4

Clinical Medicine and the Disease Process

WHERE WE WANT TO BE IN THE YEAR 2010

There will be a worldwide drop in deaths and debilitating illness resulting from many important changes in the way health providers around the world prevent, diagnose, and treat the disease. Unlike the situation at present, health providers will be able to identify and offer preventive therapy for persons at risk for severe and complicated malaria. Further, health providers will be able to quickly identify and treat individuals who do become infected, even if they live in an area far from a fully equipped health post. Anemia and hypoglycemia, important and potentially life-threatening complications of malaria, will be diagnosed and treated promptly. The threat of transmitting AIDS through contaminated blood transfusions, a major problem in the 1980s and 1990s, particularly in Africa, will be significantly lessened with the advent of inexpensive and stable blood substitutes. Efforts to take into account area-specific drug sensitivities when designing local treatment policies will result in a much more effective use of chemotherapeutic agents and containment of the spread of drug resistance. Research on malaria pathogenesis will give physicians new points of attack for treating particularly difficult cases. Health providers in areas of the world where malaria is not a problem will know enough about the disease to recommend effective preventive regimens to those who plan to visit malarious areas and to recognize the disease in returning travelers.



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MALARIA: Obstacles and Opportunities 4 Clinical Medicine and the Disease Process WHERE WE WANT TO BE IN THE YEAR 2010 There will be a worldwide drop in deaths and debilitating illness resulting from many important changes in the way health providers around the world prevent, diagnose, and treat the disease. Unlike the situation at present, health providers will be able to identify and offer preventive therapy for persons at risk for severe and complicated malaria. Further, health providers will be able to quickly identify and treat individuals who do become infected, even if they live in an area far from a fully equipped health post. Anemia and hypoglycemia, important and potentially life-threatening complications of malaria, will be diagnosed and treated promptly. The threat of transmitting AIDS through contaminated blood transfusions, a major problem in the 1980s and 1990s, particularly in Africa, will be significantly lessened with the advent of inexpensive and stable blood substitutes. Efforts to take into account area-specific drug sensitivities when designing local treatment policies will result in a much more effective use of chemotherapeutic agents and containment of the spread of drug resistance. Research on malaria pathogenesis will give physicians new points of attack for treating particularly difficult cases. Health providers in areas of the world where malaria is not a problem will know enough about the disease to recommend effective preventive regimens to those who plan to visit malarious areas and to recognize the disease in returning travelers.

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MALARIA: Obstacles and Opportunities WHERE WE ARE TODAY Despite advances in the understanding of the pathogenic and clinical aspects of malaria, clinicians still do not know why some people tolerate malaria infections with few or no symptoms, whereas others are severely affected. Indeed, it remains a mystery why some people die of malaria but others do not. Clinical Aspects of Malaria It is important to distinguish between the disease caused by malaria parasites and the frequently asymptomatic infection caused by the same parasites. It is important to recognize that one may be infected without having the disease. The disease affects individuals who lack certain anti-illness immunity factors acquired by exposure to malaria or conferred by maternal antibodies transferred across the placenta (World Health Organization, 1990). The specific components of this immunity have yet to be determined, but at-risk groups include those in whom immunity has not yet developed (young children in endemic areas, travelers, and military personnel) and those in whom established immunity has lapsed (pregnant women, inhabitants of an endemic area who leave and then return, and residents of an area in which a successful malaria control program has stopped). Any one of four species of malaria parasite can cause illness, but Plasmodium falciparum causes almost all severe and complicated disease. Malarial illness is frequently several different, often overlapping syndromes. Severe Malaria Among the best known and serious complications of severe malaria, occurring particularly although not exclusively in children, are cerebral malaria, hypoglycemia, and anemia. Cerebral Malaria Cerebral malaria can be defined as altered consciousness in a patient who has P. falciparum parasites in the blood and in whom no other cause of altered consciousness can be found (World Health Organization, 1990). Cerebral malaria is frequently the only manifestation of a severe falciparum infection in children (Molyneux et al., 1989a); adults with the syndrome commonly have problems in other organ systems, usually the lungs and the kidneys (Warrell, 1987). Between 10 and 50 percent of people with cerebral malaria die, depending on the level of endemicity, how the syndrome is defined, the level of care available, and the age of the patient (Rey et al., 1966; Bernard and Combes, 1973; Stace et al., 1982; Warrell et al., 1982).

