Special to The Japan Times: October 28, 1998
by Richard Humphries

An old enemy is making a comeback. The progress of the AIDS pandemic generates more headlines, but the annual mortality rate of that modern killer does not begin to approach the death toll exacted by a disease which has been around for millennia--malaria.

The World Health Organization estimates that up to 500 million people will contract malaria in the next year. As many as 2.7 million of them will die and 1 million of those will be children. Forty-one percent of the world's population is at risk. As with AIDS, these numbers have mushroomed in the last few decades. Unlike AIDS, malaria can be cured but also unlike AIDS, malaria research has not benefited from the active campaigning of vocal, well-organized pressure groups. Worldwide government spending is about $85 million per year and pharmaceutical companies spend a similar amount, a small fraction of the amounts spent on AIDS ($1.5 billion for research this year), cancer, or other diseases.

Malaria is caused by the bite of an infected female mosquito of the genus anopheles. The mosquito carries the parasite plasmodium, which, after an incubation period of as little as seven days, can infect its victim. There are four main strains of malaria: vivax, falciparum, malariae, and ovale. Plasmodium falciparum, otherwise known as cerebral or brain malaria, is the biggest killer. The mortality rate for pregnant women with falciparum is 50 percent.

While there have long been effective drugs, the development of drug-resistant strains of the disease has recently become a problem. A systematic effort at malaria eradication was made in the 1950s and ‘60s, although not all areas were targeted, especially in Africa, and the effort did not succeed in the areas that were. Nevertheless infection and mortality numbers declined for several years. Now, however, malaria is fighting back. In Senegal alone, deaths have increased sevenfold in just five years.

The battle against malaria is being fought, and fought hard, by a few dedicated researchers around the world. One beachhead is at Mae Sot, along Thailand's border with Myanmar where the Shoklo Malaria Research Unit (SRMU), supported by Thailand's Mahidol University, Britain's Oxford University and the Wellcome Trust, has for several years been conducting a variety of research projects. Its director, Dr. Francois Nosten, is an extremely articulate medical professional from France.

According to Nosten, SMRU's work is done in area refugee camps because, "..from a research standpoint, the fact that people were living in a relatively stable area and relatively limited area made it much easier to look for better treatment. It is (also) much easier to evaluate the efficacy of a drug, if you can follow the people. There was a need because malaria created a problem. The setting was such that you could actually do something since we combined the two aspects, treatment and research."

Working with larger populations also improves the quality of the research, Nosten said. For example, many studies have been done since 1975 on mefloquine, one of the better known malaria drugs. The total number of people recruited in all the studies worldwide totals some 20,000. Of that number 13,000 were recruited by Nosten and his group. Participation in the studies is completely voluntary, and the necessary forms and information in translated into languages the participants can understand.

The Southeast Asian region has a much lower malaria mortality rate than Africa but for research purposes, Thailand is a key site. Until the 1960s, the malaria treatment of choice was chloroquine, a relatively inexpensive drug but in recent years. In many cases, Thailand was the first place this happened.

Asked why, Dr. Nosten said, "That's a very interesting question and we really don't know the answer. It has been like this ever since malaria parasites (were) known to develop resistance back in the ‘60s, and the first (resistant) strains appeared in Thailand. In fact they didn't appear on this border but on the Cambodia one in Pailin, in the gem mines of Pailin. And they migrate because people carry the parasite with them when they move. There is a strong link between Cambodia and the gem business here because Mae Sot is a big trading gate for gems. . . The worry is that the big resistant strains are not staying at the focus areas but spreading."

Indeed, within 15 years of their appearance in Thailand, chloroquine-resistant strains were already turning up in Africa, where the malaria problem is far more serious. Less than ten years after that, resistance to the drug was widespread across the continent. Africa continues to suffer the highest malaria mortality rate in the world. The average rate of infection in the Thai border area is one infected bite per person per year. In some parts of Tanzania the average is 300 infected bites per person, per year. In Sudan, 40 percent of hospital patients are there because of malaria.

Nosten pointed out an all-too-obvious fear, "Until now, they have been able to treat malaria with chloroquine, a cheap drug, cheap to make. But once chloroquine is gone it's up to more expensive drugs. And when all those drugs are gone, then what are we going to do?"

