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Epidemiology

Ahead of the tropical challenges

Brazil keeps ahead in the research and prevention in diseases typical of poor countries

eduardo cesarRondônia, 2002: motorcyclist distributes medicines and collects blood for testingeduardo cesar

If a time machine brought back Oswaldo Cruz to Brazil of 2004, the great Brazilian sanitarian, on this hypothetical journey, could conclude that the advances in research in tropical diseases have been timid over the last hundred years. The country still suffers from endemic diseases like malaria, has not managed to rid itself of leprosy and leishmaniasis, has watched with impotence the expansion of tuberculosis and cholera, and is frequently shaken by outbreaks of dengue, which, for sharing the same mosquito that transmits yellow fever, imposes the risk of bringing back the scourge that Oswaldo Cruz workd so hard t the beginning of the 20th century.

The truth is, though, that Brazilian researches in the last few decades have not ceased to bring original contributions towards understanding and seeking treatment for tropical diseases, which have become one of the most important areas of scientific research in health in the country. And at several moments the researchers have been working practically alone, since the majority of the pharmaceutical industries have never been inclined to investigate drugs of an exclusive interest to poor countries. The tools for combating yellow fever are one example of this original contribution.

To prevent an outbreak of this ailment in areas with a great incidence of dengue – the two diseases share the same transmitting mosquito, the Aedes aegypti –, epidemiologist Eduardo Massad, a professor from the School of Medicine of the University of São Paulo (USP), is working with mathematical models to establish zones to block the entry of the sylvatic disease, on the border of São Paulo with Mato Grosso do Sul. The habitual way out, in the imminence of an outbreak of yellow fever, would be to vaccinate the whole population. But this implies risks.

“It is not a harmless vaccine”, says Massad. For every million doses, one death occurs. The mathematical model helps to define the areas where vaccination is really indispensable – as the incidence of dengue and infestation by mosquitoes are very high – and where this is not necessary. It is also possible to make forecasts about the contingent of persons that should be vaccinated to create a safe margin in blocking the disease – which is not necessarily 100% of the individuals from the area.

This kind of research, which is based in good measure on the use of mathematics and computers, is still seen with reservations by the specialists in tropical medicine from the old guard, those who accompany the sick and know their symptoms by heart. “I went to a congress recently and saw that the enthusiasm with the research we are doing comes more from young doctors”, Massad says. But nobody doubts that this area has an enormous contribution to offer for the prevention of tropical diseases. Eduardo Massad’s group is getting ready to make, over the next four years, the greatest effort ever made in Brazil to diagnose the spectrum of the arboviruses, viral diseases transmitted by mosquitoes and ticks.

In four regions of the state of São Paulo – the capital, the north coast, the south coast, and in São José do Rio Preto – researchers are going to look for arboviruses in people, domestic animals, wild animals, and mosquitoes. One of the objectives of the work is to analyze the probability of the arrival in Brazil of the West Nile Fever virus, which causes encephalitis. Birds that carry the virus and mosquitoes of the Culex genus that transmit it are plentiful, even in the capital city of São Paulo. The work will involve researchers from several areas and is going to propose strategies for prevention that would be unimaginable in the heroic times of Oswaldo Cruz.

The researchers’ tools are changing. Genomics has a great vocation for expanding knowledge about microbes and their vectors. Last year, researchers from the Schistosoma mansoni Genome project, funded by FAPESP under the ONSA network (the acronym for Organization for Nucleotide Sequencing and Analysis, the virtual network of genomic laboratories of the state of São Paulo), concluded the sequencing of 92% of the estimated 14,000 genes of the parasite that causes schistosomiasis.

The ailment, which is contracted by means of contact with water contaminated with the larvae of the worm, is also called water belly in Portuguese, because of the swelling it causes in the abdomen. If it is not treated, it results in a chronic state, with an increase in the size of the liver, anemia, swollen veins in the esophagus, and the vomiting of blood. Thanks to the improvement in basic sanitation and to the advent of two medicines, schistosomiasis was now becoming a treatable and less dangerous disease.

