Malaria in infants : asymptomatic and symptomatic infections the first year of life

Malaria causes the majority of deaths in children below five years of age, but asymptomatic infections are more frequent. An understanding of the interplay of human and parasite factors which predispose to symptomatic malaria has guided clinical and preventive practices including intermittent preventive treatment and bed net usage, to reduce the global malaria burden. Yet, the asymptomatic state which potentially offers a window for understanding protection against symptomatic malaria is rarely monitored. In-depth knowledge of how individuals with parasites are protected against symptoms at one time but not another time is needed. In this thesis, the overall aim was to identify over time, the unique characteristics of asymptomatic infections, for in-depth understanding of protection against symptomatic malaria in the first year of life. Therefore, the host and parasite factors influencing susceptibility to Plasmodium falciparum asymptomatic infections or symptomatic malaria were investigated among 1264 infants followed from birth to twelve months of age in Kintampo, a high malaria transmission area of Ghana. In study I we profiled the monthly order of malaria parasite positivity detected by light microscopy at scheduled home (19231 visits) and unscheduled hospital visits (5254 visits) and distinguished periods of asymptomatic infection from symptomatic malaria. We discovered four main longitudinal sequence patterns of infection: some infants had (i) only symptomatic infections, some (ii) only asymptomatic infections, (iii) both symptomatic and asymptomatic infections (iv) and some infants were parasite negative throughout the first year of life. There was significant variation in parasite densities and age at infection between the groups of infants. In study II, we investigated the maternal, host genetic, demographic and parasite parameters which predisposed the groups of infants to symptomatic malaria or asymptomatic infections. Improved socio-economic status, adequate antenatal care, less exposure of mothers to malaria during pregnancy and improved nourishment of infants were associated with reduced symptomatic malaria in the first year of life. In study III, we used qPCR to study in-depth the extent of parasite positivity below the detection limit of light microscopy within the infection patterns discovered in study I. The qPCR, rather than the microscopy, detected symptomatic and asymptomatic infections frequently in the scheduled home and unscheduled hospital visits, and particularly asymptomatic infections in the first six months of life. By qPCR, parasites undetected by microscopy were found in the four microscopy-defined sequence patterns of infection, and while some infants were still parasite negative, others remained with either asymptomatic infections only or alternating asymptomatic infections and symptomatic malaria through the first year of life. The findings show many undiagnosed infections and suggests complexity of protection against symptomatic malaria that is highly influenced by socio-economic status and that partly begins in utero. We conclude that frequent sampling and analysis by molecular methods were useful for identifying the complete infection profiles and the determinants of protection against symptomatic malaria in infants living in a high malaria transmission area. Despite living in the same transmission area, infants experienced diverse patterns of symptomatic and asymptomatic P. falciparum infections the first year of life. Further understanding of the underlying mechanisms for asymptomatic infections will help improve malaria control and elimination strategies