There have been attempts to develop a vaccine. One promising possibility, which was pursued by the Colombian scientist Manuel Patarroyo, was called SPF 66. Patarroyo's research suggested that the vaccine was very effective. The U.S. Army became interested in the project, but insisted upon independent trials before validating Patarroyo's findings and engaged upon a four-year-long collaboration with the SMRU. Unfortunately, Nosten's team proved that the vaccine did not work.

Not all treatment drugs work well, either. The SMRU has team also found that halofantrin, an antimalarial drug used often in Africa is dangerous, with a level of toxicity that can stop the heart.

Nevertheless, there have been some successes with treatment. While chloroquine will not cure falciparum in the Thai-Myanmar border area and even mefloquine (the prophylaxis of choice for foreign visitors) is less than 40 percent effective, a new drug called artesunate seems to be working well.

Perhaps "new drug" is not the correct term. Artesunate is one of several drugs known as artemisinen derivatives. These were isolated from qinghao, an ancient Chinese herbal remedy for malaria that was used by locals in China for 1500 years. Now, the best Thai border area treatment for falciparum is a combination of artesunate and mefloquine. Dr. Nosten and his team have been following the results of this treatment for four years and have observed a 98-percent cure rate.

Still, there is no reason for complacency. As Nosten said, "But what is the situation is that the parasite has always been able to develop a resistance to all the drugs so people are not willing to consider that artemisinen will be any different and for some reason the parasite will never be able to develop resistance. Also mefloquine is associated with some side effects and we do not expect it will be effective forever. The parasite has already developed resistance to a certain extent. If you use mefloquine alone you treat less that 40 percent but we can still use it in combination. When it becomes completely resistant you can't use it anymore so you have to use something else. That's what we are studying at the moment--other combinations. We have to keep ahead of the parasite all the time."

The need to stay ahead of this disease is profound. When colonial powers referred to certain areas of the globe as "white men's graves," aside from demonstrating a certain unfeeling racism unfeeling about populations other than their own, they were making a point about dangers inherent in certain regions. Today many of these areas support much larger populations. They are visited not by a few traders, slavers, and missionaries, as in the past, but by tourists and businesspeople in their thousands. A significant loss in the battle against malaria might serve to once again mark off certain areas of the world as "no-go" areas. The human and economic costs would be enormous.

Drugs alone will not win the war against malaria, just as they will not win the war against AIDS unaided. When asked about the profit motive of drug companies, Dr. Nosten thought the answers were not that simple. "Even if the rich countries would spend more money to develop new drugs for malaria," said Nosten, "drugs are not the answer for malaria control. You need more than drugs to control malaria. One of the main factors that can confront malaria anywhere is development, economic development. Look at Thailand. You need education and information but basically you need development."

Given the economic difficulties in Asia and elsewhere that are currently impeding development, this could prove difficult. The war against malaria, though, is one that humanity cannot afford to lose. It is an enemy that, throughout history, has shown no mercy.

I know this little thing
Myriad men will save
Oh death where is thy sting
Thy victory, oh grave

British army surgeon Ronald Ross (1857-1932) wrote that verse in 1897, after he had identified the mosquito, and in particular the female anopheles type, as the vector, or transmitter, of malaria. Ross' work built upon that of a French surgeon, Alphonse Laveran, who in 1880 was the first to identify plasmodium, the malaria parasite. Both men were to receive Nobel Prizes in Medicine for their work and Ross can certainly be forgiven his exuberance at the time. It seemed that the age-old killer of millions (in scientific understatement, anopheles means 'unhelpful') might finally be brought to bay.

Malaria has an ancient pedigree. In the ancient Greek Hippocratic text "Epidemics I," an outbreak of falciparum (or cerebral) malaria on the island of Thasos was described. It is now thought that sometime after 500 BC, the disease became endemic in the Greek, and by extension Mediterranean, world. Its affect on population numbers and on settlement and agricultural patterns may have helped to shorten ancient Greece's Golden Age.

Ancient physicians, from Hippocrates to Galen (and through them well into the Middle Ages) believed that the fevers characteristic of malaria were due to an excess of yellow or black bile in a person. One Hippocratic remedy was to administer regular quantities of barley gruel and hydromel (a mixture of honey and water). Interestingly enough, this concoction, together with the onset of the disease, would typically lead to an iron deficiency which some researchers believe does act to inhibit the disease. Another remedy, promoted by Dioscorides (40-80 AD), a Greek physician with the Roman army, was less effective and certainly less appealing. His cure was a mixture of bedbugs with meat and beans.