Sequencing opens up a new front for research in combating the ailment that embodied the very image of underdevelopment – children with swollen bellies in the midst of a complete lack of sanitation. And it joins other important contributions, such as the vaccine recently developed by the team of researcher Miriam Tendler, from the Oswaldo Cruz Institute Foundation, in Rio de Janeiro. The vaccine was produced following the isolation and cloning of proteins of the Schistosoma.

Vigor
The generations that succeeded the generation of Oswaldo Cruz, Adolfo Lutz, Carlos Chagas and Emílio Ribas are not recalled much in the history books, but they played an equally important role. They did not carry out forced vaccinations, nor did they take part in the creation of institutes charged with combating diseases that annihilated millions. But in a consistent manner they did keep up the flow of the investigations. They are names like Leônidas de Melo Deane (1914-1993), from the School of Medicine at USP, the Evandro Chagas Institute and the Oswaldo Cruz Foundation, who studied the epidemiology of malaria. Or Oswaldo Paulo Forattini, from USP’s Faculty of Public Health, a scholar who studied disease-transmitting mosquitoes, with contributions to research into sylvatic yellow fever and the epidemic of encephalitis in the Ribeira Valley, three decades ago.

“Many Brazilian researchers have managed to maintain a vigorous activity”, notes Erney Plessmann de Camargo, a professor of the Biomedical Sciences Institute (ICB) at USP, he himself one of these researchers. “And different from the times of Oswaldo Cruz, these ventures have not depended on the government or on institutes created with specific purposes, but have come from the demands of the researchers themselves”, says Camargo, who currently presides the National Council for Scientific and Technological Development (CNPq). His first works were on the biochemistry of protozoa that cause malaria, in collaboration with another prominent name, Luiz Hildebrando Pereira da Silva, who was kept away from Brazil after 1964 and made a career in the Pasteur Institute in Paris.

Both Erney Camargo and Luiz Hildebrando coordinate different groups, responsible for researching into tropical diseases in the state of Rondônia. The two groups corroborated the existence in the Amazon of asymptomatic carriers of Plasmodium vivax, a protozoon that causes about 80% of the cases of the illness in Brazil. The other 20% are caused by Plasmodium falciparum, the most aggressive species of the malaria parasite. The confirmation of the existence of asymptomatic carriers of Plasmodium vivax won an international repercussion and yielded an article in the famous British magazine, The Lancet. But the researches of the two groups are not limited to malaria. The team from the ICB raised evidence of the existence of an as yet unknown species of the Leishmania protozoon that could be a new causal agent of American tegumentary leishmaniasis, a disease that attacks the skin and mucous membranes and which victimizes 28,000 Brazilians every year.

Malaria kills 2 million people a year, above all children in Africa. It is the main public health problem of the northern region in Brazil, where 99% of the national cases occur. It kills, on average, 20 Brazilians every year, but cases are counted in hundreds of thousands. The treatment based on quinine has been known since the beginning of the 19th century. For decades, scientists from several countries have been trying, in vain, to find a vaccine.

The American army, though, through the Walter Reed Research Institute, has been one of the main sponsors of the vaccine to have so far attained the best results, created by Manuel Patarroyo, from the Colombian Immunology Institute. But recent tests have shown that the immunization brought about by the vaccine does not reach 30% of the people. The interest of the United States Army in malaria comes from way back. The disease has killed thousands of soldiers since the War of Secession, up to campaigns in Africa and the Vietnam War.

Treatment
“There are difficulties in getting efficient vaccines for diseases caused by protozoa”, says infectologist Marcos Boulos, a professor in infectious and parasitic diseases at USP’s Faculty of Medicine. Brazilian researchers like Luiz Hildebrando Pereira da Silva, working at the time at the Pasteur Institute in Paris, and the couple Ruth and Victor Nussenzweig, at New York University, took part in this effort.

While the world was looking for the vaccine, Brazilian researchers dedicated themselves to research that could really only be done here, like those on the mechanisms that proliferate the illness. A strategy was developed that succeeded in reducing malaria cases by half in 2002. It consists of diagnosing and the treating the patients quickly, to reduce the contingent of contaminated mosquitoes. This is the way, because the malaria vectors of the Anopheles family are getting more and more resistant to insecticides. “Our research into malaria is of an international level”, says Boulos. “Brazil and Thailand stand out in this field.”

