Calculations of the mortality rate in some villages surrounding the river Isère gave evidence of a rapid and significant increase in deaths in stable populations between 1828 and 1843 (Table 1). This increase in mortality rate (+ 21% in Aiton to + 167% in Notre-Dame-des-Millières for 15 years) was not observed in the population of the rest of France for the same period (from 2.51 to 2.35: – 6%) 2122, suggesting that the phenomenon was geographically localized.

At this time, local doctors explained this increase in mortality in the valley by a bad flow of the streams in the flood-plain, due to a neglect of maintenance of hydraulic developments 25. Two reasons were advanced for the increase of marsh fever transmission in the population: first, the embankment operation of the river Arc resulted in the raising of the water level, not suitable for the discharge of the tributaries; and second, the artificial silting of the waterholes on the sides of the dike was not undertaken.

Registered data from the psychiatric hospital of Betton, in the vicinity of Aiton, provided important testimony of fever progression in the locality for this period 26. The hospital was opened in 1828 in a place reported as free from marsh fever by a medical investigation. In 1834, the medical staff of Betton hospital noticed that residents and employees were suffering from intermittent fever. The unhealthiness of the area was explained by the foul discharge from the local river Gelon (Figure 1), due to previous flooding management of local streams. In 1842, the hospital doctor reported that, despite the abundant prescription of quinine, 20 of the 135 patients died affected by fever in the same year.

These reports and the description of fever are consistent with the likelihood of malaria infections both in hospital residents and in the local population. Malaria transmission by Anopheles mosquitoes was, therefore, probably an additional factor causing the death of sick people in the area.

Anopheline populations of Alpine valleys were probably not monitored in the 19^th century, as malariologists did not consider them to be involved in malaria transmission before the work of Ross (1897) and Grassi (1898). Alpine Anopheles were first studied in the 20^th century. There are 13 French Anopheline species 27 and most of them are not considered to be anthropophilic, except Anopheles labranchiae, Anopheles superpictus and Anopheles sacharovi, which are only found in Corsica. These species are known to have been primary vectors of P. vivax malaria in Mediterranean countries. This suggests that Corsica had malariogenic potential 28. A recent study in the Camargue reports the anthropophilic behaviour and spectacular aggressivity of Anopheles hircanus, which is abundant in southern France, but not observed in Alpine valleys 15. The species An. atroparvus feeds on mammals and humans. It was implicated in the transmission of malaria in continental France until 1943 and was still responsible for nuisance in Alpine valleys in the 1980s 2930. Studies showed that adults were not successfully infected by older European strains of P. falciparumbefore its eradication 69, but that they were sensitive to P. vivax 313233. No relevant density was observed and the species seemed to have been progressively replaced by zoophilic Anopheles messeae in the Rhône-Alpes area since the end of the 19^th century 34. Species considered as occasional malaria vectors (i.e. Anopheles claviger, An. messeae and Anopheles plumbeus) are currently found in the area. Autochthonous cases of malaria transmission have been attributed to An. plumbeus in England and Germany 3536 and infectivity experiments have confirmed the sensitivity of European An. plumbeus to African strains of P. falciparum. This species was responsible for nuisance every summer in some towns of the Rhône-Alpes region (D. Rey, Entente Interdépartementale pour la Démoustication, personal communication).Anopheles messeae and An. claviger are considered to be zoophilic but could have been implicated as secondary vectors in malaria transmission.

There is no doubt that malaria vectors were present in Alpine valleys in the 19^th century and fluctuations in their density and longevity probably explained the pattern of mortality rates in villages. As breeding site suitability and mosquito development are influenced by temperature and humidity, relations between meteorological and mortality fluctuations were analysed.

