Editorial: Global perspectives on severe vivax malaria: incidence, outcomes, and biological mechanisms

Plasmodium vivax malaria was always considered as benign infection in comparison to Plasmodium falciparum malaria, but recently this view has changed significantly as more clinical and molecular evidence confirms that P. vivax can also lead to severe and life-threatening complications. These complications include cerebral malaria, severe anemia, acute respiratory distress syndrome, liver dysfunction, and acute kidney injury. The increasing recognition of severe vivax malaria has led to renewed efforts to understand its spread, causes, and treatment challenges.

The articles in this Research Topic offer different perspectives on severe vivax malaria. They highlight the complex interactions among parasite biology, host genetics, and treatment approaches. Together, they emphasize that effective malaria control requires a deep understanding of both the biological factors that drive severe disease and the practical challenges of managing it.

One major challenge in controlling vivax malaria is achieving safe and effective radical cure. Primaquine is currently the only widely available 8-aminoquinoline that can eliminate dormant liver-stage hypnozoites, which cause relapses. However, its use is complicated by host genetic factors, especially glucose-6-phosphate dehydrogenase (G6PD) deficiency and variations in drug metabolism. A clinical trial included in this Research Topic assessed low-dose primaquine given with artemether-lumefantrine or dihydroartemisinin-piperaquine in the Solomon Islands. While both combinations reduced recurrent parasitemia compared to treatments without primaquine, neither achieved optimal radical cure efficacy. These results indicate that currently recommended lower-dose regimens may not be enough in areas where relapsing parasite strains are common. They also highlight the need for optimized dosing strategies that balance effectiveness and safety.

A further challenge in achieving effective radical cure is poor adherence to the conventional 14-day primaquine regimen, which can contribute to treatment failure and recurrent infections. In addition, regional variations in parasite responses to antimalarial therapies must be taken into account, as these may reflect differences in parasite genetic diversity, drug susceptibility, transmission intensity, and other local epidemiological factors. In this context, tafenoquine warrants parallel consideration alongside primaquine as an alternative short-course anti-relapse therapy. Its single-dose regimen may help overcome adherence barriers associated with prolonged primaquine treatment. However, tafenoquine is not a universal replacement for primaquine and has important limitations, including the absolute requirement for reliable quantitative G6PD testing and contraindications or restricted use in individuals with significant G6PD deficiency, as well as the need for careful patient selection and safety monitoring. Therefore, the choice of radical cure should be individualized according to the patient’s G6PD status, regional parasite characteristics, local drug availability, and the realistic likelihood of adherence.

The significance of safety issues is further highlighted by a case report of primaquine-induced hemoglobinuria in a G6PD-deficient patient with the Mahidol variant from Bangladesh. This case shows the potential severe outcomes of administering primaquine without prior G6PD screening, leading in acute severe hemolysis requiring blood transfusion. The report emphasizes the practical value of point-of-care G6PD testing and genetic screening in areas where malaria is common. As global malaria programs improve access to radical cures, incorporating reliable G6PD diagnostics into everyday clinical practice will be crucial in minimizing adverse outcomes while ensuring effective relapse prevention.

In addition to treatment challenges, it remains essential to understand the biological basis of severe vivax malaria. The genomic study included in this Research Topic offers new insights into parasite factors that may be linked to disease severity. By using comparative genomic hybridization, researchers found numerous copy number variations in the P. vivax genome in isolates associated with cerebral malaria, in comparison to uncomplicated infections. These genomic changes affected genes involved in host-cell invasion, immune evasion, and drug resistance, suggesting that structural genomic variation might play a role in parasite adaptation and virulence. While further investigation is needed to determine the functional consequences of these genomic changes, the findings provide a valuable basis for identifying biomarkers of severe disease and understanding the evolutionary factors underlying parasite pathogenicity.

In patients of severe vivax malaria, there is a strong need to understand its biological determinants of disease severity. In this context, the study by Tahbildar et al. provides valuable insights into the genomic landscape of severe P. vivax infections through genome-wide analysis of copy number variations (CNVs). Using a high-resolution comparative genomic hybridization platform, the authors identified extensive CNVs across all 14 chromosomes of P. vivax isolates obtained from cerebral malaria cases. Notably, alterations were detected in genes involved in erythrocyte invasion, immune evasion, cytoadherence, and antimalarial drug resistance. Amplifications in multidrug resistance-associated genes, reticulocyte-binding proteins, merozoite surface proteins, and virulence-associated vir gene families suggest potential mechanisms that may enhance parasite adaptability and pathogenicity.

Importantly, the study also highlights CNVs within intergenic regions, raising the possibility that regulatory genomic elements contribute to parasite fitness and disease outcomes. Although the limited sample size precludes definitive causal inferences, these findings represent a pioneering effort to characterize structural genomic variation in severe P. vivax malaria.

Overall, these studies reinforce several key points. First, severe vivax malaria is a real clinical condition with multiple factors affecting both host and parasite biology. Second, managing this disease effectively goes beyond just clearing the parasite; it also requires considering host genetic factors that affect treatment safety and effectiveness. Third, advancements in molecular epidemiology and genomics are deepening our understanding of parasite diversity and may help in developing better diagnostic, prognostic, and therapeutic tools.

The combination of clinical medicine, pharmacogenomics, and parasite genomics shown in this Research Topic reflects the multidisciplinary approach needed to tackle the evolving challenges presented by P. vivax. As malaria elimination efforts progress, the ongoing issues of relapsing infections, emerging drug resistance, and severe clinical forms could threaten control efforts. Future research should focus on integrating genomic surveillance, enhancing point-of-care diagnostics, personalizing radical cure approaches, and conducting long-term clinical studies to better identify the factors that contribute to severe disease and treatment outcomes vital for creating safer and more effective strategies for malaria control and elimination worldwide.

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Footnotes

Edited and reviewed by: Ghyslain Mombo-Ngoma, Centre de Recherche Médicales de Lambaréné, Gabon