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MALARIA: Obstacles and Opportunities Cerebral malaria may develop very rapidly. In a study of 131 Malawian children with cerebral malaria, for example, symptoms such as fever, malaise, or cough had been present for an average of 47 hours prior to admission, and altered consciousness had been present for a mean of 8 hours. Eighty-two percent of the patients had a history of convulsions, and the level of consciousness had often deteriorated dramatically following the initial convulsion (Molyneux et al., 1989a). The speed with which this syndrome progresses has obvious implications for treatment strategies. In cerebral malaria, the level of consciousness can vary from mild confusion to profound coma. Some clinical findings suggest a diffuse involvement of the entire brain, while others are consistent with a theory of impairment of specific cerebral functions (Guignard, 1965; Dumas et al., 1986; Molyneux et al., 1989a; Brewster et al., 1990). Cerebral malaria can present with a variety of neurological symptoms such as seizures, increased muscle tone, hyperreflexia (sometimes with clonus), extensor plantar reflexes, and extensor posturing. In some patients, the clinical picture suggests increased intracranial pressure as a possible pathogenetic mechanism (Newton et al., 1991). Among survivors, particularly children, recovery is surprisingly rapid. In the previously mentioned Malawian study, full consciousness was regained over a period ranging from 1 to 152 hours (mean, 31 hours). After 24 hours of treatment with intravenous quinine, half of the children had recovered fully; by 48 hours, 80 percent had recovered completely (Molyneux et al., 1989a). The rapidity of the descent into unconsciousness and, in survivors, of the ascent into full awareness are unique, distinguishing, and intriguing features of cerebral malaria. The detection of P. falciparum parasites in peripheral blood would seem to be a sine qua non for cerebral malaria, but it is not. There are reports of patients in whom repeated attempts to demonstrate P. falciparum parasitemia were unsuccessful, yet postmortem examination showed unequivocal evidence of P. falciparum infection with parasitized red blood cells sequestered in the tissues (World Health Organization, 1990). The absolute level of parasitemia has some prognostic significance: the higher the parasite count, the more likely the patient is to die or develop neurological sequelae (Field and Niven, 1937; Molyneux et al., 1989a). However, many patients with cerebral malaria have scanty parasitemias, and many children with very high parasite densities have fairly mild symptoms. Current evidence suggests that mechanical obstruction of the microcirculation by parasitized red blood cells is the most likely cause of cerebral malaria. In patients with malaria, sequestration of parasitized red blood cells is seen in various human tissues, including brain, heart, liver, lung, and kidney. Patients dying of cerebral malaria show the same general pattern of sequestration, but the parasite densities in the brain are higher than in those dying of noncerebral malaria. The resulting reduction in

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MALARIA: Obstacles and Opportunities cerebral blood flow may lead to anaerobic cerebral glycolysis and increased cerebral lactateproduction. Lactate levels are elevated both in arterial blood and in cerebrospinal fluid (CSF). Since lactate in the blood does not cross the blood-brain barrier into the CSF (Posner and Plum, 1967), this finding suggests that lactate is being independently generated in both fluid systems. The magnitude of CSF lactate elevation is higher in fatal than in nonfatal cases of cerebral malaria (White et al., 1985). Lactate is also a building block utilized by the liver in the synthesis of glucose. Hepatic gluconeogenesis may be impaired in severe malaria, and this could contribute to elevated plasma levels of lactate (Taylor et al., 1988). Another potential source of high plasma lactate levels is the metabolism of the parasites: P. falciparum consumes glucose and generates lactate as a byproduct. A mass of sequestered parasites may cause localized hypoglycemia (low blood sugar) and elevated lactate concentrations in the brain. Another potential contributor to the pathogenesis of cerebral malaria is tumor necrosis factor (TNF), a cytokine. Plasma levels of TNF are elevated in adults with severe malaria (Kern et al., 1989) and in children with acute P. falciparum infections (Grau et al., 1989; Kwiatkowski et al., 1990). TNF is produced by monocytes and macrophages in response to a number of stimuli (Carswell et al., 1975; Cuturi et al., 1987) and has been shown to cause a wide variety of physiological effects in humans (Tracey et al., 1986). Some of these, such as fever and hypoglycemia, are common in children with severe malaria. Others, like low blood pressure, kidney failure, and a disruption of the blood clotting mechanism, occur frequently in adults with severe malaria. The extent to which TNF contributes to the pathogenesis of human clinical illness is unclear, but in a study of mice infected with a mouse malaria parasite, treatment with anti-TNF antibodies protected the animals from the cerebral complications of the disease (Grau et al., 1987), and high plasma levels of TNF in children with malaria are associated with an increased risk of dying (Grau et al., 1989; Kwiatkowski et al., 1990). It has also been suggested that immune mechanisms may play a role in cerebral malaria. In some rodent models of malaria, cerebral lesions contain local collections of inflammatory cells. These cerebral lesions and associated neurological symptoms can be prevented by pretreatment with corticosteroids (potent anti-inflammatory agents), cyclosporin A (an inhibitor of T-lymphocyte function), or antibodies to TNF. Inflammatory lesions are not found in human cerebral malaria, however, and neither cyclosporin A nor corticosteroids have proven to be an effective treatment for human cerebral malaria, although pretreatment with these drugs has not been possible. In this respect, human P. falciparum malaria differs significantly from certain animal malarias, where accumulations of mononuclear cells are found in cerebral vessels (Grau et al.,

