Are Studies on Severe Malaria Still Possible?

Severe malaria kills as a result of a complex interaction of parasite and host that is only now beginning to be understood. Patients presenting clinically with cerebral malaria or severe anemia are the unusual outcome of Plasmodium falciparum malaria infection with potentially lethal results. Because of the tremendous number of infections, particularly in sub-Saharan Africa, large numbers of children (primarily in Africa) and adults (primarily in Asia) still die of malaria. Chemotherapy with effective antimalarial drugs is the basis of all treatment for P. falciparum malaria, but even when adequate drugs are given quickly after arrival at a health center or hospital, many patients with malaria still die as a result of a pathology that is not easily reversed. Finding an adjunctive treatment that could hold these processes at bay until chemotherapy kills the parasite has been the goal of several research groups over the last generation.

In this issue of journal, a research team, led by Dr. Kevin C. Kain, reports on the use of rosiglitazone as adjunct therapy for patients with uncomplicated P. falciparum malaria in Thailand [1]. Rosiglitazone was used as an immunomodulatory agent in an attempt to down-regulate inflammatory responses through innate immunity pathways. All patients received atovaquone-proguanil chemotherapy. Because this was a study of nonsevere malaria, the measurements used in this placebo-controlled clinical trial focused on parasitological endpoints, such as parasite clearance times, and markers of inflammation, such as fever and cytokine production. The faster parasite clearance times and lower levels of cytokine expression show proof of principal that rosiglitazone could be used as adjunctive therapy for patients with malaria and that it deserves to be tested in a clinical trial of treatment of severe malaria, with mortality or surrogate markers of mortality as an endpoint.

The reported clinical trial was completed 4 years ago, and the research team is to be congratulated on a well-executed study. The authors have stated that they are still trying to set up an appropriate clinical trial of treatment of severe malaria. Those who have worked in developing countries are painfully aware of the multitude of practical problems that face investigators trying to execute controlled clinical trials of treatment of uncomplicated malaria. The lack of a follow-on study of severe malaria, however, leaves the most important question as yet unanswered. This is not a criticism of the research group but an observation of how difficult it is to plan, much less execute, such a study. At present, there are significant doubts as to whether clinical studies on severe malaria are even possible.

The requirements for a clinical trial of treatment of severe malaria are similar to those of any investigation of a potentially lethal infection: the ability to provide support equivalent to most intensive care units (ICUs). There is an inverse relationship between the ability to provide such care and the areas where one could expect to find persons severely ill with P. falciparum malaria. In the case of Thailand, the patients with malaria are found on the country's borders, whereas intensive medical care is usually provided in the central capital of Bangkok. This is more than just a problem of geography; most deaths due to malaria occur in the first 24-48 h after presentation, so any significant transportation delay is likely to significantly affect both the patient's outcome and one's ability to enroll the patient into a clinical study. With enormous effort and a great deal of money, one can recreate ICU-like facilities in rural areas near malaria endemic zones, but supporting them with electricity, a nursing staff, and biomedical repair facilities is a daunting challenge not to be undertaken lightly [2].

The provision of even minimal clinical facilities in rural areas, however, moves the goalposts of treatment for malaria. As clinics delivering effective chemotherapy in the form of artemisinin combination therapy moved into rural Vietnam, what was once the country's major health problem largely disappeared such that one can no longer conduct severe malaria studies in Vietnam; the requisite patients simply do not exist, and this represents a great public health accomplishment [3]. The complexity of doing malaria studies with mortality as a primary outcome can be seen in a recent clinical trial of the use of rectal artesunate for sick children being referred for further care. More than 17,000 patients were enrolled in that clinical trial, which resulted in 12,000 cases in 4 separate health care sites involving 291 rural villages in both Africa and Asia [4]. It took 6 years to complete the study and 2 more years to evaluate the data. Despite this tremendous effort, the primary indicator was no different between drug and placebo groups, except in a subclass analysis of those reaching referral clinics >6 h later [4]. However, it still remains important to obtain data from controlled clinical trials of treatment for severe malaria, because some previously accepted adjunctive therapies (such as the use of corticosteroids) have been found to be deleterious after being submitted to placebo-controlled trials [5] and because the initial promising results using iron chelation were found to be ineffective on subsequent testing [6, 7].

The difficulty of testing the next generation of malaria interventions is likely to increase dramatically with the further development of efforts to eliminate malaria, which include the widespread use of insecticide-treated bed nets and artemisinin combination therapy [8]. These simple and relatively inexpensive methods are to be welcomed as examples of successful public health interventions. However, the perceived failure of the global malaria eradication program of the 1960s, which was largely dependent of the residual spraying of house walls with DDT, should remind us that successful interventions can only be pushed so far before meeting biological barriers, not all of which can be anticipated. Despite substantial reductions in malarial morbidity and mortality as a result of the use of insecticide-treated bed nets, elimination of malaria is unlikely to occur with the use of current interventions, except under very favorable epidemiologic situations. If malaria elimination for entire countries is to be a goal, then new interventions that have been genuinely shown to work in the field are going to be required. This is true whether one is discussing severe or uncomplicated malaria studies. Malaria vaccines are a highly desirable product; the most advanced vaccine is entering advanced clinical trials that will involve thousands of African children and fully occupy most of the research capacity of sub-Saharan Africa for at least 3 years [9]. Some of the planned study sites are now marginalized by great decreases in malaria transmission. At best, one can then expect the registration of a good but limited first-generation vaccine whose applicability may be further discounted by the large-scale distribution of bed nets. It is likely that scaling up proven interventions for impact will conflict with the need to develop new antimalarial interventions, because of the competition for available field sites and staff [10].

Therefore, one needs to recognize that such a conflict exists and cannot be solved simply by some central authority. Medical research is competitive, with different groups supporting their various products and ideas for a complex matrix of reasons. Having been previously pushed out of a working malaria field site when a nearby research team decided it needed a larger area for bed nets, I can personally testify to the disappointment and conflicts of interest inherent in such occurrences, which are likely to become more frequent as areas with endemic malaria and available infrastructure shrink. Those whose professional careers depend on generating new malaria research need to be aware that future gains, no matter how promising, have to be heavily discounted against current malaria control with available interventions. Those who see no need to plan for new interventions should be aware that any infectious disease elimination program is likely to be initially successful before reaching a hard plateau against which any single intervention is likely to fail because of biological limitations. International agencies providing research grants and funds for public health interventions for malaria need to appreciate the tension between current accomplishment and future advances, and they need to recognize that this tension is very likely to increase in the near future.

• Received April 29, 2009.
• Accepted April 30, 2009.

• © 2009 by the Infectious Diseases Society of America