Alpine valleys have an unusual set of topographic and meteorological conditions that could be linked to local increases in mosquito population density. Analysis of temperature fluctuations for the Albertville area between 1800 and 1900 showed no major climatic event (Figure 2). However, temperatures in June seemed correlated with observed mortality in the following year (R² = 0.102; Anova F = 8.06, p = 0.0059, 1 df). An analysis of variation in precipitation for the same area showed that neither annual nor monthly precipitation showed correlation with mortality data (Figure 2; P > 0.05).

Weather conditions probably influenced Anopheles biology and could be an explanation for the high numbers of malaria cases. However, the importance of other factors potentially involved in mosquito habitat development and mosquito density increases were analysed.

At the beginning of the 19th century, Isère river was a braided system consisting in numerous channels and associated swamps which were famous foci of marsh fever 3738. During the summer, flood-level decrease favoured the proliferation of temporary ponds and the local population lived on harvesting aquatic vegetation for cattle breeding. Stagnant water was considered as the main cause of unhealthiness and fevers. In 1829, the Sardinian government decided to reduce local morbidity in the flood-plain by building embankment by the river (Figure 1). Engineers' archives record the different steps in the hydraulic development of the river (Figure 3) and the local evolution of fever cases. From 1830 to 1854, the embankment work on the river took place. The aim of this work was to drain the neighbouring marshes (Figure 3A). Many workers coming from the neighbouring villages were infected by marsh fever 39 and mortality in the parish increased (three-fold higher in 1840 than in 1830, Figure 4). Despite the dike, the river branches remained connected by dripping waters and infiltration during spring floods, favouring the increase of wetland surface 37 (Figure 3B). In the vicinity of Grésy-sur-Isère, the river flowed at a higher elevation in its artificial channel as compared to its natural level which resulted in recurrent floods during high-flow periods (from mid-April to mid-July) and creation of temporary pools. The architects decided to fill up the marshes and pools by way of an artificial silting operation called "warping" ; part of the river flow was diverted into specially-constructed basins in which sediment deposited during the floods. The clear water then returned to the river further downstream. (Figure 3C). Aquatic macrophytes rapidly colonized these plunge pools and valuable vegetative biomass was harvested during the summer (Figure 3D); the following years, fever cases and mortality increased once more (+75%, Figure 4) 24. New policies adopted in 1865 resulted in better cooperation between neighbouring villages permitting an efficient circulation of water along the drainage basin and the complete silting of marshes (Figure 3E). These hydraulic works contributed to the decrease of mortality (-60% between 1870 and 1900) and fever cases in the Isère valley (Figure 4) 40. The correlation of dates between hydraulic operations and mortality events in the parishes of Notre-Dame-des-Millières and Grésy-sur-Isère provide evidence that water management was the cause of fever progression.

The new channel of the river Arc (Figure 1) was built from 1830 to 1839, short-cutting the natural braided river. As a result, from 1832, the progressive raising of the channel bed by the accumulation of sediment downstream from this river was responsible for recurrent flooding of the river and its tributary, the river Gelon, over a farmed area 38. The consequence was an increase in fever cases at Bourgneuf, Aiton and Chamoux and recorded mortality started to increase from 1830–32 onwards, with a peak of 126 annual deaths between 1840 and 1845 (Figure 4).

The progressive diversion of the river Gelon into the river Isère from 1842 to 1854 limited floods and mortality decreased from 1842 to 1845 with a minimum of 93 deaths between 1855–60. Artificial silting works in the Arc and Isère valleys took place at the same time, favouring the creation and persistence of marshy lands in the area (more than 1000 ha along the river Gelon, Figure 3D). Consequently, the observed fever cases and the number of deaths increased significantly with a new peak between 1865 and 1870 (Figure 4). Drainage operations in the valley definitely removed marshy lands by 1880, as seen previously with the river Isère (Figure 3E) 3841, and a significant decrease in the number of sick people and deaths was recorded in the vicinity of the river Gelon and the river Arc (Figure 4).

