From Headache to Coma
Although improvements in prevention are promising, diagnosis and drug treatment remain the mainstay of malaria control worldwide. The keys to effective disease management are rapid diagnosis and proper treatment. A patient with malaria who comes to a clinic in the morning complaining of a headache may, if untreated, fall into a coma by midafternoon. The longer an episode of malaria goes untreated or ineffectively treated, the higher the mortality rate.
In much of the developing world, however, primary health care systems are unable to provide early diagnosis and treatment. Diagnosing malaria is difficult because the symptoms of infection, particularly early on, are nonspecific – fever, chills, headache. In rural settings, both diagnosis and treatment are often delayed because of the long distances patients must travel to reach a health center. In addition, effective antimalarial drugs may not be available in areas of drug resistance.
Workers at primary health care clinics, where most children with malaria are likely to seek treatment, must be trained to differentiate among illnesses with overlapping symptoms, including pneumonia, measles, malaria, diarrhea, and malnutrition, all of which are leading causes of death in children under five in developing countries. Right now, health workers receive training through a variety of nationally administered programs, each of which focuses on the diagnosis and treatment of a single disease. Health workers are left to develop their own methods for differentiating among diseases and setting priorities for treatment. Focusing on the most apparent problem may cause health workers to overlook an associated, potentially life-threatening condition. A health worker might prescribe an antibiotic for a child with a high fever and rapid breathing in the belief that the child has pneumonia, for instance, without realizing that the child is severely ill with malaria, which shares the same complex of symptoms.
To address this problem, WHO and UNICEF have developed a new approach to diagnosis and treatment called Integrated Management of Childhood Illnesses, which they are implementing on an experimental basis in clinics and health posts in selected districts in Uganda, Tanzania, the Philippines, Vietnam, and Indonesia. The goal is to shift resources and responsibility for training primary health care workers from the national disease-specific programs to the district level and to help health care providers accurately assess the overall needs of the sick child. Health workers are also trained to communicate key information to mothers, thus helping them ensure the health of their children. So far, it appears to be working: preliminary evaluation shows that clinic staff trained under the new approach make more accurate diagnoses and more appropriate referrals for sick children.
Beyond improving diagnosis and referral, we need to ensure the availability of effective treatment. Antimalarial drugs are among the most commonly prescribed drugs in the world, and not only because the disease is so widespread; health workers in endemic areas often overprescribe antimalarials as a result of improper diagnoses. What’s more, the few drugs we have are closely related to one another, increasing problems with drug resistance.
Today, resistance is emerging and spreading faster than new drugs can be developed. The newest antimalarials-Malerone, developed by Glaxo-Wellcome, and drugs based on the ancient Chinese herbal remedy artemisinin – are the only drugs that remain effective in areas most plagued by drug resistance, such as Thailand. Parasites resistant to these compounds have already emerged in the laboratory, and health agencies are closely monitoring their emergence in the field.
Given the speed with which parasites are becoming resistant and the length of time required to develop new drugs (even accelerated development takes 5 to 10 years from discovery to clinic), we face a looming crisis: multidrug-resistant malaria with no safe, effective alternatives for treatment. This problem exists today in Southeast Asia and will occur in most other malaria-endemic areas within the next decade.
Despite the obvious urgency of the situation, pharmaceutical companies are not developing new drugs. Over the past decade, the few major pharmaceutical companies that had antimalarial drug discovery and development programs have discontinued or downsized these programs, which were both costly and unprofitable. Today, only a few academic centers and government agencies are working on the discovery of antimalarial drugs; only a few new drugs in the late stages of clinical development remain in the pipeline. (Malerone still awaits final approval in some countries and new formulations of artemisinin are still being tested.)
There is an urgent need to develop novel compounds or compounds that focus on novel pathways – processes essential to the growth and development of the parasite – that are not the target of current antimalarial drugs. Moreover, researchers must address the problem of drug resistance from the earliest stages of drug development. One strategy to prevent resistant organisms from emerging is to use multiple drugs targeted at different pathways, or at different steps in a single pathway. Another is to identify ways to interfere with the mechanisms that spur mutation or regulate gene expression. A third important target is a protein in the membrane of the parasite that allows the organism to recognize and pump out drugs. Once the protein is expressed, the parasite can resist multiple, unrelated drugs, even those to which it had not previously been exposed. Preventing the expression of this protein or blocking its pumping action is another way to prevent or even reverse resistance.
While previous efforts to develop new drugs and vaccines have been based on empirical observations, new drug development techniques are likely to provide the basis for the next leaps in our knowledge. Techniques such as combinatorial chemistry (creating new compounds by systematically combining sets of chemical groups) and computer-aided drug design (using x-ray crystallography and computer modeling to analyze protein-drug interactions) have accelerated the process of finding new drugs and vaccines for other diseases. We need to apply these tools to malaria before we face the widespread threat of untreatable disease. Since expertise in drug development is concentrated in the private sector, the participation of the pharmaceutical industry – perhaps supported by government funding – is essential to the success of this effort.