Can we be sure that the human Plasmodium exoerythrocytic developmental stages occur exclusively in the liver?

The development cycle of the malaria parasite, Plasmodium sp., in humans takes place after an infected female Anopheles mosquito injects motile infective forms called sporozoites into the bloodstream. Sporozoites migrate via blood vessels to the liver. This pre-erythrocytic tissue stage is widely accepted to occur in humans exclusively in the liver, contrary to avian malaria where this may occur also in other parenchymatous organs. This concept is based on research conducted by English researchers Henry Shortt and P.C.C. Garnham in the late 1940s. Although Italian researchers as, e.g., Giulio Raffaele, additionally claimed the presence of the parasites in the bone marrow, this is not well acknowledged. So, the question remains whether there exists also a tissue life cycle stage in humans.

Malaria relapses were already known before 1900-a discussion.

For a long time, only two phases of the life cycle of the agents of malaria parasites were known: the cycle inside the mosquito body and the cycle in the red blood cells of humans as intermediate hosts. A possible tissue development cycle inside humans, however, had already been proposed before 1900. In general, Pieter Klaesz Pel is considered the first scientist who has described such a tissue cycle. However, a closer look at Pel's work shows that he still followed an old (conservative) way of thinking, since he still referred to "malaria poison and malaria miasma." Thus, the first idea of a possible tissue cycle must be searched in the work of earlier scientists. Referring to their observations on malaria, Vassilij Danilevsky, Arman Ruffer, Camillo Golgi and Battista Grassi suspected developing parasites in internal organs, before they can be found in the bloodstream.

Clinical implications of a gradual dormancy concept in malaria.

Malaria recurrences after an initially successful therapy and malarial fever occurring a long time after infection are well-known problems in malariology. Currently, two distinct types of malaria recurrences are defined: recrudescence and relapse. A recrudescence is thought to originate from circulating Plasmodium blood stages which do not cause fever before a certain level of a microscopically detectable parasitemia is reached. Contrary, a relapse is thought to originate from quiescent intracellular hepatic parasite stages called hypnozoites. Recrudescences would typically occur in infections due to Plasmodium falciparum. Plasmodium knowlesi, and Plasmodium malariae, whereas relapses would be caused exclusively by Plasmodium vivax and Plasmodium ovale. This schematic view is, however, insufficiently supported by experimental evidence. For instance, hypnozoites of P. ovale have never been experimentally documented. On the other hand, the nonfinding of P. malariae hypnozoites turned into the proof for the nonexistence of P. malariae hypnozoites. Clinical relapse-type recurrences have been observed in both P. ovale and P. malariae infections, and decade-long incubation times have also been reported in P. falciparum infections. We propose a gradual hypothesis in accordance with the continuity concept of biological evolution: both, relapse and recrudescence may be potentially caused by all Plasmodium spp. We hypothesize that the difference between the various Plasmodium spp. is quantitative rather than qualitative: there are Plasmodium spp. which frequently cause relapses such as P. vivax, particularly the P.v. Chesson strain, species which cause relapses less frequently, such as P. ovale and sometimes P. malariae, and species which may exceptionally cause relapses such as P. falciparum. All species may cause recrudescences. As clinical consequences, we propose that 8-aminquinolines may be considered in a relapse-type recrudescence regardless of the causal Plasmodium sp., whereas primaquine relapse prevention might not be routinely indicated in malaria due to P. ovale.

Why do Plasmodium malariae infections sometimes occur in spite of previous antimalarial medication?

Quartan malaria due to Plasmodium malariae is commonly regarded as being preventable by current antimalarials. A case of P. malariae infection occurred in spite of previous treatment of Plasmodium falciparum malaria 4 months earlier with a full therapy course of intravenous quinine hydrochloride and oral doxycycline followed by artemether + lumefantrine. Since the patient was not anymore exposed to agents of malaria in the meantime, a new infection by P. malariae after therapy is unlikely. The present observation is difficult to explain by the current view on the origin of latent P. malariae infections and recurrences which are thought to arise from intra-erythrocytic development stages susceptible to common antimalarials. The most likely explanation of our observation is a delayed pre-erythrocytic development. The latency between infection by P. malariae and the quartan malaria fever attack might have been extended further by an initial subclinical circulation of a low number of intra-erythrocytic asexual parasites in the blood stream preceeding the clinical quartan malaria breakthrough.

What is the evidence for the existence of Plasmodium ovale hypnozoites?

Relapsing human malaria is regarded to be caused by Plasmodium vivax and Plasmodium ovale. P. vivax relapses originate from dormant liver stages: "hypnozoites". Also, P. ovale, a species considered as closely related to P. vivax, is in analogy assumed to display hypnozoites. A close biologic relationship is, however, not supported by molecular genetic studies. Therefore, original literature published since the description of P. ovale in 1922 was systematically screened for the demonstration of hypnozoites or circumstantial evidence for their existence, i.e. the occurrence of true relapses. In P. ovale infection, hypnozoites have never been demonstrated by biological experiments, and the few reports published on relapses have conflicting results.