by J. Kevin Baird
University of Oxford and Eijkman Institute for Molecular Biology Jakarta, Indonesia
Malaria is an acute febrile illness caused by infection with any of five species of protozoan obligate parasites in the genus Plasmodium. These infections are transmitted via the bite of specific species of mosquitoes in the genus Anopheles. While most of Africa has only three species of those mosquitoes, the Asia-Pacific has several dozen of them transmitting malaria in a very wide variety of habitats.
Over 4 billion people live in the Asia-Pacific and almost half of them live where there is risk of acquiring malaria, and yet few people seem aware of this problem. What explains the invisibility of malaria in the Asia-Pacific? Despite extraordinary economic and technological regional progress of the past decades, very large numbers of Asians today live at the very far edges of that progress. They live in rural, remote and isolated communities beyond the reach of the benefits of even these dramatic advances, and also out of the reach of clinical and public health services. The poor health outcomes of inadequately managed malaria occur beyond the sight and reach of geographically stretched and often underfunded healthcare delivery services.
The World Health Organization (WHO) estimates that less than 10% of the global burden of malaria occurs in the Asia-Pacific. However, that estimation requires quantifying the global burden, something that experts agree the WHO cannot robustly achieve. Sickness and death caused by malaria is extremely hard to quantify, and WHO strives to do that with crude adjustments to reported confirmed cases and deaths adjusted for surveillance inefficiencies that usually cannot actually be measured. The experts at WHO concede this and express the value of the estimates is in analysis of trends over time. That important message of inherent limitations, however, seems lost when they quantify global burdens among the regions affected.
A study in India published in the Lancet in 2010 (376: 1768) found that 86% of deaths occurred at home in villages rather than in health centers where diagnosis and reporting of causes of death could occur. The same study estimated that 205,000 deaths caused by malaria in that nation alone in 2006, whereas the WHO estimated just 15,000 deaths in the same year. Which estimate is closer to the truth? We don’t know because so much malaria in the region cannot be seen in both technical and social senses.
The See Malaria in Asia Project aims to elevate public awareness of the suffering imposed by malaria all across the region. But people in the burgeoning biotechnological industries of the region should also be aware of the technical invisibility of malaria.
The gold standard for the diagnosis of malaria has not changed in 135 years – microscopic examination of a stained blood film and visual identification of the parasites within red blood cells. Competency at this visual interpretation art requires weeks of intensive training and constant practice. A master can detect about 10 parasites per microliter blood in a routine examination, and standard competency is about 50 parasites per microliter. In many areas of the Asia-Pacific these levels of parasitemia occur only in 1 of every 5 people infected, and most of the low-grade infections do not cause illness but do infect mosquitoes and sustain onward transmission. That invisible asymptomatic sub-patent reservoir is one of the greatest technical challenges to malaria control and elimination in this region. If we cannot see most of those infected, we also cannot treat them.
Immunochromatographic cassettes called rapid diagnostic tests (RDT) for malaria do not require the skill level of microscopy or any sort of laboratory equipment. People with minimal training may use RDTs at the very far peripheries of healthcare delivery, and that is the greatest advantage. They are less sensitive than competent microscopy (about 100 parasites/uL, but highly dependent on brand). Most kits use antibody capture of a parasite protein called histidine-rich protein 2 (and 3 by cross-reactivity). Unfortunately, reports of mutant strains of parasites that have deleted these proteins effectively blinds these RDTs. This is a very dangerous problem and likely to worsen rapidly given the broad coverage of RDTs globally.
A standard polymerase chain reaction (PCR) diagnosis of malaria is sensitive to about 1 parasite per uL, meaning even this state-of-the-art diagnostic is blind to any number of parasites below that threshhold. In any event, under most circumstances a PCR diagnosis is impractical in terms of cost, required expertise, and time of assay for routine diagnostic application.
A particularly tough problem
Another invisibility problem with Asia-Pacific malaria is the latent stages of Plasmodium vivax and Plasmodium ovale. When a mosquito carrying one of these species bites a human, a clinical attack usually occurs in about ten days. It takes that long for the parasite to develop in the liver into forms that can infect red blood cells. But that same bite also placed forms in the liver that did not immediately develop. They went dormant and awaken in the weeks and months to follow the bite, up to about 2 years. When they do so, a clinical attack called a relapse occurs and it is every bit as sickening and dangerous as the primary attack. In endemic areas, most acute attacks of vivax malaria derive from these liver forms rather than mosquito bites. Infection by those latent stages cannot be diagnosed before they relapse.
The way medicine deals with those latent stages is to prescribe presumptive anti-relapse therapy with a drug called primaquine to patients diagnosed with acute vivax malaria. The treatment prevents relapse by killing the latent stages as they sleep. But there is a serious problem with this drug – it is hemolytically toxic to patients who have an inborn abnormality called glucose-6-phosphate dehydrogenase (G6PD) deficiency. The toxicity is so extreme that a normal therapeutic regimen of primaquine can end in death. About 8% of Asians living where malaria is endemic have G6PD deficiency. If providers prescribe primaquine without knowing G6PD status, they risk serious harm caused by the drug. If they withhold primaquine therapy, they risk serious harm caused by the parasite. This is called a therapeutic dilemma and may be addressed with point-of-care diagnostics for G6PD deficiency. Biotechnology has only produced such kits within the past 5 years, and only 2 are commercially available today.
The business of seeing malaria is social as well as technical — we cannot attack an unseen problem. Asia-Pacific has a great deal of room for improvement in both arenas. We need both much greater awareness and far better diagnostics. There may be much more malaria in the region than now perceived by the unreliable WHO quantitative regional apportionments. Progress in awareness and technology may ultimately bring malaria into far sharper epidemiological focus and directly inform efforts aimed at eliminating it once and for all.
Photo Credit: Pearl Gan in association with Oxford University Clinical Research Unit, Vietnam; Eijkman Oxford Clinical Research Unit,
Jakarta and The Wellcome Trust.