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

Abstract

Background Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life. Methods and findings To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI −15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI −0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI −15.9% to +25.0%], P. falciparum: +3.2% [CI −3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI −8.7% to +21.1%], P. falciparum: −1.4% [CI −4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity. Conclusions PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.

Haematological response in experimental human Plasmodium falciparum and Plasmodium vivax malaria

“…In malaria volunteer infection studies, despite the low parasite counts, participants still experience a significant inflammatory response, with elevated levels of IFN-γ and IL-6 [ 65 – 67 ] potentially contributing to inhibition of erythropoiesis [ 68 ]. Additional contributors to the loss of unparasitized cells in acute clinical malaria include haemolysis, decreased red blood cell deformability, antibody and complement binding to erythrocytes, loss of complement regulatory proteins on the surface of unparasitized erythrocytes [ 69 ] and increase in splenic size [ 70 ] with associated splenic clearance of uninfected erythrocytes [ 71 ]. However, the role of these processes in low-parasitaemia infections such as volunteer infection studies has been more difficult to define [ 16 ].…”

“…Second, in the P. vivax infection studies, the calculation of total parasite burden prior to antimalarial treatment did not account for parasite sequestration. Recent studies have suggested that in chronic P. vivax infection, a very high proportion of parasitized erythrocytes are sequestered in the spleen [ 52 ], and it has also been shown that splenic accumulation may occur even in early P. vivax infection [ 70 ]. It is possible that this may in part explain the low contribution of peripheral parasitized cells to the malaria-attributable erythrocyte loss, in this study and in others [ 14 ].…”

Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study

“…Splenic trauma or rupture are rare during clinical malaria and performing splenic studies in untreated clinical disease may require indirect, noninvasive evaluation. Recent positron emission tomography and magnetic resonance imaging in experimental human volunteer infection studies indicate greater splenic tropism and metabolic activity in early Pv infection compared to Pf [82], suggesting that splenic accumulation of Pv occurs even early in infection. Our cohort requiring splenectomy may also not be representative of the wider population.…”

Positron emission tomography and magnetic resonance imaging of the brain in experimental human malaria, a prospective cohort study

“…Non-human primate PET studies have identified intense FDG uptake associated with accumulation of parasites in the spleen 22 , and we have recently described enhanced splenic uptake in the same population of participants following both experimental P. falciparum and P. vivax infection. In the latter study splenic uptake was significantly increased in P. vivax compared to P. falciparum infection , suggesting splenic tropism with this species 16 , 23 . In the current study, interval change in radiotracer uptake was largely uniform across all brain subregions, irrespective of blood supply or white–grey matter differentiation for all participants.…”