A cohort study on the duration of Plasmodium falciparum infections during the dry season in The Gambia

Abstract

BackgroundIn areas where Plasmodium falciparum malaria is highly seasonal, a dry season reservoir of blood-stage infection is essential for initiating transmission during the following wet season, bridging transmission seasons several months apart. Understanding infections during the dry season could thus inform approaches for malaria control.MethodsIn The Gambia, a cohort of 42 individuals with qPCR positive P. falciparum infections at the end of the transmission season (December) were followed monthly until the end of the dry season (May) to evaluate the duration of detectable infections. The influence of human host (age, sex, haemoglobin concentration and genotype, and P. falciparum-specific antibodies), and parasitological (parasite density, gametocyte density and genotypic multiplicity of infection) factors was investigated.ResultsA large proportion of individuals infected at the end of the wet season had detectable infections until the end of the dry season (40.0%; 16/40), with the majority of these infections also harbouring gametocytes (81.3%; 13/16). 22 infections were classified as persistent (detectable for at least 3 months), 17 were classified as short-lived (undetectable within 2 months), and 3 were treated (due to symptoms). At the start of the dry season, the majority of persistent infections (82%; 18/22) had parasite densities >10 p/µL compared to only 5.9% (1/17) of short-lived infections. Persistent infections (59%; 13/22) were also more likely to be multi-clonal than short-lived infections (5.9%; 1/17), they were most common in 5 to 15 year old children (63%; 12/19), and were associated with individuals having higher levels of P. falciparum-specific antibodies (p = 0.058).ConclusionsAsymptomatic persistent dry season infections in The Gambia were multiclonal with higher parasite densities at the beginning of the dry season, mostly occurring in school age children and adults with higher P. falciparum-specific antibodies. Screening and treating asymptomatic, malaria-infected individuals during the dry season may reduce the human reservoir of malaria responsible initiating transmission in the wet-season.

Can malaria parasites be spontaneously cleared?

“…Often cited as compelling evidence for chronic infections comes from longitudinal studies of untreated individuals living in high seasonal transmission settings in Africa where individuals can harbour subclinical infections from the rainy season throughout the dry season (when mosquito densities and transmission is greatly reduced) [7,[10][11][12][13]. While it is common for these studies to report that a proportion of participants harboured infections throughout the dry season (20-47%), the inverse is not acknowledgedthat the majority of participants 'cleared' their infections (53-80%) [7,10,14,15]. However, the relative contribution of spontaneous clearance to these observations is unclear, particularly as clearance and reinfection events may be missed in the 5 to 6 months between seasonal surveys.…”

“…Studies which have utilised more sensitive molecular diagnostics in following the natural course of untreated submicroscopic P. falciparum infections can provide more robust evidence for spontaneous clearance events, as well as more accurate estimates of the duration of infections. All 'intensive' sampling studies (i.e., at least monthly sampling) utilising sensitive Plasmodium spp.-specific PCR molecular methods observe events of spontaneous clearance regardless of transmission setting (Table 1) [2,3,15,[24][25][26][27][28][29]. The observed duration of submicroscopic infections ranged from days [2,24] to several months [3,25,[27][28][29] before spontaneous clearance was observed, with a large proportion of individuals (17-87%) in most studies clearing infections within 1 month and the majority of individuals (67-100%) spontaneously clearing P. falciparum parasitaemia with 12 months (Table 1).…”

“…While diagnosis by Plasmodium spp.-specific PCR can determine the presence of P. falciparum at a given time, additional molecular characterisation of the infecting parasite strain(s) is required to capture the subtleties of multiclonal infection dynamics. Genetic characterisation of parasites in high-transmission settings suggests that, while some individuals appear to be chronically infected when simply reporting their binary infection status, genotyping studies demonstrate that individuals are constantly clearing one infection then being infected with new parasite strains [10,11,13,15,20,24,26,30]. This results in a cycle of concurrent submicroscopic infections that, without genetic characterisation, can appear as a single chronic infection (as demonstrated in Figure 1) [10,11,13,15].…”

“…Genetic characterisation of parasites in high-transmission settings suggests that, while some individuals appear to be chronically infected when simply reporting their binary infection status, genotyping studies demonstrate that individuals are constantly clearing one infection then being infected with new parasite strains [10,11,13,15,20,24,26,30]. This results in a cycle of concurrent submicroscopic infections that, without genetic characterisation, can appear as a single chronic infection (as demonstrated in Figure 1) [10,11,13,15]. It is therefore possible that longitudinal studies that rely solely on PCR for detection of parasites may overestimate the duration of submicroscopic P. falciparum infections and underestimate rates of spontaneous clearance.…”

“…Studies which evaluated clonal dynamics of the natural course of submicroscopic infections by genotyping or sequencing various P. falciparum genes such as AMA1, MSP1, MSP2, GLURP, and var genes demonstrate that spontaneous clearance of clones can occur [2,3,10,15,20,[24][25][26][27][28][29][30][35][36][37]. Furthermore, spontaneous clearance of clones occurs more frequently, and faster (days to weeks) than when simply evaluating binary infection status by PCR (months) (Tables 1 and 2) [2,3,10,15,20,[24][25][26][27][28][29][30]36,37].…”