 2 weeks, and/or for Post Kala Azar Dermal Leishmaniasis (PKDL) skin lesions. Kumar [3] also measured human disease with active case detection/ house to house searches and follow up of fever cases with 39-aminoacid–recombinant kinesin antigen (rK39) rapid diagnostic tests. For the survey [25], identification of VL cases was key objective of the wider cohort study, in which the survey was embedded. VL cases in the cohort study were defined as “a combination of a clinical history typical for VL (fever of >2 weeks’ duration, lack of response to antimalarial drug treatment), a positive result by the rK39 rapid diagnostic test, and a good response to specific VL treatment, with or without confirmation of parasites. Each case reported was verified from medical records by a study physician”. The modelling studies used available surveillance data for human disease indicators.

Insecticides used by the included studies(28). Also, the insecticides used in the studies vary, mostly in line with insecticide development over time and specific to countries (Tables 1 and S1).

DDT is used in the earlier studies in India [22,23], DDT continues to be used in Indian studies only (Joshi [17] for the India arm of the study, Kumar [29], Chowdhury [21] for the Indian arm of the study, Coleman [30], Kumar [31], Poché [32]). Mandal [33], and Kumar [3] switch during the studies from DDT to alpha-Cypermethrin. It needs to be noted that DDT has been banned in Bangladesh since 1998 as it is an environmental hazard [20].

Alpha-Cypermethrin is also used in Bangladesh [15], Brazil [14] and Nepal (Joshi [17] for the Nepal arm of the study, Das [18]).

Deltamethrin is used in Bangladesh only (Joshi [17] for the Bangladesh arm of the study, Chowdhury [16], Chowdhury [20], Banjara [19], Huda [4]). This has been tested in more recent studies, as there was a delay in getting approval for using deltamethrin for sandfly control and reintroducing it through the national programme [20].

Lambda-cyhalothrin is only used in Nepal (Chowdhury [21] for the Nepal arm of the study)

Quality assessment of the included studies. (Table 1: Summary IRS results and S1 Table: Evidence Table)

Quality analysis showed, when measuring against the CONSORT criteria that the RCTs only scored medium high scores, between 11 and 18 of 25 CONSORT criteria are met. Mostly trial registration criteria are not met. But also, processes of randomisation are not fully explained. For the intervention studies, most studies scored between 10.5 to 15.5 of 18 modified CONSORT criteria. The early studies Kaul [23] and Mukhopadhyay [22] only met 5.5 of the 18 criteria.

Entomological indicators.

cRCTs and RCT. In the group of cRCTs and RCT, the studies show mostly very positive results in relation to the main indicator used “total Phlebotomus argentipes” caught, and also considering the different insecticides used for IRS (Table 1: Summary IRS results).

For alpha-Cypermethrin, in the cRCTs and RCT applied in Nepal only, Chowdhury [15] showed reductions of the vector between 14 and 80%, with a considerable effect even at the end of the measurement period (two rounds of IRS). These data were established over a period of up to 22 months, with measurements for the indicator available for up to 15 months. Das [18], with measurements up to five months post IRS, showed Phlebotomus argentipes density decreasing from 11.0 to 0.6 per house per night, labelling therefore IRS highly effective for reducing vector density. Joshi [17] for the Nepal arm of the study shows a reduction of total sandflies captured of 52 and 53% in two different sites.

Deltamethrin is used in Bangladesh only, Joshi [17], for the Bangladesh arm of the study, shows a reduction of 94% of total sandflies caught. Chowdhury [16] showed Rate Ratio reductions to 0.15 after 2 months post IRS compared to control, 0.24 after 5 months. The positive effect of IRS was not detectable any more after 12 months. Huda [4] applied IRS with simultaneous treatment of breeding sites with Temephos, this combination showed even a 74% reduction of female Phlebotomus argentipes captured after 12 months. However, Banjara [19] showed only a reduction of 25.13% of total sandflies caught, after one month. The effect of IRS was not detectable any longer in subsequent measurements.

