iClinic - September 13, 2000
Médecins Sans Frontières

The need is therefore for simple, rapid and cheap diagnostic assays which can screen the large numbers of the world's poor who are at risk of debilitation or death from HIV, malaria, tuberculosis and some of the nastier tropical diseases such as lymphatic filariasis.

This is no easy task, according to Mark Perkins, head of diagnostics research at the World Health Organisation (WHO).

Cost, complexity and the lack of trained personnel rule out many of the newer techniques used in the rich world - such as the polymerase chain reaction, which can pinpoint HIV and other infectious agents using genetic probes.

Nevertheless, a number of small firms are busy trying to simplify, speed up and, if possible, cheapen the process of diagnosing infection, so that doctors in the tropics can reliably determine what is wrong with their patients.

Testing, testing

Among these firms is Sequella, a biotechnology and diagnostics company based in Rockville, Maryland, US. Its researchers have developed two tests for tuberculosis, of which there are eight million new cases every year. These tests, they believe, are distinct improvements on the traditional means of detecting the disease.

Those involve the laborious process of "tuberculin-testing" with injections of a mixture of tuberculosis proteins, followed by chest X-rays and finally the isolation of the guilty bacteria from a patient's sputum. All of this takes more than a month.

Sequella is busily testing a skin patch that is impregnated with a protein called MBP64, which is derived from a strain of tuberculosis normally used for vaccination.

Tests in Japan and the Philippines show that after three days with the skin patch, those infected with Mycobacterium tuberculosis, the germ that causes tuberculosis, develop redness and swelling round it. That distinguishes them from those who have merely been vaccinated against the disease: they do not react to MBP64, but do come out positive, along with the actively infected, in tuberculin testing.

According to Sequella, early trials show that the patch picks up 98% of those infected, yields few false positives and is easier to use in the field than tuberculin-testing, since no needles are required. The firm hopes to launch it within two years.

Sequella's other tuberculosis technology is called the "Bronx box". This is used to detect antibiotic-resistant bacteria, which are a growing problem for those fighting the disease.

The trick begins with a type of virus called a bacteriophage. Phages are parasites of bacteria, and the phage that Sequella works with specialises in M. tuberculosis.

Genetic engineers have, however, tinkered with the phage, and have arranged for it to produce a fluorescent protein called luciferase when it infects a bacterium.

The "Bronx box" test, so called because its inventor, Bill Jacobs, works at Albert Einstein University in New York, involves taking a sputum sample from a patient, adding the souped-up phage to it and incubating the mixture for a couple of days in the presence of various antibiotics.

Those bacteria that are resistant to one drug, but not another, will thrive in the one culture but not the other, thereby providing a healthy home for the phages, which churn out luciferase and produce light that can be detected on X-ray film.

Another approach to cheap diagnosis is "dipstick" testing for the presence of a disease-specific chemical (this is the method used in home-pregnancy kits).

Several infectious ailments can now be detected this way without the need for laboratory equipment.

"Optimal", a test for malaria, is one example. It has been developed by Flow Laboratories, a small diagnostics firm based in Portland, Oregon, US.

Optimal is designed to diagnose malaria within 15 minutes, as opposed to the several days it can take for hard-pressed technicians to get round to counting up the parasites in blood smears.

The new test consists of two strips on a piece of card. One strip is impregnated with antibodies that bind specifically to a protein called parasite lactate dehydrogenase (pLDH) which is present in all four forms of human malaria. The other carries antibodies which recognise pLDH from only the nastiest one, Plasmodium falciparum.

A drop of blood, which will be loaded with pLDH if it is taken from an infected individual, is mixed with a detection agent which will produce a coloured band if the sample binds to the antibodies on a strip.

One coloured band means that an individual has the disease. Two means that he or she has the worst sort, falciparum malaria, which requires urgent attention.

Such clear-cut results are an improvement on the more subjective read-outs from microscopy, and are welcomed not just by health workers in poor countries, but also by the American army, which has put Optimal through its clinical paces in such malaria-ridden places as Peru and Thailand.

Simplicity and speed are thus now available for an encouraging variety of diseases.

The real bugbear is cost. And here the news is not so good. Although developing new diagnostic techniques is cheap compared with developing new drugs (largely because they do not have to undergo such comprehensive and expensive clinical trials), it is frequently not cheap enough to create tests that will be commercially viable if their only market is in the poor world.

Companies which make tests for HIV, malaria or tuberculosis may be able to sell to poor countries more or less at cost, because they can make up their profit margins by charging more to travellers or to rich-country consumers who are at risk at home.

But this is not an option for tests for those diseases that afflict only those in the tropics.

AMRAD ICT, an Australian diagnostics company, has discovered this to its cost. AMRAD ICT makes a number of dipstick tests for tropical ailments, including one for lymphatic filariasis, which afflicts 120m people around the world. Clinical trials have shown this test to work well in some affected regions, and it is certainly an improvement over conventional testing, which requires the collection of blood samples in the middle of the night when the parasites are at their height.

But need does not necessarily make a market according to Dean Moss, the firm's general manager. AMRAD ICT simply cannot afford to sell this test - or others in development - at the price that poor countries can afford to pay, roughly half the cost of production.

The firm has been losing money, and was recently sold by its parent, AMRAD, to Binax, an American company more interested in diagnostics for diseases of the rich.

Production of the filariasis tests will continue, much to the relief of the WHO, which is starting, in collaboration with Merck and SmithKline Beecham, a massive drug-donation programme for the disease.

But tests for rarer tropical diseases may not be pursued. This might be seen as ironic in the light of western interest in such things as drug-donation programmes (in which drug companies give away their products in countries which cannot afford to buy them) and vaccine-purchase funds (which guarantee sales to firms that come up with effective new vaccines for poor-world diseases).

Such schemes are pointless if the drugs and vaccines are not targeted to those in genuine need. Better diagnostics would mean better use of medicines, so rich countries should consider ways of making them more available too. It may be less glamorous than drug delivery, but it is no less necessary.

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