Channelizing rivers, artificial silting operations and drainage network development were disturbance patterns, and played a major role in water-table and flood-level fluctuations over space and time 4243. Fluctuation of mortality rates in the parishes located around the confluence seem closely linked to the variation of hydrological factors.

Mean temperature recorded in June between 1828 and 1900 were correlated with the number of deaths the following year. In Finland, similar correlations were observed between summer temperature and malaria deaths the following year for the same period 5. The authors explained that summer temperature probably regulated the density of vectors in adult stages. In alpine valleys, Anopheles were currently observed in the larval stages in spring. Thus fluctuations in June temperature probably influenced the capacity for larvae to reach the adult stages and therefore vector density and malaria transmission. Nevertheless, weather conditions did not explain Anopheles density in larval stages and other factors related with hydrosystems functioning were probably implicated in the high mortality rates.

As demonstrated in this study, mortality rates in the Isère valley in the 19^th century were linked to the river-water alluvial flood-plain management. Demographic data were consistent with periods of expansion and decrease of mosquito habitats, suggesting that malarial fevers transmitted by Anopheles were related to local death rates. Agricultural practices in the flood-plain consisted of harvesting sedge for cattle during summer, when adult mosquito densities were at their highest.

Before flood management was introduced, secondary arms of the braided rivers dried up in summer, favouring the proliferation of temporary ponds suitable for mosquito breeding. Outdoor contact between people and adult Anopheles occurred in late summer and in autumn. After the embankment of the river Isère and its tributaries, breeding sites for Anopheles were created by infiltration and overflow during the spring flood. The stagnation of water in the valley created conditions suitable for mosquito proliferation. Consequently, the high Anopheles population densities must have increased malaria transmission during summer in the marshy valley and must explain increasing mortality in the parish. During the first years of silting operations in the flood-plain, the presence of valuable vegetation and residual ponds colonized by Anopheles in the warping basins from mid-summer onwards, facilitated contact between vectors and people during late summer. This prolonged contact between humans and mosquitoes was probably favourable to the outdoor transmission of malaria until autumn. As dyking works on the river Isère were carried out progressively from downstream (Grésy-sur-Isère) to upstream (Notre-Dame-des-Millières), artificial silting-up began later upstream. This time-lag between hydraulic operations could explain the delay in mortality peaks observed in the two parishes in 1860–70. The complete silting-up of the flood-plain and its drainage may have progressively eliminated ponds suitable for Anopheles development, and could explain the definitive decrease of mortality rate in local populations since 1880.

During the period of endemic malaria, an indoor transmission of Plasmodium was also suspected in winter, as reported in other countries 95. Indeed, An. atroparvus, which is considered to be the primary vector of malaria in France, could be found in farm buildings and it remained semi-active and occasionally feeding during winter 444546.

The more dangerous species of Plasmodium, P. falciparum, was present for a long time in southern Europe in the 19^th century 10. However, its implication in malaria epidemics in alpine valleys may have been outclassed by P. vivax, which is more robust in the face of the hard climatic conditions that occurred in winter in this place. Even if P. vivax has nowhere been reported as a direct cause of death, recent studies have demonstrated that its burden was underestimated and that it should no longer be considered responsible of benign malaria 4748. In alpine valleys like in the English marshes, vivax malaria must have been one of the determinants of unhealthiness, in interaction with poor nutrition and other diseases 49 even if epidemics like cholera in 1854 and 1867 had not a serious impact on demography (less than 1% of the Savoie population died from cholera in both epidemics, which were restricted to the main towns; 50).

The availability of quinine derivatives for anti-malarial treatments certainly had a significant impact in malaria decrease in the end of the 19th century in Europe 451. In the Rhône-alpes region, the use of quinine is poorly documented, and it was probable that most of rural people could not buy it 26. However, the decline in quantities of quinine sold by an office of the Isère valley in 1867 suggested that malaria cases were decreasing 52, which was concordant with mortality data of the period.

