Abstract
Recent malaria is associated with an increased risk of systemic bacterial infection. The aetiology of this association is unclear but malaria-related haemolysis may be one contributory factor. To characterise the physiological consequences of persistent and recently resolved malaria infections and associated haemolysis, 1650 healthy Gambian children aged 8–15 years were screened for P. falciparum infection (by 18sRNA PCR) and/or anaemia (by haematocrit) at the end of the annual malaria transmission season (t1). P. falciparum-infected children and children with moderate or severe anaemia (haemoglobin concentration < 11g/dl) were age matched to healthy, uninfected, non-anaemic controls and screened again 2 months later (t2). Persistently infected children (PCR positive at t1 and t2) had stable parasite burdens and did not differ significantly haematologically or in terms of proinflammatory markers from healthy, uninfected children. However, among persistently infected children, IL-10 concentrations were positively correlated with parasite density suggesting a tolerogenic response to persistent infection. By contrast, children who naturally resolved their infections (positive at t1 and negative at t2) exhibited mild erythrocytosis and concentrations of pro-inflammatory markers were raised compared to other groups of children. These findings shed light on a ‘resetting’ and potential overshoot of the homeostatic haematological response following resolution of malaria infection. Interestingly, the majority of parameters tested were highly heterogeneous in uninfected children, suggesting that some may be harbouring cryptic malaria or other infections.
Highlights
In addition to an estimated 229 million clinical cases of malaria globally in 2019 [1], there is a large, hidden pool of Plasmodium spp. infections that go undiagnosed due to the absence of fever or other characteristic clinical signs [2]
Finger prick blood samples were obtained for malaria microscopy (Giemsa stained thick films), rapid diagnosis by lateral flow assay for P. falciparum histidine-rich protein II (PfHRP2) (SD BIOLINE Malaria Ag P.f, Abbott), preparation of dried blood spots for P. falciparum qPCR analysis and haemoglobin (Hb) estimation by Hemocue (Hb201+, Radiometer)
The study was approved by The Medical Research Council Gambia (MRCG) Scientific Coordinating Committee and by the Gambia Government/MRCG Joint Ethics Committee
Summary
In addition to an estimated 229 million clinical cases of malaria globally in 2019 [1], there is a large, hidden pool of Plasmodium spp. infections that go undiagnosed due to the absence of fever or other characteristic clinical signs [2]. There is considerable debate as to the health and developmental consequences of subclinical Plasmodium spp. infections, in children, as well as their role in the acquisition of sustained antimalarial immunity and their contribution to malaria transmission [2, 5] As these asymptomatically infected individuals rarely seek antimalarial drug therapy, infections may persist for months or years [6] and seed continual infection of mosquitoes in areas of highly seasonal transmission, maintaining parasite circulation across dry seasons. In a pilot study of asymptomatically infected children in Burkina Faso, we observed evidence of persistent haemolysis together with raised plasma haem and haem oxygenase 1 (HO-1) [8], features previously associated with neutrophil dysfunction in children [9] and an inability to control non-Typhoidal Salmonella infections in mice [10]. Plasma concentrations of the anti-inflammatory cytokine IL-10, which can directly activate HO-1, were raised in persistently infected individuals compared to uninfected controls [8]
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