The role of asymptomatic P. falciparum parasitaemia in the evolution of antimalarial drug resistance in areas of seasonal transmission

Abstract

In areas with seasonal transmission, proper management of acute malaria cases that arise in the transmission season can markedly reduce the disease burden. However, asymptomatic carriage of Plasmodium falciparum sustains a long-lasting reservoir in the transmission-free dry season that seeds cyclical malaria outbreaks. Clinical trials targeting asymptomatic parasitaemia in the dry season failed to interrupt the malaria epidemics that follow annual rains. These asymptomatic infections tend to carry multiple-clones, capable of producing gametocytes and infecting Anopheles mosquitoes. Different clones within an infection fluctuate consistently, indicative of interaction between clones during the long course of asymptomatic carriage. However, the therapy-free environment that prevails in the dry season dis-advantages the drug resistant lineages and favors the wild-type parasites. This review highlights some biological and epidemiological characteristics of asymptomatic parasitaemia and calls for consideration of polices to diminish parasite exposure to drugs “therapy-free” and allow natural selection to curb drug resistance in the above setting.

Introduction

Malaria may be perennial or epidemic in sub-Saharan Africa and transmission can vary from stable to unstable, depending on the prevailing climatic conditions. However, the clinical manifestation of the disease varies over a spectrum, ranging from severe disease to mild intermittent fever. Nonetheless, malaria parasites are often carried as asymptomatic infections with no defined clinical symptoms. This asymptomatic parasitaemia can exist at microscopically detectable levels, however it often persists below this threshold (Babiker et al., 1998, Bottius et al., 1996, Diallo et al., 2012, Owusu-Agyei et al., 2002).

Malaria can be a chronic disease, where individuals exposed to repeated infections can develop a state of protection from clinical symptoms. Thus acute infection can often switch into asymptomatic parasitaemia that may last for many months (Babiker et al., 1998). This phenomenon is a common feature of the epidemiology of Plasmodium falciparum. The prevalence of asymptomatic parasitaemia is now known to be much higher than previously thought, thanks to molecular tools which can identify a larger proportion of infected individuals contributing to the parasite reservoir than those identified using microscopy (Bottius et al., 1996, Diallo et al., 2012, Owusu-Agyei et al., 2002).

Such a high prevalence of asymptomatic carriage poses a threat to the current success of control programmes, and the prospect of sustainable malaria control in geographically defined areas with low levels of transmission. In such areas, Artemisinin-based combination therapy (ACT) together with additive measures (e.g. insecticide impregnated bed nets) has brought symptomatic malaria incidence to very low rates (Kaneko et al., 2000). As a result, these areas have turned into potential sites for sustainable control, that require sensitive surveillance tools to detect sub-patent asymptomatic infections, and prevent local outbreaks or epidemics. However, attempts to eliminate asymptomatic parasitaemia have failed to interrupt the regular malaria outbreaks that follow annual rains (De Martin et al., 2001, El-Sayed et al., 2007, von Seidlein et al., 2003). In addition, the wide-spread use of asymptomatic-targeted therapy carries the risk of selecting resistant parasites that may exist at low prevalence, but have a survival advantage under such a uniform drug pressure (Charles et al., 1962).

However, epidemiological and laboratory experimental evidence suggest that the therapy-free environment that prevails amongst asymptomatic parasite carriers can favour wild-type, drug-sensitive parasites and disadvantage the mutant, drug-resistant lineages (Abdel-Muhsin et al., 2004, Huijben et al., 2011, Kublin et al., 2003, Wargo et al., 2007). This is demonstrated by an increased frequency of wild-type parasites in the dry season prior to start of the malaria transmission in areas of seasonal transmission, such as Sudan, The Gambia and Indonesia (Asih et al., 2009, Babiker and Mackinnon, 2005, Ord et al., 2007). This review focuses on how current knowledge on the biology of asymptomatic parasitaemia and evolution of drug resistance, in areas of seasonal transmission, can be exploited to curb drug resistance genotypes and maximize the efficacy of therapy to control cyclical malaria outbreaks.