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Background: Madagascar, as other malaria endemic countries, depends mainly on international funding for the implementation of malaria control interventions (MCI). As these funds no longer increase, policy makers need to know whether these MCI actually provide the expected protection. This study aimed at measuring the effectiveness of MCI deployed in all transmission patterns of Madagascar in 2012-2013 against the occurrence of clinical malaria cases. Methods: From September 2012 to August 2013, patients consulting for non-complicated malaria in 31 sentinel health centres (SHC) were asked to answer a short questionnaire about long-lasting insecticidal nets (LLIN) use, indoor residual spraying (IRS) in the household and intermittent preventive treatment of pregnant women (IPTp) intake. Controls were healthy all-ages individuals sampled from a concurrent cross-sectional survey conducted in areas surrounding the SHC. Cases and controls were retained in the database if they were resident of the same communes. The association between Plasmodium infection and exposure to MCI was calculated by multivariate multilevel models, and the protective effectiveness (PE) of an intervention was defined as 1 minus the odds ratio of this association. Results: Data about 841 cases (out of 6760 cases observed in SHC) and 8284 controls was collected. The regular use of LLIN provided a significant 51 % PE (95 % CI [16-71]) in multivariate analysis, excluding in one transmission pattern where PE was -11 % (95 % CI [-251 to 65]) in univariate analysis. The PE of IRS was 51 % (95 % CI [31-65]), and the PE of exposure to both regular use of LLIN and IRS was 72 % (95 % CI [28-89]) in multivariate analyses. Vector control interventions avoided yearly over 100,000 clinical cases of malaria in Madagascar. The maternal PE of IPTp was 73 %. Conclusions: In Madagascar, LLIN and IRS had good PE against clinical malaria. These results may apply to other countries with similar transmission profiles, but such case-control surveys could be recommended to identify local failures in the effectiveness of MCI.
Districts of Madagascar are divided into five main operational zones (Fig. 1), which correspond to the transmission patterns of Madagascar [11]. The two coastal regions exhibit hyperendemic patterns with a transmission lasting all year in the East and more than 6 months per year in the West. In the central highlands, the transmission is unstable, and episodic or epidemic. In the fringe areas, i.e. at intermediate altitudes, the transmission pattern is seasonal, lasting from November to May (rainy season). In the South, the period of transmission is short and episodic. Fringe, central highlands and South are prone to outbreaks. SHC and malaria transmission patterns in Madagascar The selection of study sites was based on a network of sentinel health centres (SHC) for surveillance of fever-associated diseases that has been established in order to cover all the ecosystems of Madagascar [12]. Each location where at least one SHC existed in 2012 was included in the study, thus defining 31 study sites. All malaria transmission patterns were represented: 13 sites were located in the Western transmission pattern, seven in the East, five in the Fringe, four in the Central Highlands and two in the South (Fig. 1). These patterns encompass respectively 21.0, 27.5, 13.7, 31.9 and 5.9 % of Malagasy population. The design consisted in recruiting non-complicated clinical malaria cases in health facilities belonging to the SHC network, and controls in the population living in their catching same areas. All 31 SHCs were proposed to participate in the study protocol. In the participating SHCs, patients presenting with clinical malaria cases or their tutors were asked to answer a short one-page questionnaire about socio-demographic data and exposure to MCIs: LLIN, IRS and IPTp. Inclusion criteria were (1) fever, i.e., axillary temperature ≥37.5 °C [13] or self-reported symptoms of fever; (2) RDT or microscopy positive for any Plasmodium species; (3) age ≥6 months; and (4) informed consent of the patient or his/her tutor. CareStart® Malaria RDT (Access Bio Inc., Monmouth Junction (NJ), USA) was used, which is the RDT commonly used in the public health system in Madagascar. Cases were retained in the database if they came from the same commune as controls. Data were collected from September 2012 to August 2013. Controls were selected from a cross-sectional survey (CSS), which took place in the same areas in the context of the very same MEDALI project, between September 2012 and January 2013. The methodology of this CSS has been previously described [10]. Briefly, it was a cross-sectional household survey in which a two-stage cluster sampling technique was used to randomly select two fokontanys (smallest administrative subdivision in Madagascar) near each SHC. In each fokontany, the investigators followed a random path to include 50 households, i.e. approximately 225 individuals per site. The sample size of controls was calculated for a concomitant cross-sectional survey, leaving controls in excess [10, 14, 15]. Heads of households and all members of the household eligible for the survey were interviewed about socio-demographic features and exposure to MCIs, their axillary temperature was measured, and a RDT (CareStart® Malaria) was performed. Inclusion criteria were: (1) age ≥6 months, (2) having signed individual informed consent including agreement for blood sampling, and (3) being able to take a per os treatment in case of positive RDT. Parents or tutors signed and answered the questionnaire for minors and impaired individuals. Controls were retained in the database if they came from the same commune as cases, if they were permanent residents of the household, and if they had no malaria at the time of survey (i.e. fever or history of fever, and RDT or microscopy positive for any Plasmodium species), or in the last 3 months (i.e. diagnosis of malaria, or history of fever treated with anti-malarial drugs, or history of fever with unknown management). The primary objective for sample size calculation was to detect the association between occurrence of clinical malaria due to any Plasmodium species, and exposure to MCI. It was assumed that at least three controls would be found for each case. A sample size of 800 cases and 2400 controls has a power of 87, 70, and 49 % for detecting OR of 0.7, 0.75 and 0.8, respectively, considering the following parameters: coverage of intervention of 50 % in controls, cluster effect of 2, and alpha risk of 5 % [16]. Bed net use was defined as “use every night during last 3 months” because it is more stringent than the “last night” definition [10, 14]. The association between exposure to MCIs and being a case was estimated by generalized estimating equations models (GEE) taking into account an exchangeable within-site correlation structure using gee function on R software [17]. GEE models allow for a robust estimation of ORs and their confidence intervals while controlling for clustering [9]. Controls were neither matched with cases nor limited to three controls per case, but adjustment variables (age, sex, and transmission pattern) were forced in all models. All multivariate model fits were evaluated using binned residual plots [18, 19]. Whether malaria transmission pattern, age less than 5 years, or season of detection of cases influenced the effectiveness of MCI was tested by introducing interaction terms in the models. Whenever season modified the effectiveness measured, the analysis was rerun on the cases that occurred in the same quarter as the collection of data on controls. The protective effectiveness (PE) of an intervention was defined as 1 minus the odds ratio of the exposure to this intervention as suggested previously [8]. In order to evaluate the number of clinical cases of malaria prevented by each MCI with significant PE, the PE value was first multiplied by the coverage of the MCI in the general population, thus giving the proportion of cases avoided or “community effectiveness” (CE), as described previously [8]. The estimated number of cases avoided was defined as the annual number of clinical cases multiplied by CE/(1 − CE). Coverage values were extracted from the concomitant CSS mentioned previously [10], and number of malaria cases in 2011 by districts was provided by the National Malaria Control Programme. All surveys followed ethical principles according to the Helsinki Declaration. Informed consent was obtained from the individuals, or the parents/tutors of the children before inclusion. The protocol was approved by the National Ethic Committee of the Ministry of Public Health of Madagascar (approval #CNE 57/MSANP/CE of July 24th, 2012).
