By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: The diagnosis of malaria depends on detection of the parasite, but the spleen is where the money is.

SOURCES: Kho S, Qotrunnada L, Leonardo L, et al. Hidden biomass of intact malaria parasites in the human spleen. N Engl J Med 2021;384:2067-2069.

Woodford J, Gillman A, Jenvey P, et al. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study. PLoS Med 2021;18:e1003567.

The spleen plays an important role in the pathophysiology of malaria, and some recent work has further defined its importance and uncovered some differences in its role in infections caused by Plasmodium vivax and Plasmodium falciparum.1

The spleen is affected early in infection by each of these species. In a study by Kho and colleagues, seven malaria-naïve volunteers were experimentally infected with P. vivax (n = 3) or P. falciparum (n = 4). Positron emission tomography/magnetic resonance imaging (PET/MRI) was performed just prior to infection and again a median of nine days later. Splenic volume increased by 28.8% and 22.9% after infection with P. vivax and P. falciparum, respectively, with increases in fluorodeoxyglucose uptakes of 15.5% and 5.5%. At the same time, there was no significant change in tracer uptake in bone marrow or liver after infection with either species. Thus, each species has high tropism for the spleen where they exhibit metabolic activity, but to a greater extent with P. vivax compared to P. falciparum.

In Papua, Indonesia, Kho and colleagues also directly examined spleens removed (most often removed due to trauma) from patients with mostly untreated malaria due to P. falciparum in nine patients and P. vivax in six patients. They visualized non-phagocytosed intact erythrocytes containing the parasites in densities that were hundreds to thousands of times higher than their corresponding density in peripheral blood. This was especially true for P. vivax-infected red blood cells, for which the median splenic density was 3,590 times as high as in peripheral blood, with a mean of 95% as rings or trophozoites and 5% as schizonts. Estimates indicated that the 98.7% of asexual-stage P. vivax parasites were sequestered in the spleen in an environment rich in immature reticulocytes, while the circulatory system contained only the remaining 1.3%.2 In P. falciparum infections, the median density was 289 times higher in the spleen than in peripheral blood and a mean of 81% as rings or trophozoites and 19% as schizonts, while the estimated asexual-stage total biomass in the spleen was at least twice that in the circulation.

COMMENTARY

The development of symptoms in malaria is reported to occur when the density of parasitemia reaches approximately 100 parasites per microliter of peripheral blood. The data reviewed here demonstrate that the peripheral blood is not the major site of residence of the parasite. P. falciparum, in particular, generally is considered to be an intravascular pathogen by virtue of the sequestration of erythrocytes containing mature forms within small- and medium-sized vessels and, thus, avoiding clearance by the spleen. However, the results reviewed here indicate that the P. falciparum biomass in the spleen is twice or more that in the circulation. This phenomenon is even much more striking with P. vivax infection, for which the ratio is approximately 76:1.

Although both species have an endosplenic lifestyle, this appears particularly true of P. vivax to the extent that it has been suggested that chronic malaria is perhaps optimally considered as an infection of the spleen rather than of the blood. As stated by Kho et al, “Vivax malaria should be considered predominantly an infection of the reticulocyte-rich spleen, with secondary involvement of the intravascular compartment. While important for transmission and pathogenesis, the circulating compartment is not the principal site for parasite biomass and parasite interactions with cells mediating immune responses.”2 These results provide an important insight into the pathophysiology of malaria. 

REFERENCES

  1. Buffet PA, Safeukui I, Deplaine G, et al. The pathogenesis of Plasmodium falciparum malaria in humans: Insights from splenic physiology. Blood 2011;117:381-392.
  2. Kho S, Qotrunnada L, Leonardo L, et al. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study. PLoS Med 2021;18:e1003632.