A real breakthrough in the treatment of malaria came during the period of Spanish rule in South America. Sometime in the early 1600s, the Spanish authorities first became aware that local Indians were treating themselves for fever with concoctions made from the bark of the cinchona tree. These trees grew at an altitude of 2500 meters in a district that is now part of Ecuador. The Jesuit order brought samples to Europe and Pope Innocent X ordered a series of tests done on the substance. The new cure soon became known as the Jesuit's bark.

Sometime around 1650 a document, known as the Schedula Romana, was prepared that listed recommended dosages, preparation and administration of the Jesuit's bark. It noted that correct administration "removed" the sickness and that although some patients had relapses, they were "readily relieved by additional doses." The bark quickly became popular and commanded a high price, too high for many. Louis XIV and his chief ministers benefited from it (though not England's Oliver Cromwell who died of malaria), the workmen building Versailles did not and died in great numbers.

A further advance was made in 1820 when quinine, the active ingredient in the bark, was isolated. Still the cause of the disease remained elusive. Not much progress had been made from the time of Galen to that of the 17th-century English physician Thomas Willis who declared "a hot and bilious temperament, a youthful age, and a hot climate", to be the cause. In the 1800s it became accepted wisdom that miasmal air (malaria means "bad air" in Italian) such as that rising from swamps in the evenings, was the culprit. European colonial powers, with their own people's welfare in mind, engaged in a process of swamp drainage where European settlement was greatest and built hill stations above the fetid zones. A process of observation was narrowing the possibilities and laying the groundwork for the work of Laveran and Ross.

Once the parasite and its vector had been identified, coordinated health efforts were stepped up in many parts of the world. Swamps were drained. Quinine was distributed in large quantities and mortality numbers began to decline worldwide. Economic and educational development played a clear role in this. Paradoxically, the World War II brought an increase in fatalities, while at the same time spurring scientists to developed synthetic drugs (Dutch cinchona plantations had been seized by Japan) to treat it.

The postwar era saw the deployment of massive chemical intervention in the form of DDT, a substance first synthesized in 1874 from chlorine, alcohol, and sulfuric acid, combined with new synthetic treatments such as chloroquine.. Malaria was entirely cleared from some regions and significant progress was made in others, particularly in India. However, DDT proved to have serious negative effects on the food chain and malaria has proved far more resilient than initially expected. Death still retains its sting.

Although as recently as 1945, Japan was recording an estimated 20,000 cases of malaria a year, it is not a place one associates with the dreaded disease. In fact, by 1960 indigenous malaria had become extinct in this country. Still, every few years there is a case of what is called ‘domestic' malaria. These involve unusual methods of transmission. One is as "airport malaria" and has also occurred in America and Europe. A case was recorded in 1971, when a mosquito escaped from a plane in Tokyo and bit a woman living near the airport. She contracted falciparum malaria but survived. Other methods of transmission, according to the Research Group on Chemotherapy of Tropical Diseases, have been blood or platelet transfusions, accidental needle pricking, and mother-to-child transmission.

Many more people, roughly 120 a year, develop malaria symptoms in Japan after having been infected outside the country. Still, the relative infrequency has caused problems with Japan's health-care professionals whose limited experience with the disease has caused them to make late or even wrong diagnoses. One such victim in 1997 was the Japan-based New York Times reporter Nicholas Kristof, who found on his return from a trip to central Africa that he had contracted malaria. He later detailed his unpleasant experiences at a Tokyo hospital in an article for his paper.

Japan's Infectious Disease Surveillance Center, part of the Ministry of Health and Welfare, has recognized this problem. In its English language Web site it states, "Since medical experts who have clinically experienced malaria are very few in Japan, cases taking more serious courses due to delayed diagnosis and treatment have been seen....The prognosis of the patients will be worsened depending largely on delayed diagnosis or treatment especially in falciparum malaria, so early diagnosis and treatment are musts." It advises that an immediate blood test be conducted but offers a less than reassuring, "If there is any difficulty in identification of a malaria parasite, it will be necessary to ask a nearby expert of infectious or parasitic diseases for his or her advice."

One further complication concerns the availability of drugs for treatment. According to the surveillance center, only two drugs have been approved for use in Japan, sulfadoxine/pyrimethamine and quinine. Other antimalarial drugs can be obtained as
medicines under clinical trial from the Research Group on Chemotherapy of Tropical Diseases, but this is a process that takes time and is therefore hardly to be recommended for those who are already sick. As a result, many frequent travelers carry their own supply. (RH)