Severe malaria is a global problem, claiming at least 1 million lives annually. Few adequately powered clinical studies have been directed at improving the management of severe malaria over the years, but this situation is slowly changing. The antimalarial treatment of severe disease is being transformed by the development and deployment of the water-soluble artemisinin derivative artesunate. Parenteral artesunate is now the treatment of choice in low-transmission areas and in the 2nd and 3rd trimesters of pregnancy, and research is underway into whether it should replace quinine as the treatment of choice in African children. Development of good manufacturing practice (GMP) formulations should make parenteral artesunate more widely available in the near future. The development of artesunate suppositories offers another exciting prospect, the ability to treat patients with severe disease in remote rural settings, delaying the evolution of disease and buying them time to reach a health care facility. No adjunctive therapy has been shown to improve the outcome of severe malaria, but most studies have been underpowered. Future trials of interventions shown to be promising in pilot studies should be large and adequately powered. This will require multi-center designs and necessitate close collaboration between groups, as well as agreement on the research agenda. We suggest a list of candidate interventions for debate.

Introduction

Falciparum malaria remains a major cause of morbidity and mortality throughout the tropical world, with as many as 500 million cases annually causing 1–3 million deaths.¹ Most cases of malaria are uncomplicated and can be treated successfully with appropriate oral antimalarial drugs. However, in a proportion of patients, particularly in nonimmune individuals and/or where treatment has been delayed or ineffective drugs (chloroquine in most areas of the world) or substandard counterfeited drugs given, life-threatening severe disease can evolve requiring hospitalization, parenteral antimalarial therapy, and the treatment of complications. Severe malaria is often a multisystem disorder, presenting with multiple complications, each requiring specific management. In most of the malaria-endemic world, sophisticated intensive care facilities are not available and treatment is necessarily resource-limited. The mortality associated with severe malaria remains high, ranging from 10% to 50% depending on the setting. In this context, the main objective of the management of severe malaria is to prevent the patient from dying. Prevention of long-term sequelae and recrudescence (the usual primary endpoint of antimalarial trials in uncomplicated malaria) are secondary objectives.

The World Health Organization coordinated the production of guidelines for the management of severe and complicated malaria in 1990 and again in 2000, which also contain strict definitions of severe malaria, useful for standardizing clinical research.^2,3 More recently, in 2006, WHO published evidence-based guidelines for the treatment of malaria, which include extensive advice on the management of severe malaria as well as a clinically useful distillation of the WHO severe malaria definitions (Table 1).⁴

Table 1

WHO criteria for severe malaria

Unfortunately, the clinical evidence base on which to base guidelines is small, as most of the clinical trials on severe malaria management have been either negative, underpowered, or both. Until the SEAQUAMAT trial in 2005, no proposed intervention in severe malaria had ever been shown to reduce mortality. This review will briefly recapitulate the evidence for current “best practice” but will also concentrate on the many gaps in our knowledge and how they might be addressed.

Initial Assessment and Management

Severe malaria is a medical emergency. Initial management is based on that of any acutely and severely ill patient. The initial rapid clinical assessment should focus on the airway and circulation and include assessments of conscious level, respiratory status, and state of hydration. Hypoglycemia should be ruled out or, if the patient is comatose, treated empirically. Convulsions, which can present with subtle symptoms, especially in children, should be treated promptly. Intravenous rehydration should be commenced if indicated, oxygen given if there is clinical or blood gas evidence of respiratory distress or hypoxia, and an appropriate antimalarial drug administered. If the presence of severe malaria is suspected (Table 1), the patient should be transferred to the highest level of care available (preferably an intensive care unit).^2,4

In areas of high transmission, peripheral parasitemia is common and relatively uninformative unless very high, and other common infections may produce clinical pictures similar to the spectrum of syndromes produced by severe malaria. In cases with impaired consciousness, a lumbar puncture should be performed to exclude meningitis⁵ and the possibility of bacterial sepsis considered in all seriously ill individuals. Blood cultures are rarely available in endemic areas, but where they have been done systematically, bacteremias were found in a significant proportion of clinically severe patients with parasitemia.^6,7 Clearly if there are focal signs suggesting a bacterial infection (such as pneumonia), broad-spectrum antibiotic cover should be given. However, at present there is no robust method of excluding bacterial sepsis in patients with parasitemia and “severe malaria” in high-transmission areas. In the absence of such a test, a strong case can be made for a broader use of empirical antibiotics (in addition to the antimalarials), although so far no clinical trials have addressed this issue.