DDT has only been used by Joshi [17] in India, with a percentage reduction that varied from 52 to 124% of total sandfly captures between sites, with measurements five months post IRS.

Intervention studies. As for DDT (Table 1: Summary IRS results), this is first used in two earlier studies in India [22,23]. These two smaller intervention studies, with control villages, resulted in a reduction of more than 90% of total sandflies caught in the intervention villages in both studies, with measurable effects up to one year post IRS [22,29], in a before and after study, shows a positive effect one month post IRS, in three of four of the study districts: “significant difference in the density of sandflies during pre- and post-spray period in Vaishali, Saran and East Champaran districts (p <0.05) and there was no significant difference in Muzaffarpur district (p> 0.05)”. Chowdhury [21] for the Indian arm of the study, shows reductions of up to 75.36% one month post IRS, which were not sustained afterwards. Coleman [30] also shows a difference between intervention and control villages and total sandflies captures (total sandflies captured at one month post IRS 99 for the intervention villages, 217 for the control villages), and the effect was not observed after one month. Kumar [31] shows over a period of 13 months post IRS, percent reductions of sandfly density between 4.29% - 86.77%. Poché [32] reports a short-lived positive effect of IRS, results “suggest relative Phlebotomus argentipes abundance within IRS treated and untreated villages do not differ significantly”. Mandal [33], and Kumar [3] switch during the studies from DDT to alpha-Cypermethrin: reporting for the former for the initial IRS percentage reductions of total Phlebotomus argentipes captured of 34.1% after two weeks, 25.9% after one month and only 14.1% after three months [33] and similar results by Kumar [3].

Alpha-Cypermethrin was used in these last two studies [3,33] for the subsequent rounds of IRS, with percentage reductions of 90.5% after two weeks, 66.7% after one month and 55.6% after three months [33]. Kumar [3] summarised the follow up of up to three months post IRS as “a significant difference was observed in Phlebotomus argentipes densities collected in sprayed and unsprayed villages during the 15 days, 1 month, and 3 months post-IRS collections (t = 4.6; P <0.01).”

Alpha-Cypermethrin is also used in Brazil [14], targeting predominantly Lutzomyia longipalpis, with positive effects on the vector indoors–and outdoors.

Deltamethrin is used in the intervention studies in Bangladesh only [20], with some reductions of total Phlebotomus argentipes caught, of 22.61% after one month, and 6.73% after five months.

Lambda-cyhalothrin is only used in Nepal (Chowdhury [21] for the Nepal arm of the study), with good percentage reductions in one study area, between 95.73% two weeks post IRS, reduced to 68.29% after 6 months. However, these results were not repeated in another study area, where a sustained percentage reduction was not observed.

Surveys and modelling studies. The studies in this group are very heterogenous.

The survey included [25] (Table 1: Summary IRS results), embedded in a VL cohort study, establishes that reported IRS coverage is poor, and may be a contributing factor to VL incidence (only 12% of all households had been reportedly sprayed).

For the modelling studies, Gupta [24] estimates incidence decreases in relation to an “intensified control strategy”. Part of this strategy is IRS, in this case first using DDT, followed by alpha-Cypermethrin. The authors show that “model simulations suggest a median 1,071 cases (IQR 849–1,333) were averted in Vaishali between March 2015-December 2017.” Hasker [26], analysing the most appropriate “buffer zone” for perifocal application of IRS, concludes that “covering a perimeter of 500m with IRS, seems to be a rational choice”.

Stauch [27], estimating transmission thresholds in relation to application of interventions, including IRS, however, considers “thus, IRS may only be a transient measure to effectively reduce sand fly density”.

Human disease indicators. The studies only seldom measure human disease indicators (Table 1: Summary IRS results), or present surveillance data for human disease indicators. These data are not in direct comparison to IRS intervention, or case numbers are too low for clear measurements.

