Abstract
Asymptomatic malaria infections may affect red blood cell (RBC) homeostasis. Reports indicate a role for chronic hemolysis and splenomegaly, however, the underlying processes are incompletely understood. New hematology analysers provide parameters for a more comprehensive analysis of RBC hemostasis. Complete blood counts were analysed in subjects from all age groups (n = 1118) living in a malaria hyperendemic area and cytokines and iron biomarkers were also measured. Subjects were divided into age groups (<2 years, 2-4, 5-14 and ≥15 years old) and clinical categories (smear-negative healthy subjects, asymptomatic malaria and clinical malaria). We found that hemoglobin levels were similar in smear-negative healthy children and asymptomatic malaria children but significantly lower in clinical malaria with a maximum difference of 2.2 g/dl in children <2 years decreasing to 0.1 g/dl in those aged ≥15 years. Delta-He, presenting different hemoglobinization of reticulocytes and RBC, levels were lower in asymptomatic and clinial malaria, indicating a recent effect of malaria on erythropoiesis. Reticulocyte counts and reticulocyte production index (RPI), indicating the erythropoietic capacity of the bone marrow, were higher in young children with malaria compared to smear-negative subjects. A negative correlation between reticulocyte counts and Hb levels was found in asymptomatic malaria (ρ = -0.32, p<0.001) unlike in clinical malaria (ρ = -0.008, p = 0.92). Free-Hb levels, indicating hemolysis, were only higher in clinical malaria. Phagocytozing monocytes, indicating erythophagocytosis, were highest in clinical malaria, followed by asymptomatic malaria and smear-negative subjects. Circulating cytokines and iron biomarkers (hepcidin, ferritin) showed similar patterns. Pro/anti-inflammatory (IL-6/IL-10) ratio was higher in clinical than asymptomatic malaria. Cytokine production capacity of ex-vivo whole blood stimulation with LPS was lower in children with asymptomatic malaria compared to smear-negative healthy children. Bone marrow response can compensate the increased red blood cell loss in asymptomatic malaria, unlike in clinical malaria, possibly because of limited level and length of inflammation. Trial registration: Prospective diagnostic study: ClinicalTrials.gov identifier: NCT02669823. Explorative cross-sectional field study: ClinicalTrials.gov identifier: NCT03176719.
Highlights
Malaria is a major cause of anaemia in sub-Saharan Africa with a multifactorial aetiology, including hemolysis, dyserythropoiesis and inflammation induced functional iron deficiency [1]
Parasite density (PD) was significantly higher (p
Hb levels did not differ between asymptomatic malaria and smear-negative healthy subjects, while the presence of higher reticulocyte response in asymptomatic malaria indicate that red blood cell (RBC) losses are adequately compensated by bone marrow response
Summary
Malaria is a major cause of anaemia in sub-Saharan Africa with a multifactorial aetiology, including hemolysis, dyserythropoiesis and inflammation induced functional iron deficiency [1]. In asymptomatic malaria where Plasmodium falciparum (Pf) infection does not result in signs of illness and hemoglobin (Hb) levels are less severely affected [8,9,10,11]. Defining malaria-attributable anaemia is difficult, as many prevalent comorbidities may lead to dyserythropoiesis and inflammation induced functional iron deficiency. Only one study reported reticulocyte numbers in asymptomatic malaria patients [10]. Semi-immune children between 5–15 years old with asymptomatic malaria, had lower Hb levels, increased reticulocyte numbers and erythropoietin levels as well as TNF-α levels, compared to healthy non-malaria carriers, indicating dyserythropoiesis. Pf is known to induce a strong pro-inflammatory response and thereby the development of anaemia, malaria can induce tolerance to subsequent infections or immune challenges which may limit the development of anaemia in asymptomatic malaria [13, 14]
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