Antimalarial Treatment

For most of the last 300 years, the cinchona alkaloid quinine has been the drug of choice for severe malaria. In the 1950s, it was supplanted by the synthetic 4-aminoquinoline antimalarial chloroquine, but with the inexorable worldwide rise of chloroquine resistance, quinine returned to widespread use in the last decades of the 20th century. The situation is now rapidly changing once more with the rediscovery and development by Chinese scientists of the artemisinin derivatives, the most rapidly acting of all antimalarial drugs.

Artemisinin Derivatives

The artemisinin derivatives are the most exciting recent development in the treatment of severe malaria. They are rapidly parasitocidal, and—crucially unlike quinine—they kill young circulating parasites before they sequester in the deep microvasculature. To examine whether these advantages over quinine could be translated into a reduction in severe malaria mortality, between 2003 and 2005, 1461 patients (including 202 children) in 4 south and southeast Asian countries were recruited into SEAQUAMAT (South and Southeast Asian Quinine versus Artesunate in severe Malaria Trial), the largest ever clinical drug trial in severe malaria.¹³ Mortality in those randomized to artesunate was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; a relative reduction of 34.7% (95% CI 18.5–47.6%; P = 0.0002). The NNT (Number Needed to Treat to save one life) was 11.1 (95% CI 5.8–121) in Bangladesh, 12.6 (7.3 to 45) in Burma, 16.6 in Indonesia, and 21.2 in India. The mortality difference was particularly marked in those patients with large numbers of circulating young parasites, consistent with the hypothesis that artesunate’s advantage lies in its ability to kill young parasites before they sequester (unpublished observations). As a result of the SEAQUAMAT study, parenteral artesunate is now recommended by WHO as the drug of choice for the treatment of severe malaria in low-transmission areas and in the second and third trimesters of pregnancy (Table 2).⁴

Table 2

Extracts from current WHO guidelines for the treatment of severe malaria (reproduced with permission)

The current recommendation for treating severe malaria patients in high-transmission areas is either quinine or an artemisinin derivative. This patient group consists mainly of African children, who bear the largest part of the global malaria disease burden and for whom the potential advantage for parenteral artesunate is not as clear-cut as in southeast Asian adults. Severe malaria in children progresses more rapidly than in adults, leaving a smaller time window for the killing of young parasites by artesunate to deliver a clinical advantage. In the 1980s and 1990s under WHO oversight, a number of studies were carried out in both Africa and Asia comparing quinine with artemether, a lipid-soluble artemisinin derivative administered intramuscularly (it can also be given rectally, but not intravenously). An individual patient data meta-analysis showed that, whereas overall there was no significant difference in mortality between the two drugs [14% vs. 17%, odds ratio (95% confidence interval) 0.8 (0.62 to 1.02), P = 0.08], there was substantial heterogeneity in the treatment effect; in the Asian patients (mainly adults), artemether was associated with a modest, but significantly lower mortality than quinine [OR (99% CI) 0.59 (0.35 to 1.01), P = 0.012], but this effect was not seen in African patients (mainly children).¹⁴ Intramuscular artemether has since been shown to be erratically absorbed (unlike intramuscular artesunate, which was rapidly absorbed and quickly hydrolyzed to DHA); it is unclear whether artemether’s lack of effect on mortality in African children is due to this or to the absence of a true difference in efficacy between quinine and the artemisinin derivatives in African childhood severe malaria^15,16; hence the need for evidence from randomized clinical trials comparing quinine and artesunate in African children. AQUAMAT (African Quinine versus Artesunate in severe Malaria Trial), a multicenter study based on the SEAQUAMAT design, is currently underway. This trial plans to recruit 5,306 patients by 2010, and is powered to detect a 25% reduction in mortality from 8% to 6%.

The only widely available parenteral artesunate formulation is made by Guilin Pharmaceutical factory in China. Although it is effective (it was used in the SEAQUAMAT study) and is registered in many countries, it is manufactured to Chinese GMP (Good Manufacturing Practice) standards and is not yet “international GMP certified” (although there are plans for this). It is currently particularly difficult to treat severe malaria in the United States, as both parenteral artesunate and quinine are unlicensed, and intravenous quinidine, the mainstay of severe malaria therapy in the U.S., is increasingly unavailable as its use in cardiology declines.¹⁷ A new GMP formulation of artesunate is being developed by the U.S. Army and will hopefully obtain FDA approval in the next year or so.