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MALARIA: Obstacles and Opportunities 1987). At present, there is no satisfactory animal model for human cerebral malaria. The clinical management of patients with cerebral malaria requires prompt, specific antimalarial treatment, in addition to the general supportive care required for unconscious patients. Because of the extensive spread of chloroquine-resistant P. falciparum, the current drugs of choice for patients with cerebral malaria are intravenous quinine and, when quinine is unavailable, quinidine (Phillips et al., 1985; Miller et al., 1989; World Health Organization, 1990). In patients who have not undergone any previous treatment, a “loading dose” should be used with each drug to produce therapeutic blood levels as quickly as possible (White et al., 1983a). The size of the loading dose may vary, depending on local parasite sensitivities and on any preadmission drug treatment. Serious side effects include quinine- or quinidine-induced hypoglycemia (White et al., 1983b; Phillips et al., 1986b) and quinidine-related changes in the electrical conduction of the heart. Both can be mitigated by slow, controlled infusions of the medications (Phillips et al., 1985; Miller et al., 1989; Molyneux et al., 1989b). Pregnant women are particularly likely to develop hypoglycemia during the course of treatment with intravenous quinine (Looareesuwan et al., 1985). When the patient is able to eat and drink, tablets or capsules can be substituted for the intravenous medication. There is no consensus regarding the optimal duration of treatment with these two drugs. In certain parts of the world (e.g., Thailand) where the malaria parasite is less sensitive to quinine, a second drug (tetracycline) is used to eliminate parasitemia following resolution of coma (World Health Organization, 1990). The degree of supportive care provided to patients depends on the available facilities. Very high body temperatures can be reduced with tepid sponging and fanning. Convulsions can be treated with any of a number of standard medications. For example, a recent study showed that prophylactic administration of phenobarbitone decreased the number of subsequent convulsions in a group of adults with cerebral malaria (White et al., 1988). The number of patients studied was too small, however, to allow determination of whether decreasing the number of convulsions had any effect on overall survival or the incidence of sequelae. Exchange transfusion (replacement of a patient's blood with donor blood over a short period of time) has been used effectively to treat patients with severe malaria, especially those with high blood levels of parasites (Kurathong et al., 1979; Roncoroni and Martino, 1979; Yarrish et al., 1982; Kramer et al., 1983; Files et al., 1984; Chiodini et al., 1985; Hall et al., 1985; Miller et al., 1989). The technique is not practical in malaria-endemic areas where the prevalence of human immunodeficiency virus (HIV) seropositivity is high or in settings where close clinical monitoring of patients is not fea-

