Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Abstract

With malaria elimination back on the international agenda, programs face the challenge of targeting all Plasmodium infections, not only symptomatic cases. As asymptomatic individuals are unlikely to seek treatment, they are missed by passive surveillance while remaining infectious to mosquitoes, thus acting as silent reservoirs of transmission. To estimate the risk of asymptomatic infections in various phases of malaria elimination, we need a deeper understanding of the underlying mechanisms favoring carriage over disease, which may involve both pathogen and host factors. Here we review our current knowledge on the determinants leading to Plasmodium falciparum symptomless infections. Understanding the host-pathogen interactions that are most likely to affect transitions between malaria disease states could guide the development of tools to tackle asymptomatic carriers in elimination settings. Being AsymptomaticPeaceful coexistence with the infected host, rarely causing clinical symptoms, is a common but poorly understood phenomenon that occurs for many human pathogens [1]. Because such asymptomatic cases of infection occur without eventual overt symptoms, they do not come to clinical attention, thus representing a large hidden reservoir of active infection that permits their persistence and eventual spread to other human hosts. This is the case for many malaria infections in semi-immune individuals from endemic areas, which commonly cause a mild febrile illness or no apparent symptoms at all, while keeping parasite numbers at low densities [2] (Box 1).Carriage of asymptomatic malaria (see Glossary) infections, being at the same time difficult to detect and to manage, has considerable implications for the design and use of malaria elimination strategies. Symptomless infections that persist during the dry season in areas of seasonal transmission have been suggested to seed the malaria outbreaks after annual rains when mosquitoes reappear [3]. Similarly, asymptomatic parasitemia may potentially contribute to persistence of transmission in low-transmission settings [4]. However, the precise contribution of asymptomatic malaria to transmission in areas that have achieved substantial reductions in the malaria burden remains a matter of debate [5], as is the assumption that detecting and targeting these individuals for radical treatment, as opposed to using mass drug administration approaches, would be an efficient and effective tactic. Moreover, eradication in Europe, North America, and other parts of the world using no better diagnostics than microscopy [6] suggest that key determinants of success might not be finding the last parasite. From a practical point of view, the proportion of asymptomatic infections in certain situations and phases of malaria elimination may impose the need for modifications of detection methods (active versus passive case detection) [7] if, for example, symptom-based surveillance at health facilities is insufficient and mass blood surveys are necessary to inform the design of elimination i...

Asymptomatic only at first sight: malaria infection among schoolchildren in highland Rwanda

“…As for asymptomatic parasitaemia, predominating in the present study, findings are less clear-cut: in Yemen [6] and DR Congo [36], no influence on children´s cognition was observed while this was the case in Uganda [10], Mali [16], and Kenya [9]. Overall, asymptomatic parasitaemia is abundant; it accounts for three in four infections detected in community settings [4], and many of those are submicroscopic [2, 3]. While some of these infections become symptomatic, most can remain asymptomatic for several months [37, 38].…”

“…Owing to the enormous morbidity and mortality of clinical malaria in young children, the epidemiology and consequences of asymptomatic infection in different settings and age-groups has received comparatively little attention. Increasingly, however, the underrated impact of asymptomatic and/or submicroscopic infections is now being recognized [2, 3, 5–10]. …”

“…However, the significance of these asymptomatic Plasmodium infections is likely underestimated as they contribute to inflammatory responses, anaemia, cognitive impairment and delayed physical development [5, 9, 10, 15–20]. Moreover, submicroscopic infections tend to persist for longer than symptomatic ones [13, 21], thereby constituting a sizeable transmission reservoir [2, 3, 14]. This has particular importance in areas of low endemicity considering the increase of submicroscopic (and frequently asymptomatic and untreated) infections with declining malaria transmission [2, 3, 11, 21].…”

“…Moreover, submicroscopic infections tend to persist for longer than symptomatic ones [13, 21], thereby constituting a sizeable transmission reservoir [2, 3, 14]. This has particular importance in areas of low endemicity considering the increase of submicroscopic (and frequently asymptomatic and untreated) infections with declining malaria transmission [2, 3, 11, 21]. …”

Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL), a Resistance Mechanism for Two Distinct Compound Classes

“…1 Globally, malaria cases have declined by 18% since the turn of the century, falling from an estimated 262 million in 2000 to 214 million in 2015, and malaria deaths have decreased by 48%, falling from ∼839,000 to ∼438,000 in the same time period. 2 Of the 100 malaria endemic countries, 35 are pursuing elimination.…”