• by Bruce Carlson
  • October 26 2018

Despite Gains Over Malaria Infections, Diagnostics Need Still Growing

Deaths from malaria have fallen steadily worldwide over the past 20 years due to intensive global investment in malaria prevention and treatment. The malaria mortality rate fell by 60 percent from 2000 to 2015 worldwide, while the incidence is estimated to have decreased by 37%, according to the World Health Organization (WHO). A growing number of countries have nearly or completely eliminated the disease.

Despite this tremendous progress, malaria is still a widespread disease and laboratory testing for malaria is still in high demand. Nearly half of the world’s population is still at risk of contracting malaria, by some estimates. Even in 2015, when mortality and incidence rates had fallen, there were still roughly 212 million malaria cases and an estimated 429,000 malaria deaths, the WHO reports. About 90 percent of those malaria cases and deaths occurred in Sub-Saharan Africa.

Current state of testing

The gold standard for malaria testing is still the classic blood smear. A drop of blood is smeared across a slide and stained, then an experienced laboratory professional examines it under a microscope for signs of infected red blood cells and the Plasmodium parasite.

However, high-quality microscopes and experienced laboratory professionals are not always available in malaria endemic areas so a market has arisen for malaria rapid diagnostic tests (RDTs), or “dipstick” tests. These tests detect proteins produced by the Plasmodium parasite in the infected person’s blood via lateral flow immuno-chromatographic antigen-detection. A drop of finger-prick blood is applied to a cassette along with a buffer, and a colored line appears in a display window to indicate a positive result.

Only one malaria RDT is FDA approved for use in the United States, the BinaxNOW Malaria test sold by Abbott. It provides a result in about 15 minutes and negative results need to be confirmed with a blood smear. Also, a blood smear is required to determine which species of malaria was detected and the severity of the infection.

There are more than 200 malaria RDT products on the market worldwide, all designed on the same general principle, with sales of about 312 million tests in 2016. Sales in Africa increased from 240 million in 2015 to 269 million in 2016. The WHO encourages their use in its effort to have people tested for malaria before beginning treatment. The organization has launched programs to evaluate the quality and performance of the various RDTs and offers advice to organizations that procure them and to researchers who want to evaluate them.

The demand for rapid testing is growing, in part due to malaria drug resistance, according to the Malaria Consortium. In the past in areas where microscopy was not available, clinicians would treat almost all instances of fever as a potential case of malaria and start relatively inexpensive chloroquine or sulfadoxine-pyrimethamine therapy. As Plasmodium has grown resistant to these drugs, many countries now recommend artemisinin-based combination therapy as first-line treatment. This treatment is more expensive and as a result, there is a stronger financial incentive to test for malaria and receive a positive result before initiating treatment.

Future directions for malaria tests

While the market for malaria RDTs remains strong, a new development could impact how these tests are designed.

Some malaria RDTs are made to indicate the presence of any of the four species of Plasmodium that cause human disease by detecting universal antigens, such as aldolase or plasmodium lactate dehydrogenase (pLDH). Other RDTs detect only P. falciparum, the parasite responsible for the deadliest type of malaria. The most common antigen detected by these tests is Plasmodium falciparum histidine-rich protein 2 (PfHRP2).

In the past few years, academic researchers have been monitoring the spread of P. falciparum strains that have a deletion mutation for PfHRP2. The mutation has been found in Central America, India, and other malaria endemic regions outside of Africa. Some of these mutant strains also lack P. falciparum histidine-rich protein 3 (PfHRP3), which cross-reacts with PfHRP2. In these double-mutation parasites, an RDT test would produce a false negative result, and risk leaving infected individuals untreated and capable of spreading the disease.

Deletion mutations have not risen to the level of public health significance yet. The prevalence of mutations is low, and in regions outside of Africa, P. falciparum accounts for only a small percentage of malaria cases. Still, the WHO is monitoring the spread, as the mutations could render RDTs less effective in the future unless the tests are redesigned.

Meanwhile, the latest malaria diagnostic tests are moving toward increased sensitivity. The Alere™ Malaria Ag P.f test is marketed as “ultra-sensitive” RDT and can detect parasites in individuals who have such a low level that they don’t have symptoms. There are also molecular techniques available, such as quantitative polymerase chain reaction (PCR) tests, though the cost of PCR limits their use in malaria endemic regions. These new tests are so sensitive that they exceed the needs of basic clinical use, which has public health experts wondering how best to take advantage of them. One idea is to use them to detect hidden reservoirs of the parasite in order to identify and treat asymptomatic infected people and reduce transmission.   

Finally, there is a demand for point of care tests for glucose-6-phosphate dehydrogenase (G6PD) deficiency. This relates to P. vivax, a species of Plasmodium that causes a less severe, relapsing form of malaria and is the most common Plasmodium species in malaria-endemic tropical areas. Active infections caused by P. vivax can be treated with the same drugs as P. falciparum. However, P. vivax remains dormant in the liver between active infections. A different class of drugs is required to clear the parasite from the liver and render a complete cure. These drugs work well, but doctors hesitate to prescribe them because a small subset of patients – those with G6PD deficiency – have a potentially fatal reaction. If G6PD deficiency tests were cheap and freely available in endemic regions, more patients could safely receive treatment for P. vivax. Abbott offers an FDA-cleared point of care G6PD deficiency test: the BinaxNOW G6PD Test, a qualitative screening test that distinguishes normal from deficient G6PD activity level. However, PATH, a public health nonprofit organization, is pushing for the development of a quantitative point of care G6PD deficiency test that can more accurately distinguish among intermediary deficiencies, which is critical for treatment decisions. The FDA approved a new drug for treating dormant P. vivax in July 2018 (Krintafel [tafenoquine] from GlaxoSmithKline), capable of curing relapsing malaria in a single dose. With the arrival of an exciting new treatment, there is even more of a need for a rapid, cheap point of care G6PD deficiency test to guide its use.

While great strides have been made in been made in reducing malaria infections worldwide, the disease is by no means conquered. As the WHO reminds us, it has taken a tremendous financial and political commitment to get to where we are today, and it will take a powerful, coordinated global response to meet the goal reducing the global malaria burden by 90% by 2030. The gains achieved since 2000 are “fragile and unevenly distributed,” according to the WHO Global Technical Strategy for Malaria 2016–2030 report. “The human toll of malaria, and the global risk it still poses, remains unacceptably high.”