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MALARIA: Obstacles and Opportunities sible. Despite optimal care, between 10 and 30 percent of children with cerebral malaria die, and a similar proportion suffer neurological damage (Molyneux et al., 1989a). In most cases, the actual cause of death is unknown (World Health Organization, 1990). Hypoglycemia Many illnesses cause hypoglycemia, a condition which requires immediate, specific treatment to prevent permanent brain damage and death (Kawo et al., 1990). Because its clinical presentation (confusion, coma, and convulsions) closely mimics that of cerebral malaria, the coexistence of hypoglycemia in some patients with severe malaria was not suspected until quite recently (White et al., 1983b). As a result, an unknown number of patients may have died or suffered brain damage from what is an eminently recognizable and easily treated condition. The emergency treatment of hypoglycemia is an intravenous bolus of a very concentrated sugar solution, followed by a continuous intravenous supply of glucose until the patient can take food and fluids by mouth. Hypoglycemia is an especially common finding in pediatric malaria. In two recent studies, 23 and 32 percent of pediatric patients, respectively, were admitted with hypoglycemia (blood glucose levels less than 2.2 millimoles per liter, or 40 milligrams per deciliter) (White et al., 1983b; Taylor et al., 1988). The prognosis is particularly poor for such patients. In the Malawi study, 37 percent of those with hypoglycemia died and 26 percent were discharged with neurological sequelae (Taylor et al., 1988). These rates are six to nine times higher than those for cerebral malaria patients with normal blood sugar levels. Studies on hypoglycemia in children suggest that the condition develops through one or more of several mechanisms. One theory suggests that malaria infection may impair the liver's capacity to produce glucose from circulating precursors. It may also be that the sequestration of parasitized red blood cells in tissue capillaries slows the circulation enough to cause a change in tissue metabolism, thereby enhancing glucose consumption. Malarial Anemia Red blood cells infected with malaria parasites either are destroyed outright when schizonts mature and merozoites burst from the cell or are cleared from the circulation by the spleen. In acute malarial infections, splenomegaly is often associated with mechanical destruction of normal red blood cells, perhaps because the cell architecture becomes distorted. Several studies of patients with acute malaria have shown that there is also a decrease in the bone marrow production of new red blood cells (Marchiafava and Bignami, 1894; Abdalla et al., 1980; Phillips et al., 1986a). Cytokines such as TNF may be involved in this marrow suppression and dyserythropoiesis (abnormal red blood cell production). In addition, red blood cells coated with low levels of immunoglobulin G may be

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MALARIA: Obstacles and Opportunities removed from the circulation by the spleen more rapidly than is normally the case. The loss of red blood cells from these various mechanisms is therefore generally greater than would be expected from parasitemia alone and often causes significant anemia. When red blood cell losses are mild, anemia is well tolerated, but anemias can quickly become life-threatening in patients with high parasitemias (Phillips et al., 1986a; Molyneux et al., 1989a). There is no consensus about what constitutes “life-threatening” anemia in a malaria patient, and the only effective treatment currently available is blood transfusion. The administration of blood carries its own inherent risks, and these are compounded by the danger of transmitting AIDS in areas where a substantial proportion of the population is HIV seropositive. Once the parasitemia has cleared, bone marrow production of red blood cells resumes, and the red blood cell mass is gradually restored to its preillness level (Phillips et al., 1986a). While the danger of contracting AIDS is a real problem for patients with malarial anemia who undergo transfusion, there is no evidence at the present time to suggest that HIV infection places individuals at increased risk of severe malaria. The possibility of such an association, however, warrants continued surveillance. Other Clinical Features In areas of the world where malaria transmission fluctuates, adults do not acquire significant immunity and may be at risk for developing a severe infection involving many organ systems (World Health Organization, 1990). Women who are pregnant for the first time appear to be particularly susceptible to this form of the disease (Looareesuwan et al., 1985). Acute Clinical Complications Adults with severe malaria often require a higher level of supportive care than do children, including mechanical ventilation for pulmonary edema and hemodialysis or peritoneal dialysis for kidney failure, the two most frequent and serious noncerebral complications of the disease (World Health Organization, 1990). The principles of antimalarial drug therapy in these settings are the same as for treating cerebral malaria in children. Special care should be taken in treating pregnant woman with intravenous quinine, since they are more likely than other adults to develop hyperinsulinemic hypoglycemia (Looareesuwan et al., 1985). Pulmonary edema is a serious complication of falciparum malaria and is associated with a high mortality rate (World Health Organization, 1990). Its cause is unknown. Pulmonary edema resembles adult respiratory distress syndrome, with increased pulmonary vascular permeability.

