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We know a lot about malaria: the epidemiology of the disease and the genome of the parasites that infect us. We have made great advances, with new and effective drugs, methods to control the vectors, rapid diagnostic tests and the potential for effective vaccines. We have seen malaria gradually disappear from temperate climates by the 1950s. Despite all these advances, the disease still remains a cause of widespread poor health in many tropical areas. Although we know malaria causes fever, to this day defining when a fever is caused by malaria remains a challenge. The clinical signs of fevers, including those caused by malaria, have been known for centuries, if not millennia (see Aulus Cornelius Celsus as an example). From the beginning of the 18th century, however, malaria gradually emerged – from at least 128 different fevers recorded between 1774 and 1794 by Vicq d’Azyr (see Peter) – as a distinct clinical entity within the still complex group of intermittent (periodic) fevers. During the 18th century, albeit with some continuing ambiguity, malaria gradually became accepted as a defined set of intermittent fevers responding to ‘therapeutic tests’ using Cinchona bark or, from the 1820s, by using quinine. But difficulties in the diagnosis of genuine malaria persisted until the causal parasite and vectors had been recognised at the end of the 19th century. After examining clinical and statistical data on malaria gathered during the 19th century, the Malaria Commission of the League of Nations concluded that few of the data were sufficiently reliable to be used in comparative studies. The principal writer of the report, Nicolaas Swellengrebel, pointed out that a shift in the meaning of the word malaria had occurred: from ‘mal-aria’ (bad air) as the cause of many fevers, to the name of a disease (plasmodiosis) reflecting the causative parasites – Plasmodia. Comparison with past clinical experience and the rapidity of the response to both Cinchona bark and quinine in many reported cases and case series left comparatively little room for doubt that the drug had beneficial effects on the disease. As noted at the end of the 19th century by a German writer promoting careful statistical evaluation of treatments in general, ‘to substantiate the efficacy of . . . quinine in malaria, one may not need statistics’. By contrast, it was not possible to make similarly confident causal inferences about the effects of most other interventions, whether purported advances in treating malaria or measures to control and prevent malaria at the population level. Multiple interventions were often poorly characterised and delivered without any formal comparison groups. Uncertainties and disputes resulted from this lack of formal comparative studies, with inevitable confusion about which antimalarial policies to apply, particularly at the population level. From the end of the 19th century, when the life cycle and vector of malarial parasites were identified, other antimalarial interventions were deployed beyond drugs, including, for example, approaches to limit breeding places for mosquitoes; provide physical protection of buildings and people against the insects; and to deploy antilarval and antimosquito procedures, such as petrol, larvivorous fish and Paris Green as a pesticide. In this paper, we consider methods used from the 17th to the 21st centuries to assess the effects of Cinchona bark and of quinine and its derivatives for (i) treating and (ii) preventing malaria in individuals and (iii) in attempts to control malaria in populations.

Evaluating Cinchona bark and quinine for treating and preventing malaria