Understanding the Importance of Asymptomatic and Low- Density Infections for Malaria Elimination

Abstract

In recent years, the use of more sensitive diagnostic techniques has demonstrated a significant number of malaria infections at densities beneath the limit of detection of conventional microscopy and rapid diagnostic tests (RDT). These low-density infections are almost always asymptomatic, found in all endemic settings, including those nearing elimination, and in all ages of the population. They typically account for a high proportion of all infections and since they have also been shown to be infectious to mosquitoes, low-density infections are thought to be important contributors to maintaining malaria transmission. However, there is currently no direct evidence that specifically targeting this low-density parasite reservoir will hasten progress towards elimination. In this chapter we review the data to date and identify knowledge gaps. We present potential scenarios for the causes of low-density infections, if and how these might drive transmission, and the likely impact of specifically targeting them.

Global & Temporal Patterns of Submicroscopic Plasmodium falciparum Malaria Infection

“…Malaria prevalence across different settings varies with age 39 , a feature attributed to the development 14 of immunity after exposure, as well as age-related effects apparently independent of exposure 40,41 . As 15 a result, increasing age and increased immunity have been associated with lower parasite densities 40,42 16 and our analyses confirmed a higher proportion of submicroscopically infected individuals in surveys 17 of adults compared with children.…”

“…These observed differences, 21 together with the results observed for South America therefore support an effect of transmission 22 history on the submicroscopic reservoir which is distinct from the age structure of the infected 23 population and unlikely to be driven by geographical bias. 24 A number of hypotheses could explain these results, including systematic variation in asexual blood 1 stage multiplication rate of Plasmodium falciparum 46 or various haemoglobinopathies and human 2 genetic traits that have been linked to lower average parasite densities 41,47 . It is also not possible to 3 definitively preclude systematic variation in diagnostic quality across settings, although this is perhaps 4 unlikely: for example, a recent analysis found that whilst microscopy quality varies across settings, it 5 does not do so systematically with transmission intensity 48 .…”

Maximizing Impact: Can Interventions to Prevent Clinical Malaria Reduce Parasite Transmission?

“…The factors that contribute to infection causing disease are complex, and beyond the scope of this review, but they include host immunity, parasite density, and parasite surfaceprotein diversity. The proportion of infections that cause disease, versus those that remain asymptomatic, varies according to host and parasite factors [5]; in settings with moderate to high transmission intensity, this proportion generally decreases with age as immunity to the parasite builds up over time with repeated exposure [6]. In all settings, it has become clear that asymptomatic infections are more common than previously thought, as revealed by molecular diagnostic tools, which are more sensitive than light microscopy for parasite detection [7].…”

“…While individuals with fever are less likely to have microscopically detectable P. falciparum gametocytes than those without fever at the time of sampling [15], the majority of both symptomatic and asymptomatic infections likely include mature gametocytes that are detectable by, at least, molecular diagnostic methods [16]. Additionally, the duration of time that gametocytes are present is essential for quantifying transmission potential because a longer duration increases the opportunities for mosquito bites [5]. The duration of an asymptomatic infection remains difficult to quantify but likely ranges from a few weeks [17] to many months [18,19] and depends on factors such as the level of host immunity.…”

“…The proportion of those infections that lead to clinical malaria disease (dark gray), as opposed to remaining subclinical or asymptomatic (light gray), decreases with age [63,64]. Both types of infection contribute to transmission (diagonal lines), which also varies with age due to changes in the relative infectiousness and duration of the infections and the frequency of bites by malaria vectors [5,8]. The proportions shown here are hypothetical, and the exact proportions will vary across geographic locations according to epidemiological, environmental, and ecological factors [8,[62][63][64].…”