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MALARIA: Obstacles and Opportunities Acute renal failure in malaria has the pathological characteristics of acute tubular necrosis, but the causal mechanism remains unknown. Hypovolemia from dehydration probably contributes to the problem in some severely ill patients, but it does not appear to explain all cases (Sitprija, 1988). There are a number of other acute but less frequent complications of malaria, which are discussed in some detail in a set of treatment guidelines recently prepared by the World Health Organization (World Health Organization, 1990). These include significant bleeding, impaired fluid balance, and impaired gastrointestinal and liver function. Chronic Complications Among the most frequent chronic complications of malaria are P. malariae glomerulopathy and hyperreactive malarial splenomegaly (HMS). Plasmodium malariae glomerulopathy, a nephrotic syndrome with massive proteinuria, hypoalbuminemia, and edema, results from P. malariae infection. Patients with renal involvement do not respond to treatment with antimalarial drugs or with corticosteroids or other antiinflammatory drugs used to treat other forms of immune complex-associated nephrotic syndrome (Houba, 1975). HMS, previously known as tropical splenomegaly syndrome, manifests itself clinically as persistent and progressive splenic enlargement (Bryceson et al., 1983). In patients with high levels of antimalarial antibodies, spleen size and antibody levels can be reduced with long-term antimalarial treatment. The prevalence of HMS is variable, but the condition is especially common in West Africa, Indonesia, and Papua New Guinea. Uncomplicated Malaria The vast majority of malaria patients suffer from so-called uncomplicated disease. They may have a variety of symptoms, including fever, headache, malaise, cough, nausea, vomiting, and diarrhea, and are usually treated empirically (that is, without the benefit of a bloodfilm examination) in many malaria-endemic areas. Even if local health care systems were able to perform a diagnostic blood film on every patient suspected of having malaria, the interpretation of the smear, especially in malaria-endemic areas, would be difficult. This is because a negative blood film does not exclude malarial illness, and a positive blood film does not necessarily confirm a diagnosis of malarial illness, since many individuals with positive films may have no symptoms caused by the malaria parasites. Antimalarial drugs are usually administered orally, although intramuscular injections of quinine can be used when appropriate (Mansor et al., 1990; Waller et al., 1990). A proportion of patients presumed to have uncomplicated malaria improve, either because the chosen drug was effective against the parasite,

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MALARIA: Obstacles and Opportunities because they already had or rapidly developed immune responses that controlled the disease, or because they had another, self-limiting disease such as the flu rather than malaria. Some patients for various reasons do not improve, and either return for more definitive care or seek help from other sources (traditional local treatments or over-the-counter medications). Some may worsen and die, although this progression cannot be assumed, especially in a semi-immune population. Most travelers who contract malaria initially develop the uncomplicated form of the disease. In a nonimmune patient, however, the progression to severe malaria is often very rapid. When the circumstances are appropriate, both patients and their doctors should be alert to the possibility of malaria infection and should treat the disease as a medical emergency. As is true for all malaria patients, the choice of drug treatment for travelers depends on the species of malaria parasite involved, where the infection was contracted (parasite drug sensitivities vary substantially around the world), what (if any) malaria chemoprophylaxis was used, and the pertinent details of the individual's medical history (World Health Organization, 1990). Malaria Chemoprophylaxis and Treatment Nonimmune visitors to malaria-endemic areas are at risk for developing severe and complicated malaria and therefore benefit from a regimen of preventive drug therapy. In the past, chloroquine chemoprophylaxis was effective and safe and was recommended for all who were at risk of acquiring the disease. The spread of chloroquine-resistant P. falciparum and P. vivax (Rieckmann et al., 1989), however, has complicated matters, particularly since each of the currently available alternatives to chloroquine has some toxicity. Mefloquine is the latest addition to the antimalarial armamentarium (Department of Health and Human Services, 1990). There is no consensus regarding the optimal chemoprophylactic regimen for persons living in or visiting the range of locales in which malaria infection is possible (Bradley and Phillips-Howard, 1989; Department of Health and Human Services, 1990). It is important for both travelers and physicians to realize that no prophylactic regimen is completely effective in all cases and that rapid diagnosis and prompt treatment are important. Pregnant women living in endemic areas constitute another group for which malaria chemoprophylaxis has been recommended. Babies born to first-time mothers with malaria often weigh less than babies born to uninfected mothers (Brabin, 1983; McGregor, 1984). Malaria can also cause severe anemia in women during their first pregnancy (Gilles et al., 1969; Brabin, 1983; McGregor, 1984). Although women living in malaria-endemic areas frequently receive chemoprophylaxis during pregnancy, few studies have