Huda [4] compares case finding with different methods, without comparing the results directly to IRS intervention only. The authors recommend for programmes to introduce elements of active case finding through index-based fever camps.

Kumar [3] also measured human disease with active case detection/house to house searches and concluded that the elimination strategy achieved its goals “the case reduction rate was increased from 22.6% in 2014 to 58.8% in 2016.”

Hasker [25] studies a cohort in India and follows up on VL cases, the study determines annual incidence of the population, without prospectively analysing IRS as an intervention. However, IRS is established as a potential protective factor of VL.

Crosscutting results. The studies show a trend over time of insecticide use (Table 1: Summary IRS results). DDT is used in India only, over time, very broadly speaking, the studies show a reduced effect on vector populations, from Kaul [23], Mukhopadhyay [22], followed by Kumar [29], Chowdhury [21], Coleman [30], Kumar [31] and Poché [32]. Finally, in the studies by Mandal [33] and Kumar [3], during the studies, the insecticides are changed in the overall programmes, where the studies are embedded in, from DDT to alpha-Cypermethrin.

Alpha-Cypermethrin and Deltamethrin are now the insecticides mostly applied in studies (for the former Joshi [17], Das [18] and Chowdhury [15] (all Nepal), for the latter Joshi [17], Chowdhury [16] and [20], Banjara [19] and Huda [4] (all Bangladesh).

Many studies have several study arms, particularly also assessing insecticide bioavailability and residual activity, using bioassays. These study arms follow the recommendations of the WHO/TDR monitoring and evaluation tool kit for IRS [34]. These study arms, but also study arms to train personnel for quality delivery of IRS—including qualitative study arms, show the importance of quality assurance for IRS. Most of the studies of the Regional Initiative include these different methods, for example for bioassays Kumar [3], Mandal [33], Huda [4], Banajar [18], Chowdhury [20], Kumar [31], Coleman [30], Chowdhury [16,21] and Joshi [17].

Combination of different interventions are also evolving over time in the included studies. Whereas early studies, Kaul [23] and Mudhopadhyay [22], typically test only one intervention, in this case the use of DDT. This is also the case for later studies, as for example Chowdhury [15] and Mandal [33], with study arms examining different interventions, but mostly not adding and combining different interventions in one study arm.

However, later studies also often try combinations of interventions, for example Huda [4] adds Temephos to the use of IRS in one study arm, but also tests different ways to identify VL cases, with one study arm combining fever camps and installation of durable wall lining.

Study design evolves over time. Clearly, early intervention designs, as applied by Kaul [23] and Mukhopadhyay [22] are replaced by cRCTs, with the first cRCT for vector control and VL by Joshi [17]. However, intervention designs continue with later studies, more embedded in existing programmes, and assessing programmes on multiple levels [3,20,21,30].

Gap analysis. When analysing gaps, following hierarchy of evidence principles, and trend over times, a gap analysis of studies assessing effectiveness of IRS for the control of VL shows the following elements:

• From 2009 onwards an increase in numbers of studies is available
• There is a trend over time from intervention studies to more complex studies, with five cRCTs and one RCT included.
• When looking at study questions, these are highly variable, and not always focused on the effectiveness of IRS only.
• When looking at study arms, there are increasingly studies mixing different combinations of interventions. On the other side, there are fewer studies, assessing IRS only. This is more important in the different transmission scenarios, particularly in the Regional Initiative, now mostly entering elimination of VL.
• Human disease parameters are seldom measured.
• Studies are more often embedded in ongoing programmes, with the data available in the programmes.
• When looking at geographical coverage, most included studies were conducted in the countries of the Regional Initiative, namely Bangladesh, India and Nepal (16 of 17 effectiveness studies, and of all studies 18 of 21). There is only one study from Brazil [14]. Notably absent are studies from other VL affected countries, like South Sudan and Sudan. Also absent are studies from the other South-East Asian countries reporting VL cases and sandfly vector population.