Lethal malaria: Marchiafava and Bignami were right

Abstract

One hundred and twenty years ago, the Italian malariologists Marchiafava and Bignami proposed that the fundamental pathological process underlying lethal falciparum malaria was microvascular obstruction. Since then, several alternative hypotheses have been proposed. These formed the basis for adjunctive interventions, which have either been ineffective or harmful. Recent evidence strongly suggests that Marchiafava and Bignami were right.

Keywords: P. falciparum; cerebral malaria; malaria; pathology.

Figure 1.

Ettore Marchiafava (1847–1935) (left) and Amico Bignami (1862–1929) (right).

Figure 2.

Drawing by Yap Loy Fong from Field's classic text illustrating the cerebral microvasculature in a Chinese woman who died of cerebral malaria near Kuala Lumpur [31]. The blood vessels are packed with red cells containing mature stages of Plasmodium falciparum. Field stated that “it was not illogical to assume that anoxia from arrest of the capillary circulation may have been the cause of death.”

Figure 3.

Post-mortem brain smear taken from a patient who died from cerebral malaria. Three capillaries are seen traversing the figure. There is 1 schizont in the upper capillary. The middle capillary shows intense sequestration and packing with schizonts on the left and mature trophozoites on the right. The lower capillary (arrow) contains no parasitized erythrocytes.

Figure 4.

Cross-section electron micrograph showing a cerebral venule packed with erythrocytes containing mature stages of Plasmodium falciparum from a Thai patient who died from cerebral malaria [10]. Courtesy of E. Pongponratn.

Figure 5.

In fatal cerebral malaria, sequestered Plasmodium falciparum parasites are usually of similar stage of development within a vessel segment but differ in stage between vessels, indicating temporal differences between vessels in the upregulation of the vascular ligands. The upper vessel is packed with late schizonts, whereas the lower venule is packed with mature trophozoites. Courtesy of K. Silamut.

Figure 6.

The AQUAMAT trial was an open randomized comparison between parenteral artesunate and quinine in 5425 African children with severe malaria [38]. The lower panel shows the relationship between mortality (%) in the AQUAMAT trial and the estimated number of malaria parasites sequestered, derived from a model based upon measurement of PfHRP2 in plasma [34]. The error bars are the 95% confidence intervals for the mortality proportion. The upper panel shows the treatment effect (mortality difference: %) in the lower, middle, and upper tertiles of plasma PfHRP2 concentrations. These data show that deaths in patients with low numbers of sequestered parasites are not prevented by artesunate, which suggests that these fatalities were probably caused partly by a disease process other than malaria (most likely sepsis).