Prognostic value of circulating pigmented cells in African children with malaria

Giovanni Maria Lancisi, in 1716, was the first to describe the presence of black pigment in human liver, brain, and spleen, but he did not associate these changes with malaria. In 1825, Etienne Bailly reported the dark color of cortical gray matter he observed during autopsies in 1822 of patients from Rome with malarial fever, and Richard Bright confirmed this in his autopsy accounts in 1831. However, these observations of discolored tissues were not extended to the recognition of malarial pigment in corpuscles until Schutz, in 1846, and Meckel von Helmsbach, independently a year later, described brown pigment in the blood of people who died of “pernicious fever.” These early accounts of malarial pigment have recently been reviewed by Poser and Bruyn [1]. It is now recognized that this pigment in patients with malaria, known also as hemozoin, is a degradation product of hemoglobin formed in the process of detoxifying free heme and that it can be found in parasitized erythrocytes, monocytes, and granulocytes of patients with malaria. The formation of malarial pigment (i.e., hemozoin) is a coordinated 2-component process involving both lipids and histidine-rich proteins of Plasmodium falciparum [2]. Malarial pigment has a number of biological effects, some of which may affect immune defense mechanisms. It inhibits macrophage function [3, 4] and dendritic cell functions [5], and it can suppress erythropoiesis [6, 7]. By suppressing prostaglandin E2 production, it leads to tumor necrosis factor overproduction, which in turn is associated with malarial anemia [8]. In addition to these pathophysiological effects, hemozoin in circulating cells may also be useful in diagnosing malaria [9] and in predicting outcome. In 1995, two independent, small studies demonstrated the potential of intraleukocytic pigment as a prognostic factor in malaria [10, 11]. The Gabonese study showed a correlation between the presence of pigment in monocytes and the degree of anemia in children with malaria and a correlation between pigment in neutrophils and parasitemia [10]. The Thai study suggested that the number of pigment-containing neutrophils in adult patients with malaria was a rapid and simple prognostic test [11]. In a follow-up study from Nigeria, the pigment-containing neutrophil count was also a simple marker of disease severity in childhood malaria [12]. However, none of these studies was large enough to detect an association between circulating pigment and mortality. To obtain more-definitive evidence of the prognostic significance of circulating pigments for, primarily, malaria-associated mortality, our clinical network for Severe Malaria in African Children (SMAC) undertook a large, multicenter study of the prognostic significance of circulating pigment [13]. Because our sites spanned Africa and included a variety of different epidemiological settings, the sample could more completely include the epidemiologic diversity of falciparum malaria in Africa and could generate a sample size large enough to identify any association between circulating pigment and disease outcome. Between the beginning and the completion of the SMAC study, 3 other smaller studies (from Gabon [14], Mali [15], and Kenya [7]) were performed; they reported findings similar to those described in the earlier studies.