The tight relationships existing between malaria epidemiology and land altitude have been extensively studied both in mountain and costal regions [12, 13]. In this Saharevo project, the longitudinal study performed among villagers described with accuracy the seasonality and the intensity on P. falciparum infection there. This survey, based on the analysis of data collected over 10 years, enables in-depth determination of malaria epidemiology in areas of intermediate altitude in order to set up adapted strategy in accordance with current malaria elimination policies in Madagascar.
Introducing a vector control plan in the eastern foothills of Madagascar
Saharevo is located in an intermediate zone in between coastal areas with high-transmission equatorial malaria and highland areas with unstable malaria transmission but malaria epidemic risks . In term of malaria epidemiological patterns, this village displays mesoendemic malaria. Strong seasonal variations of malaria incidence indicate that malaria transmission increases from January – when rainfalls are maximal, and peaks in April – coincident with rainy season completion, before getting back close to zero level. Coincidence between transmission peak and rainy season is related to vectors density and behavior. This is supported by the fact that April is also the season of paddies water-filling, multiplying surfaces for hosting An. funestus breeding sites , the major malaria vector in Saharevo. Thus, altogether, rice field proximity, altitude, and economic status influence malaria prevalence in surrounding communities [15–17].
Before and during the time of this project, no interventions to control vectors have been conducted in the region, since this was not part of the national the national policy for foothills areas at that time. The annual EIR in Saharevo was estimated at 2.78 in 2004 and this indicates a low malaria transmission in the foothills areas of Madagascar, at least when compared to EIR in coastal areas in Madagascar or in other areas in mainland Africa [18, 19]. By contrast, despite the weak transmission, parasitological data presented herein are consistent with a relatively high level of malaria endemicity in Saharevo (Figure 2). As in many rural areas in Madagascar, the poor quality of traditional houses in Saharevo promotes the in and out journey of mosquitoes at ease, especially since no vector control measures have ever been implemented in this zone for more than a decade including the project period. On top of that, the villagers currently display a low immunity against malaria; hence most of mosquito bites are likely to lead to an infection (malaria with or without clinical signs). From our previous study carried out in Mahasolo, located in the western foothills area of Madagascar, a similar high malaria endemicity was also described despite a low malaria transmission level . This particular malaria epidemiological profile in the foothills of Madagascar could be controlled by use of indoor spraying of insecticide and insecticide treated bed nets. Moreover, the success of the vector control in the foothills areas in Madagascar has been proven and admitted since the 1950s [7, 21]. Thus, pursuing efforts in vector control activities will significantly help reducing malaria transmission intensity, malaria incidence and malaria prevalence among population in Saharevo in particular, and in extended foothill areas in general. Therefore, it is clearly stated in the national strategy for malaria control revised in April 2009 that all activities will be strengthened from 2009 to 2012 to achieve malaria elimination in Madagascar. Scaling-up the vector control based on the use of insecticide-treated bed nets and the indoor spraying of insecticides is on top priority.
Introducing new malaria case management in the eastern foothills of Madagascar
Until the final year of the project, P. falciparum was predominant in Saharevo (98% of malaria cases). Chloroquine has been used as the first line treatment and the failure rate to this treatment was more than 15% as reported herein or elsewhere [7, 22, 23]. Even though there was no early treatment failure and mainly late parasitological failures that occurred after day 7, this indicates a limited therapeutic efficacy of this drug. It is only in 2005 that amodiaquine was used. Amodiaquine has revealed its high efficacy in this study which has been used as a reference to lead changing in treatment policy in Madagascar .
The incidence of malaria attacks was the highest in two to four years old children although the prevalence of asymptomatic carriers preferentially affected the five to nine years old group. Before amodiaquine introduction, prevalence of asymptomatic carriers tent to peak three months later than incidence of malaria attacks. This supports that a former malaria attack offers a better tolerance to face further infections. When amodiaquine was used to treat malaria infection in Saharevo, this shift immediately disappeared simultaneously with a minor proportion of asymptomatic carriers (Figure 4), although no significant reduction of malaria incidence could be really observed. This highlights the rapid effect on malariometric parameters following a changing in drug policy. The importance of adopting an efficient treatment was also illustrated. The benefits of amodiaquine use will be definitely implemented with the deployment of the artemisinin-based combination therapy artesunate + amodiaquine. It is worth mentioning that recent articles report how efficacy this combination is, especially in Madagascar [24, 25].
