Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria.

Enhanced therapeutic efficacy achieved in treating Plasmodium vivax malaria with an 8-aminoquinoline (8-AQ) drug such as primaquine (PQ) together with a partner drug such as chloroquine (CQ) is usually explained as CQ inhibiting asexual parasites in the bloodstream and PQ acting against liver stages. However, PQ's contribution, if any, to inactivating non-circulating, extra-hepatic asexual forms, which make up the bulk of the parasite biomass in chronic P. vivax infections, remains unclear. In this opinion article, I suggest that, considering its newly described mode of action, PQ might be doing something of which we are currently unaware.

How does primaquine prevent Plasmodium vivax malarial recurrences?

Flannery et al. and Luiza-Batista et al. recently reported on liver and blood stages of Plasmodium vivax in humanized mice. The biology of P. vivax can be investigated using the mouse models, which will also facilitate drug research. This could lead to better treatment and control of P. vivax malaria.

Theoretical origin of genetically homologous Plasmodium vivax malarial recurrences.

Malaria caused by Plasmodium vivax is being diagnosed with increasing frequency in Africa. Some southern countries where it has been detected are Angola, Botswana, Mozambique, Namibia, Zambia and Zimbabwe. Knowing the parasite origin of P. vivax infection recurrences (which can be reinfections, recrudescences or relapses) is important epidemiologically for malaria elimination in Africa. Although hypnozoites will no doubt be a source, we should try to determine how frequently the origin of non-reinfection recurrences of P. vivax malaria involving closely related parasites may be non-circulating merozoites rather than hypnozoites.

Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives.

This article is inter alia a brief, first-stop guide to possible adverse events (AEs) associated with tafenoquine (TQ) intake. Safety and efficacy findings for TQ in Plasmodium vivax malaria prophylaxis and radical cure are summarized and some of the latest TQ-related studies (published in 2020 and 2021) are highlighted. In addition, little-known biological and other matters concerning malaria parasites and 8-aminoquinoline (8-AQ) drug action are discussed and some correct terminology pertinent to malaria is explained.

Transition from Plasmodial Hypnozoite to Schizont Demonstrated.

The progression to schizont formation of individual activated hypnozoites has been observed in vitro for the first time by Voorberg-van der Wel et al. Green-fluorescent protein-positive hypnozoites turned red-fluorescent (mCherry) upon activation. Thus, we now have empirical parasitological proof that supports the 40-year-old hypnozoite theory of relapse in malaria.

Killing of Plasmodium vivax by Primaquine and Tafenoquine.

Primaquine administration results in H2O2 accumulation in bone marrow, where gametocytes and asexual parasites are therefore killed. This finding, by Camarda et al., supports the theory that the nonperipheral blood origin of recurrent Plasmodium vivax malaria is both hypnozoites (relapse source) and merozoites (recrudescence source), not hypnozoites only.

New Evidence for Hypnozoite-Independent Plasmodium vivax Malarial Recurrences.

Information provided in recent, related papers has wide-ranging implications concerning, inter alia, the transmission of malaria, drug treatment, and eradication of the disease. Additionally, the research results represent support for the idea that recurrences of Plasmodium vivax malaria can arise from both liver hypnozoites and extravascular merozoites in bone marrow.

Biological concepts in recurrent Plasmodium vivax malaria.

A curious aspect of the evolution of the hypnozoite theory of malarial relapse is its transmogrification from theory into 'fact', this being of historical, linguistic, scientific and sociological interest. As far as it goes, the hypnozoite explanation for relapse is almost certainly correct. I contend, however, that many of the genotypically homologous, non-reinfection, relapse-like Plasmodium vivax recurrences that researchers ascribe to hypnozoite activation are probably hypnozoite-independent. Indeed, some malariologists are starting to recognize that homologous P. vivax recurrences have most likely been overattributed to activation of hypnozoites. Hitherto identified, non-hypnozoite, possible plasmodial sources of recurrence that must be considered, besides circulating erythrocytic stages, include parasites in splenic dendritic cells, other cells in the spleen (in addition to infected erythrocytes there), bone marrow (importantly) and the skin. I argue that we need to take into account the possibility of a dual or multiple extra-vascular origin of P. vivax non-reinfection recurrences, not arbitrarily discount it. The existence of a P. vivax reservoir(s) is a topical subject and one of practical importance for malaria eradication. Pertinent drug-associated matters are also discussed, as is the dormancy-related significance of clues provided by blood-stage-induced malarial infection.