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MALARIA: Obstacles and Opportunities measured the clinical value and cost-effectiveness of this practice. In one placebo-controlled trial in the Gambia, malaria chemoprophylaxis (dapsone plus pyrimethamine) administered by traditional birth attendants resulted in lower levels of parasitemia, fewer cases of anemia, and fewer low birth weight babies, but only in women experiencing their first pregnancy (Greenwood et al., 1989). RESEARCH AGENDA Pathogenesis Despite a partial understanding of the host-parasite interactions in malaria, it is not known why some patients die from the disease. The remarkable recoveries enjoyed by most patients with cerebral malaria suggest that much of the pathology of this condition is reversible. If the pathogenic processes could be interrupted, or if the vulnerable organ systems could be supported until antimalarial drugs exerted their effects, the mortality rate due to serious malaria infections likely would decrease. Parasite sequestration, a characteristic of all P. falciparum infections, is associated with multi-system organ impairment in only a small proportion of patients. Similarly, severe malarial anemia develops in only a few of those at risk. In addressing these questions, a focus on the determinants of malaria disease, as distinct from the factors involved in malaria infection, may suggest new preventive and therapeutic options (Playfair et al., 1990). RESEARCH FOCUS: Determination of why some patient groups suffer severe disease (cerebral malaria and life-threatening anemia), while other, seemingly similar groups tolerate high parasitemia with only mild symptoms. RESEARCH FOCUS: Continuation of investigations into the pathogenesis of severe malaria (cytokines, parasite sequestration, hypoglycemia, increased intracranial pressure) and development of treatments targeted at the important mechanisms. Treatment Travelers to endemic areas who get malaria despite complying with a particular chemoprophylactic regimen occasionally are used as sentinels to detect the spread of drug resistance. Since their levels of exposure and degree of immunity differ significantly from those of the local population,

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MALARIA: Obstacles and Opportunities however, this method is not particularly useful for helping formulate national treatment policies in endemic areas. The ability to determine the level of local parasite sensitivities to different drugs is important. In vitro assays, which measure the growth of parasites in increasing concentrations of a drug, are available for most of the commonly used antimalarial drugs. However, the results of in vitro assays often correlate poorly with in vivo efficacy studies in the same setting, primarily because the former cannot assess patient-specific factors, such as differences in drug metabolism and level of immunity, that can influence drug sensitivity. RESEARCH FOCUS: Development of more effective methods of tracking and assessing drug resistance in malaria-endemic countries. RESEARCH FOCUS: Development of clinically and operationally useful assays that can predict parasite sensitivity to various drugs and drug combinations. Even in parts of the world where chloroquine resistance is widespread, the drug retains some clinical efficacy and can bring about some symptomatic improvement in many semi-immune patients, even though such patients may still harbor parasites. However, the importance of this clinical improvement with respect to assessing the effectiveness of various treatment options is unknown. RESEARCH FOCUS: Determination of the long-term effects of low-grade parasitemia on the development of anemia, on the patient's susceptibility to reinfection, and on the acquisition of antimalarial immunity. There is a worldwide shortage of effective antimalarial drugs. Quinine is the only widely available and effective medication for the parenteral treatment of severe disease, but unfortunately quinine resistance has been documented in Thai patients (World Health Organization, 1990) (see Chapter 8). RESEARCH FOCUS: Development of new drugs and new routes of administration for existing drugs to treat patients with severe falciparum malaria infections. Chemoprophylaxis Plasmodium falciparum infections can progress very rapidly; the time from the first onset of symptoms to the development of coma averaged 48 hours

