Rapid diagnostic tests: The way forward?
Calls for research into treatments for developing world diseases are not new. But it's only recently that these have been for better diagnosis.
For malaria, good diagnostics are urgently needed to save lives, reduce overtreatment and ensure that the resources of overburdened health systems are directed to the right place.
But in developing countries, even if available, diagnostics are likely be outdated. Most healthcare is delivered in rural, 'peripheral' health centres with little facility for laboratory-based tests. Water and electricity supplies may not be available or reliable in such settings, and conditions may be hot, humid and dusty, with the added risk of pathogens from the environment contaminating samples.
It is not simply a case of transferring diagnostics from developed countries. As the Foundation for Innovative Diagnostics (FIND) says, "Impoverished populations need diagnostics that are better, not worse, than those in industrialised countries."
Diagnostic tests need to be quick, simple to use and easy to interpret with little training. They must also be completely self-contained, with no maintenance or calibration required. And they need to work — patients who have travelled miles to a health centre can't easily come back if a test doesn't work or takes days to give a result.
Rapid diagnostic tests (RDTs), which can diagnose infectious diseases in as little as five minutes, are being hailed as the solution.
But despite success in the laboratory, in the hot, humid areas where malaria is endemic, questions remain over how RDTs will fare. And even if they work, how can researchers persuade policymakers that RDTs are the way to go?
Malaria is often diagnosed on symptoms alone, which are shared with a number of other fever-causing diseases such as influenza and dengue fever.
This often leads to overtreatment by clinicians who have been trained for decades that fever means malaria. An estimated 500 million malaria treatments a year are prescribed for a different cause of fever. And in areas suffering high levels of malaria transmission, the WHO recommends that antimalarial drugs are given to all children with fevers.
But this practice endangers those patients who do not receive treatment for the true cause of their fever.
The practice is also immensely expensive for healthcare systems. "You can make a serious and unnecessary dent in a ministry of health budget with the level of overdiagnosis that we have at the moment," says Chris Drakeley from the UK-based London School of Hygiene and Tropical Medicine, who has worked extensively on malaria in Sub-Saharan Africa.
Overtreatment wasn't so much of a problem when older, cheaper antimalarials were being used, says Drakeley. But the newer, WHO-recommended artemisinin combination therapies (ACTs) can cost ten times as much as older drugs.
Moreover, overprescription of ACTs will inevitably lead to drug-resistance. "We don't have any drugs to replace them. If and when resistance develops to ACTs we'll see a huge resurgence [in malaria]," warns Prudence Hamade, head of the Malaria Working Group at Mèdicins Sans Frontiéres (MSF).
The international malaria community's proposal to subsidise the cost of ACTs globally will see them used more widely, raising the risk of resistance. Tighter controls will be needed for antimalarial distribution, fuelling the need for adequate diagnostics, says Hamade.
The current 'gold standard' for malaria detection uses microscopy to detect parasites in the blood, which can differentiate between the four types of malaria parasite. But microscopy is not always available — especially in the very poorest countries — and is not always performed and interpreted as well as it could be, says Drakeley.
Many people are treated for malaria when the parasite is not found in their blood and there's a lack of confidence in the medical profession for laboratory-based testing. Drakeley says this is often because doctors "know that the labs don't have the best microscopes or the best slides and the reagents are old".
Many people are treated for malaria when the parasite is not found in their blood
Training is also a problem, particularly in areas of low malaria transmission — as Drakeley says, it is difficult to train people when there are few parasites to see in samples.
RDTs seem ideal for scenarios with little laboratory equipment or highly-trained staff. The tests can detect parasite proteins — antigens — in blood taken from a finger prick. Antibodies on an absorbent strip detect the antigen if present and give a positive result, usually indicated by a change in colour.
There are two main types of RDTs widely available for malaria. The most common detects the histidine-rich protein 2 (HRP-2) antigen. The second detects the parasite enzyme lactate dehydrogenase (LDH).
These have their limitations. HRP-2 antigens can stay in the bloodstream for days or weeks after treatment, limiting the test's usefulness in distinguishing between treated or new infections. LDH will only be detected if live parasites are present in the blood.
HRP-2 tests can also only detect Plasmodium falciparum. LDH tests detect all types of the malaria parasite but studies have shown that the HRP-2 test is more sensitive in areas of medium to high malaria transmission, which describes much of the African continent.
Other, more practical, difficulties face the tests in the field.
