The burden of Plasmodium vivax malaria has been grossly underestimated, according to a report in PLOS Medicine. The study was conducted by J. Kevin Baird, PhD, Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia, and colleagues.
There are five types of malaria infections. P falciparum receives the bulk of the attention, inasmuch as it causes 193.5 million cases each year. P falciparum cases are more fulminant, killing many within 2 weeks of diagnosis. P vivax causes 14.3 million cases per year, and infections are more indolent, but patients are twice as likely to die over the long term.
(The other three types — Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi — are more region-specific and likely make up less than 5% of cases of malaria globally.)
In an interview with Medscape Medical News, Baird described a child who was near death: “She was dying slowly, not quickly and spectacularly, like with P falciparum, but slowly. She was just being ground into the earth by this infection. And to me, that is how P vivax causes harm. And we don’t count it. We don’t measure it.” He said the tendency is to attribute the child’s “dwindles,” or gradually declining health, to other things — to diarrhea, to malnutrition, or to other chronic infections.
Baird also said that it’s important to overturn the long-held belief that there is little P vivax in Africa and that many people are immune because of being “Duffy negative,” or lacking a red blood cell receptor antigen for the malaria parasite.
“We have to entertain the possibility that the immunity of Duffy negativity for endemic vivax in Africa is an illusion,” Baird said. “It may well be that Africa is home to endemic transmission of the virus that doesn’t frequently appear in the diagnostics that we use to see parasites…. Parasitemia is a flawed way to measure the burden of this infection.”
Vivax parasites reside in the spleen, liver, and bone marrow and so are not detected on blood smears, which is the traditional way of diagnosing malaria. Serologic surveys in sub-Saharan Africa indicate that the prevalence is 11% to 60%. Polymerase chain reaction is valuable for diagnosis.
Emphasizing the need for better diagnostic tools, Baird added, “So you can have a thriving infection and transmission without parasitemia.”
Ric Price, MD, professor of global health, Menzies School of Health Research, Darwin, Australia, told Medscape Medical News, “The hidden reservoir of infection [with vivax] makes it quite difficult to quantify because…it’s not causing clinical disease…. It makes it much more difficult to eliminate.” Price previously worked with the study’s authors but was not involved in this study.
He added, “Recurrent episodes of malaria can cause a cumulative risk of anemia, and that has effects on stunting, on malnutrition, and anemia. And when that anemia becomes severe, the patients are more susceptible to other diseases: sepsis, respiratory tract disease, and diarrhea…. This is an indirect mortality.”
Options to treat the hypnozoites in the liver stages of vivax infection are limited. “Primaquine and taquenofine are 8-aminoquinolones, and they are the only drugs that can affect the liver stages,” Bright continued.
Baird and Price noted the importance of two genetic polymorphisms. First, “With treatment of P vivax, people who have severely impaired or null cyp2CD6 genotypes failed treatment,” Baird told Medscape. This is because “primaquine is a prodrug; it has to be activated by cyp2CD6 in order to work.”
The second polymorphism is that of G6PD deficiency. Price said this “was actually selected throughout Africa and Asia because it protects you against malaria, like sickle cell with falciparum.” The problem with G6PD deficiency is that primaquine and tafenoquine can cause a life-threatening acute hemolytic anemia in those who are deficient of this enzyme.
In summary, P vivax is widespread, and the burden of this disease is greater than has been previously understood. Genetic polymorphisms of Duffy, cytochrome P450 cyp2D6, and G6PD affect the manifestations and treatment of malaria; G6PD deficiency has the most notable impact. Inability to treat the latent stage seriously limits the ability to eradicate P vivax malaria.
Baird and Price have disclosed no relevant financial relationships.
PloS Med. Published online October 7, 2021. Full text
Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.