The case study of malaria transmission in Alpine valleys is not unique. Historically, epidemic marsh fevers have often been associated with poor water management. Consequently, regional measures have sometimes been taken to control morbidity. In Italy, Toricelli (1665) recommended the silting-up of alluvial marshlands by encouraging storage and deposition of flood sediments in the marshes 5354. In the surroundings of Pisa and Lucca, in the 18^th century, the drainage of freshwater and seawater was followed by a rapid decrease in malarial fever cases in the area 55.

In the Rhône-Alpes region of France, at the end of the 18^th century, a drainage network in the flood-plain of the river Leysse was established in order to irrigate meadows and harvest vegetation. Recurrent flooding of the river favoured mosquito breeding-site establishment and led to the destruction of the irrigation system. Consequently, malaria cases increased drastically around 1830, with 50% of the parish population being ill, as Anopheles benefited from stagnant water in the neglected drainage network 56. Malaria was eradicated after the dyking of the river Leysse, efficient drainage and reclamation of the flood-plain (1850–1870). In the same way, the vast operation of drainage (almost 100 000 ha) of Pontine marshes (Italy) undertaken in the 1930s by Mussolini succeeded to the previous failed attempt during the Roman period and improved the global healthiness of the parish 457.

In most cases, a decrease in malaria was followed by a period of further and more serious outbreak of the disease due to carelessness in the maintenance of equipment and hydraulic developments. Moreover, changes in agricultural practices, urbanization and the building of transport networks led to a considerable alteration in the function of the hydrosystem and were also factors implicated in new malaria outbreaks 105859.

Progress in human health and hygiene associated with the availability of quinine derivatives for anti-malarial treatments may have had a significant impact in malaria decrease in the early 20^th century 606162. Life style has progressively changed during the 20^th century, with the desertion of many rural areas, the modification of agricultural practices and land use 463. Since the end of the 19^th century numerous wetlands have disappeared, disconnected from waterways or drained for agriculture and urbanization development needs. At the present time the most important breeding sites for mosquitoes in the Rhône-Alpes area are located in flood-plains of the river Rhone and its tributaries. Currently, Alpine valleys have no malariogenic potential due to a low density of anthropophilic Anopheles populations.

Today, scientists agree about the existence of global warming and that vector-borne diseases could spread further at their northern limits with climate change 17. Mosquitoes and Plasmodium species are highly sensitive to climatic factors; moisture and temperature influence their development and survival 816. Therefore, progressive warming would theoretically influence the vectorial capacity of mosquitoes and, subsequently, malaria transmission, if they are infective 64. Currently, ancient primary vectors like An. labranchiae and An. superpictus have density relevant for malaria transmission in European countries 18. However, this situation of anophelism without malaria tends to show that the vulnerability of western Europe, in the global warming context, is low due to the quality of socio-economic and environmental conditions 51.

Mountains and in particular the Alps are susceptible to the effects of rapid climate change 65. Glacial ice melting and fluvial flooding will increase and predictions are that flood flows may increase by as much as 20% by 2050 6366. Preventative hydraulic operations are, therefore, planned, for example in the valley of the Isère, where the last serious flood occurred in 1859. According to the Integrated Upstream Isère Project, agricultural lands upstream of Grenoble will be used to convey and store flood-waters of the river Isère in a few years 67. The river bed will be dredged in order to increase its water-carrying capacity and the project includes the restoration of riverside ecosystems like wetlands. This kind of development project, based on the return of river sections to their natural state, may favour the creation of temporary ponds and pools suitable for a colonization by mosquitoes. Alpine anopheline populations could, therefore, develop in the future, justifying a preventative investigation of factors suitable for malaria outbreaks. As these flood management strategies are relatively recent 68, only speculations can be made on what future hydrologic landscapes may be, and what it will change for these areas in terms of malaria vulnerability, in a global change context. If historical studies provide explanations for past epidemics, they could also highlight future health policy challenges.