It is not always possible to use RDTs under strict conditions in a busy outpatient clinic, says Drakeley. And even when the tests are performed well, negative results are still often ignored as doctors err on the side of caution and due to pressure from patients who feel they need antimalarial drugs.
Drakeley and his colleagues conducted a study of the HRP-2 test in northwest Tanzania. They found that half of the people who tested negative for malaria in the test were still given antimalarial drugs — a rate of overprescription similar to that after diagnosis with microscopy.
"We thought we were introducing a fancy new test that the doctors would automatically use and there'd be a drop in overtreatment of malaria — this clearly wasn't the case," he says, adding that doctors are often reluctant to take to new tests that don't have a body of evidence behind them.
But Heidi Hopkins, an assistant adjunct professor at the University of California, San Francisco in the United States, who researches RDT use in Uganda, found that adequate training overcame this reluctance.
She worked with the Uganda Malaria Surveillance Project and other partners to test training in HRP-2 tests at three sites in rural Uganda. They found that unnecessary antimalarial prescription was reduced to virtually zero.
Hopkins stresses that the training was not just in the technicalities of carrying out a test but also the management of patients with a fever, so that healthworkers have clear processes for what to do with positive and negative tests.
Rolling out training and RDT use nationally will be challenging.
Dr E Mwakasungula (left) of the Joint Malaria Programme in Tanzania training a health professional in RDT use
Dr Hugh Reyburn
"This pilot study was done at a relatively small number of sites, and our trainers were highly engaged and motivated. Larger-scale roll-out under "routine" circumstances may alter the effectiveness of the training," Hopkins says.
She says that in areas of low malaria transmission, for example, positive results would be rarely seen, which may give healthcare workers less confidence in RDT results.
For RDTs to achieve widespread use, people need to be confident in their accuracy, from the government buying the product to the health worker basing a decision on a test.
Getting consistency in the harsh and variable conditions where malaria is endemic is a major problem.
MSF has found, for example, that HRP-2 tests that worked well in Africa were not so effective in Colombia, probably because of genetic differences in P. falciparum that make slightly different HRP-2 antigens.
"We can't just use the same rapid test everywhere in the world — that's something that we didn't know in the beginning," says Hamade.
The WHO is currently testing a range of RDTs against standard positive and negative blood samples from a range of different countries to see which are the best and most appropriate in different areas. They are also testing for stability at different temperatures.
The Paracheck HRP-2 RDT
MSF/Bernard de Cock
According to David Bell, who runs the programme from the WHO's office in the Philippines, testing should be complete by late 2008, with a paper published a couple of months later that will provide national malaria programmes and other RDT-buying agencies with information on which might be best for them.
The WHO is also working with FIND to ensure that methods are in place to monitor the quality of RDTs at every point in the supply chain. This means testing at manufacture, at health centres to check that batches have survived the journey, and developing positive control wells on each RDT to show the user that it is working.
And RDT researchers continue to improve upon the tests themselves.
Tests that can distinguish between the different types of malaria parasite are top of the agenda, especially in parts of Asia where different subtypes are frequently present. Those that can distinguish between multiple diseases are also desirable.
Numerous research groups are developing "lab-on-a-card" tests — consisting of a disposable, credit card-sized piece of plastic containing the necessary reagents to detect different pathogens, those that cause fever for example. A stool or blood sample is placed at one end of the card and it is then placed in a small portable device that shakes the card, causing the reagents to react. Results can be gained in less than 20 minutes at a cost of around US$1–5.
Getting them out there
Yet many developing countries still see developing microscopy as the right direction for their malaria programmes, says Hamade. Most national malaria control programmes rely on funding from the Global Fund to Fight AIDS, Tuberculosis and Malaria, and RDTs are not a part of many funding bids.
But national malaria programmes are beginning to realise their effectiveness, she says. The Global Fund, for one, is becoming more aware of the importance of diagnostics.
Large international donors such as the Bill and Melinda Gates Foundation are also funding work on diagnostics for the developing world. The Gates Foundation, for example, is one of the funders of FIND's work with the WHO, along with a large tuberculosis diagnostics programme, and laboratory research programmes.
But while diagnosis may finally be getting the attention it deserves, RDTs themselves will play only a part in eradicating malaria, and could even be a victim of their own success.
As malaria control shifts towards an elimination scenario, incongruously, this will mean the return of the microscope and the scaling down of RDT use, says Drakeley.
"In theory, cases will become so infrequent that you'll have to have a very accurate diagnosis — which RDTs aren't suitable for."