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MALARIA: Obstacles and Opportunities in the Malawian children examined in one study (Molyneux et al., 1989a), and the mean duration of illness in Gambian children prior to death was three days (Greenwood et al., 1988). One preventive option is mass chemoprophylaxis for the at-risk segments of a population. Such programs have foundered in the past because of intermittent drug supplies and difficulties in ensuring proper drug use. However, if these obstacles can be overcome, there is evidence that chemoprophylaxis may be effective in young children (Greenwood et al., 1988). The relative benefits of early treatment versus mass prophylaxis will depend on the level of malaria endemicity and have yet to be clearly defined for any particular epidemiologic setting. Furthermore, the effects of sustained malaria chemosuppression on the acquisition of antimalarial immunity and on the evolution of drug resistance require further study before this approach can be recommended. RESEARCH FOCUS: Determination of the relative efficacy of mass chemoprophylaxis in reducing malaria-related morbidity and mortality in at-risk subgroups in a variety of epidemiologic settings. RESEARCH FOCUS: Evaluation of the effect of prolonged mass administration of antimalarial drugs on the acquisition of malarial immunity and the acquisition of drug resistance. Chemoprophylaxis is recommended for pregnant women living in malaria-endemic areas, but the diminishing efficacy of chloroquine, an inexpensive, relatively safe and well-tolerated antimalarial drug, has forced a rigorous appraisal of this policy. The safety and efficacy of alternative pro-phylactic regimens in pregnancy is an open question (Steketee et al., 1988). The use of more toxic prophylactic drugs has to be weighed against other unknowns, such as the potential benefits of maternal chemoprophylaxis on birth weight and on neonatal and infant mortality rates. RESEARCH FOCUS: Assessment of the impact of effective prophylaxis during pregnancy on birth outcomes. RESEARCH FOCUS: Determination of the efficacy and feasibility of various chemoprophylactic regimens for pregnant women in different epidemiologic settings. Reliable data on the efficacy of prophylactic antimalarial drugs taken by travelers and other nonimmune individuals in endemic areas have been extremely difficult to collect. Recently, a system was developed that allows health officials to monitor U.S. Peace Corps volunteers in various

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MALARIA: Obstacles and Opportunities West African countries for the spread of chloroquine-resistant P. falciparum malaria. On the basis of data collected through this surveillance system, the dosing regimen for malaria prophylaxis with mefloquine was recently revised (Department of Health and Human Services, 1991). This relatively simple surveillance network has provided up-to-date information on disease risk and should continue to serve as a model for future attempts at collecting relevant, reliable data (Moran and Bernard, 1989). RESEARCH FOCUS: Expansion of this effort to encourage further development of rational prophylaxis regimens based on operational research and simple surveillance networks. REFERENCES Abdalla, S., D. J. Weatherall, S. N. Wickramasinghe, and M. Hughes. 1980. The anaemia of P. falciparum malaria. British Journal of Haematology 46:171-183. Bernard, R., and J.-C. Combes. 1973. La paludisme chez l'enfant. Revue du Praticien 23:4197-4213. Brabin, B. J. 1983. An analysis of malaria in pregnancy in Africa. Bulletin of the World Health Organization 61:1005-1016. Bradley, D. J., and P. A. Phillips-Howard. 1989. Prophylaxis against malaria for travellers from the United Kingdom British Medical Journal 299:1087-1089. Brewster, D. R., D. Kwiatkowski, and N. J. White. 1990. Neurological sequelae of cerebral malaria in children. Lancet 336:1039-1043. Bryceson, A., Y. M. Fakunle, A. F. Fleming, G. Crane, M. S. R. Hutt, K. M. de Cock, B. M. Greenwood, P. Marsden, and P. Rees. 1983. Malaria and splenomegaly [letter]. Transactions of the Royal Society of Tropical Medicine and Hygiene 77:879. Carswell, E. A., L. J. Old, R. L. Kassel, S. Green, N. Fiore, and B. Williamson. 1975. An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Sciences of the United States of America 72:3666-3670. Chiodini, P. L., M. Somerville, I. Salam, H. R. Tubbs, M. J. Wood, and C. J. Ellis. 1985. Exchange transfusion in severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 79:865-866. Cuturi, M. C., M. Murphy, M. P. Costa-Giomi, R. Weinmann, B. Perussia, and G.Trinchieri. 1987. Independent regulation of tumor necrosis factor and lymphokine production by human peripheral blood lymphocytes. Journal of Experimental Medicine 165:1581-1594. Department of Health and Human Services. 1990. Recommendations for the prevention of malaria among travelers. Morbidity and Mortality Weekly Reports 39(RR-3):1-10. Department of Health and Human Services. 1991. Change of dosing regimen for malaria prophylaxis with mefloquine. Morbidity and Mortality Weekly Reports 40:72-73.

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