Thanks to the zeal of the researchers, and to the increase in the investment in studies of tropical diseases as well, Brazil is showing today several signs of vitality in this field. The Manguinhos Institute, of the Oswaldo Cruz Institute Foundation, has transformed itself from being a center irradiating solutions for yellow fever and Chagas’s disease into a complex producing antiviral vaccines.

Founded in 1901 by Vital Brazil, to make serums against the bubonic plague, the Butantan Institute ended up turning itself into a benchmark for poisonous animals and, more recently, in making all kinds of vaccines. In the state of Pará, the Evandro Chagas Institute, linked to the to the Ministry of Health, is recognized in the whole world as the main center for research into leishmaniasis and into viruses transmitted by mosquitoes and ticks. “In the last twenty years, there has been a significant increase in funding for research into tropical diseases, as well as in the possibility of partnerships with research groups from other countries”, Boulos says. According to him, the interest of the developed countries in tropical diseases has gained a respite, thanks to globalization. “As 1 billion persons travel by air every year, diseases have ceased to respect frontiers.”

The trajectory of Chagas’s disease passes through one of the happiest moments of Brazilian research into tropical medicine. Carlos Chagas (1879-1934), in one fell swoop, described in 1907 the parasite (Trypanosoma cruzi, in an homage to Oswaldo Cruz), the vector (the kissing bug), the domestic reservoir (the cat), and the disease baptized with his name. This feat, unprecedented in medical history, made possible the creation of strategies to do away with the insect that transmits the disease, which increases the volume of the heart and leads to cardiac insufficiency. Between the 1980s and the 1990’s, the kissing bug was eradicated, thanks to a government campaign headed up by José Carlos Pinto Dias and to the change in housing standards in Brazilian rural regions. The daub and wattle houses in which the kissing bugs proliferated were done away with.

The concept of tropical disease arose in Europe, encompassing a collection of exotic diseases frequent in the colonial regions of a hot climate. In practice, many of these ailments are merely the ills of poverty, the lack of sanitation, and malnutrition – more frequent in the tropics than in temperate civilizations. Brazil imported this view. The Tropical Medicine Institute of the School of Medicine at USP was created, in the decade of the 1950’s, by Professor Carlos da Silva Lacaz, after he had spent a spell in Hamburg, Germany, at a similar institute.

After the nationwide mobilization at the beginning of the 20th century, research into tropical diseases has acquired a certain stigma. When medicine exploded into dozens of specialties, work with tropical diseases came to be seen as an area that was antiquated and with little charm. The new fields of knowledge seduced the students, with their promise of breaking back the frontiers of science.

In the meantime, tropical medicine, with sponsorship from the Rockefeller Foundation, was proposing to eradicate diseases, as if it itself were to end one day. This mismatch is still happening today”, explains veteran infectologist Vicente Amato Neto, a professor at USP’s Faculty of Medicine. “There is a current called ‘the new infectologists’, which says that it is more concerned with hospital infections, postoperative infections, or immunodepressive patients”, he says. “They forget that there are countless infectious diseases to fight, and that Brazil has a tradition in this.”

Worries
New challenges are always arising. The advance of viral hepatites B and C, for example, is taking on increasingly worrying dimensions, with the growth of cases of cirrhosis and liver cancer that is inflating the queues for transplants. In the view of the specialists, these lesions could be avoided if there were an early diagnosis and adequate treatment. Tuberculosis, which has reappeared as an opportunistic disease associated with Aids and become disseminated, embodies another challenge. Not to mention the fear of emergent diseases may arrive in Brazil. The epidemics of the Severe Acute Respiratory Syndrome (Sars) and chicken flu have brought this fear to the surface recently.

Brazil is also getting ready for these adversities. The recently inaugurated Klaus Eberhard Stewien Laboratory, at USP’s Biomedical Sciences Institute, is the first in the country with the maximum biosafety level 3+. It is almost the maximum possible for civilian research – there are more sophisticated installations only at the Centers for Disease Control and Prevention (CDC) in Atlanta, United States, a world-wide benchmark for emergent diseases. The laboratory is the first of a series of 12 that are beginning to be constructed in Brazil. These units will offer security and adequate conditions for investigating all kinds of agents of tropical diseases.

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