Malaria Eradication and the Hidden Parasite Reservoir.

Accumulation of erythrocytic parasites in bone marrow and the spleen has been reported in cases of Plasmodium vivax malaria. If this occurs commonly, these stages represent a possible source of early, relapse-like homologous recurrences. Moreover, they might hinder the elimination of malaria from human populations. Pertinent research suggestions have been made.

Mouse-Based Research on Quiescent Primate Malaria Parasites.

Mice engrafted with primate tissue make two important plasmodial dormancy-related questions researchable. The first is concerned with whether latent merozoites in the lymphatic system can give rise to relapse-like, recurrent malaria in primates. The second is that genetic evidence of hypnozoite activation as the source of relapsing primate malaria can be looked for.

Do hypnozoites cause relapse in malaria?

The concept that hypnozoites give rise to relapses in Plasmodium vivax and Plasmodium ovale malaria has become dogma. However, it is evident from particular contemporary research findings that hypnozoites are not necessarily the origin of all relapse-like recurrences of malaria caused by these parasites. This is the core opinion presented, and I discuss it fully. The hypnozoite theory of relapse needs to be re-evaluated in view of the recent, increased focus on P. vivax and liver stages of Plasmodium. Hypnozoites have also assumed a new significance because they might, by facilitating ongoing transmission, be a threat to the current (post-2007) goal of eliminating malaria globally. I have suggested some new research directions for finding putative nonhypnozoite sources of recurrent malaria.

Dormancy in mammalian malaria.

This analysis principally concerns biological aspects of dormancy in mammalian malaria, with particular reference to the hypnozoite. Research is needed to reveal what happens to sporozoites of Plasmodium cynomolgi between the time of inoculation and when hypnozoites are first seen in the liver 36-40 h later. It is likely that hypnozoites of relapsing malarial parasites will prove to be directly sporozoite-derived rather than merozoite-derived. There is indirect evidence that, contrary to what is generally assumed, activation of hypnozoites might not be the only cause of recurrent Plasmodium vivax malaria. Latent stages pose a threat to success in eradicating malaria; some suggestions are therefore made for demystifying work on hypnozoites and quiescent merozoites.

The hypnozoite concept, with particular reference to malaria.

In 1978, the nature of the hypnozoite was discussed in an article that appeared in a relatively obscure journal, which is also where the term was adopted for Plasmodium (a little-known fact). As a result, that commentary on the use of the word "hypnozoite" has been almost completely overlooked. Although the publication is now more than three decades old, the analysis remains valid today. It is explained in the present paper that like "merozoite" and "sporozoite", the name "hypnozoite" is applicable not only to a latent stage in the life cycle of Plasmodium but to some apparently dormant forms of other kinds of apicomplexan parasites as well. Merozoites of different genera of parasitic protozoa are not necessarily the same biologically and/or otherwise. Similarly, although the hypnozoite concept relates primarily to pre-merozoite stages, some atypical post-divisional apicomplexan forms might also be hypnozoites. Examples are likewise given of latent organisms that, in contrast, are clearly not hypnozoites, such as dormant merozoites in malaria infections. Lastly, the plasmodial hypnozoite is placed in context in relation to the relatively unfamiliar (nomenclaturally) malarial bradysporozoite, chronozoite, dormozoite, merophore, merosome and x body. This paper is based on a presentation by the author, as a Life Member of the American Society of Tropical Medicine and Hygiene, to its 59th Annual Meeting in Atlanta, Georgia, USA, 3-7 November 2010.