From these observations, drugs clearly play a pivotal role to control malaria and especially to turn towards malaria elimination in Madagascar. Interest of introducing the artesunate + amodiaquine combination relies also on its gametocytocide activity. While 86% of gametocyte carriers were < 15 year old children, forming the main parasite reservoir in Saharevo, such a policy would have an impact on malaria transmission especially in children. At the community level – especially in remote villages in foothill areas, replacing pre-packaged chloroquine by the artesunate + amodiaquine formulation for in-home treatment during rainy season should be a successful approach to ensure an efficient reduction of malaria transmission.
Improving malaria diagnosis in the eastern foothills of Madagascar
In Saharevo, almost 10% of malaria attacks occur with very low parasite load less than 200 parasites/μl. Nevertheless, co-infections with viruses or other pathogens might simultaneously occur. The parasite density required to distinguish malaria attacks from other fever causes is unclear in the context of low transmission intensity . Moreover, diagnosing co-infections and establishing pyrogenic thresholds would be strongly compromised by both practical and public health issues anyway. Most of Malagasy primary health centers can not run diagnosis for bacterial or viral infections due to a lack of equipments and resources. Also, practically, from a public health angle, there is a limited interest to determine malaria pyrogenic threshold especially in regions with seasonal transmission as it is in Saharevo and in Madagascar generally. This point is particularly relevant in the context of malaria elimination policy. Since the transition period preceding proper malaria elimination is expected to be marked by a drop of malaria prevalence and incidence, an increased proportion of malaria attacks with low parasitaemia are expected among the remaining cases both in children and adults, due to the loss and the absence of acquired immunity in the population. Then, Plasmodium sp tracking and screening have to become fundamental aspects for achieving malaria elimination, whilst any malaria case detected has to be treated irrespective of the parasitaemia. This is expected to contribute to the reduction of malaria transmission.
During the malaria transmission season (January – July), almost half of the malaria-presumed fevers were confirmed cases of malaria attacks by microscopy in Saharevo. This even dropped to less than a quarter of them during the low malaria transmission season (August – December). On that basis, in the integrated management of childhood illnesses at the community level or at a heath centres that do not use malaria biological diagnosis, more than half of the cases of fevers may be treated abusively with antimalarial. Providing tools for biological diagnosis of malaria to discriminate non-malaria cases will be crucial to develop case management programs in areas with a malaria epidemiologic context similar to that of Moramanga where Saharevo is. Microscopy is a better choice for health facilities, but rapid diagnostic test can be routinely used at the health facilities and at the community level. With regards to rapid diagnostic test, from recent experiences in Madagascar, detecting pLDH will be helpful for this purpose  since the remanence of pfHRP will increase the proportion of the false positive results .
Towards the application of malaria elimination and the strengthening of malaria control strategies in Madagascar
In Madagascar, importance of studying malaria epidemiology in foothills located at 800 to 1,000 m above the sea relies on that a third of the Malagasy population (approximately 6,623,800 inhabitants) live nowadays in such area. In accordance with the major results of our studies, the MoH plans to extend the vector control to the foothills. Malaria endemicity in intermediate areas is then expected to drop and foothills will progressively become regions prone to malaria epidemics, closer to highlands. This may imply changing in malaria trends while children under five and pregnant women will not be the only vulnerable groups. In this context, lessons from the past would help to adjust strategies in response to the malaria epidemiology evolution. As mentioned above, former success of malaria prevention through DDT indoor spraying occurred between 1940s and 1960s, especially in the highlands and the foothill areas in Madagascar [7, 21]. The sudden interruption of the DDT indoor spraying was a lot responsible of the fatal malaria epidemic in the 1980s that triggered deaths mainly in these regions [7, 29]. From this gloomy experience is highlighted how crucial it is to keep sustaining both cure and prevention to combat malaria. Madagascar can also learn from the experiences in other countries that reached a significant malaria reduction for making malaria policy change successful [30–33].