Animal toxicity studies have raised concerns about possible neurotoxicity with high doses of the artemisinin derivative drugs, but so far, despite widespread use, neurotoxicity has not been reported in humans.^18,19 The animal neurotoxicity appears particularly related to high sustained levels produced by administration of lipophilic artemisinin derivatives such as artemether, which suggests that if a problem with neurotoxicity did exist (and there is no evidence of this to date), then water-soluble derivatives such as artesunate would be much safer.²⁰ Animal studies have also shown some reproductive toxicity, with fetal resorption in rats and rabbits.^21,22 There is no evidence that this occurs in humans, but such a problem would by its nature be difficult to detect. As severe malaria is a potentially fatal illness for the mother, until further evidence becomes available, the 2006 WHO guidelines regard both quinine and artesunate as treatment options in the first trimester (Table 2).⁴

Supportive Care and Management of Complications

Good nursing care is essential in the management of severe malaria, with particular attention to fluid balance, management of the unconscious patient, and detection of potentially lethal complications such as hypoglycemia.

Other Adjunctive Therapies

The malaria literature contains many small trials of potential adjunctive therapies for severe malaria. Most of these studies to date have been underpowered, and in a recent review many were found to have “inadequate methodological quality.”⁴⁹ In many cases, meta-analyses have been conducted with multiple small trials in attempts to make sense of the data, but still the power was usually insufficient to draw conclusions. An exception is the placebo-controlled trial of anti-TNF trial in the Gambia reported in 1996, which recruited 610 patients, 124 of whom died. There was no mortality difference and a suggestion of an increased incidence of sequelae in the treatment group.⁵⁰ The classic 1982 dexamethasone study from Thailand on the other hand, although well-conducted and the largest study ever in severe malaria at the time (N = 100), is underpowered by today’s standards and may conceal a type II error.⁵¹ A meta-analysis combining it with the second malaria steroid trial from Indonesia concluded that there was insufficient power to exclude a mortality effect either way.^52,53 A meta-analysis of trials on the use of iron chelators also concluded that, although no clear benefit was demonstrated, there is not enough data to draw a definitive conclusion.⁵⁴

Exchange blood transfusion is a popular adjunctive therapy, particularly in well-resourced settings. There are a number of rationales for its use in severe malaria, including removal of parasitized erythrocytes, removal of cytokines and other soluble toxins and mediators, and improving the rheology of the blood unparasitized erythrocytes by replacing unparasitized erythrocytes with reduced deformability.⁵⁵ However, no adequately powered randomized controlled clinical trial has been performed, and a meta-analysis of small studies and case series showed no clear benefit (although the transfused patient group was significantly sicker than the control group).⁵⁶

Two adjuvant candidates aimed at the disease process in general are the antioxidant N-acetylcysteine (NAC) and the antihelminthic drug levamisole. NAC has been the subject of several small studies, in one of which it was shown to increase lactate clearance.⁵⁷ Levamisole, which inhibits binding of parasitized erythrocytes to CD36 in vitro and in uncomplicated malaria⁵⁸ has not yet been trialed in severe malaria.⁵⁹

Future Directions

The evidence base for the treatment of severe malaria is lamentably small given the global importance of the disease and the number of deaths it causes. Fewer than 10,000 patients have ever been randomized into treatment trials of severe malaria, an astonishingly small figure given the ≈ 10 million cases of severe malaria annually and our inadequate knowledge of how it should best be managed. Clearly, under-funding has played a major role in the past, but in recent years this problem has begun to be addressed as the global community has started making major investments in tackling the main infectious-disease killers. There has been an associated slow but steady development of clinical research capacity in the malaria-endemic world, and although there is a long way to go, it is for the first time becoming practical to conduct large, adequately powered clinical trials of candidate treatments for severe malaria. Major funding and logistical challenges are still associated with such projects, and research capacity building has to be an integral part of the planning. The considerable problem of agreeing on the research agenda must also be kept in mind, as only a limited number of such multicenter trials can be conducted at any one time. Only by forming multinational collaborations can we hope to address important clinical research questions with sufficient statistical power.

Which new treatments or clinical management strategies warrant assessment in these multi-center studies? In Table 3 we list a number of candidates along with a subjective assessment of the evidence supporting their inclusion and the level of controversy such a trial is likely to generate. Several have been mentioned already in this review, whereas others are more speculative and may require study in smaller trials with surrogate marker endpoints before a larger study can be justified. This is necessarily a personal list, and we are sure to have omitted a number of worthy contenders. The main objective is to stimulate debate and, ultimately, some degree of agreement. This is a prerequisite for the development of collaborations and networks to carry out the studies.

Table 3

Suggested list of candidate interventions in severe malaria

Acknowledgments: We thank Professor Nicholas White for helpful discussions

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Footnotes

1

On June 21, 2007, the U.S. FDA approved an Investigational New Drug protocol that will allow the Centers for Disease Control and Prevention to make intravenous artesunate available to clinicians who request it for patients who have severe malaria.

N.D. and A.D. are funded by the Wellcome Trust.

Authors’ addresses: Nicholas Day and Arjen M. Dondorp, Wellcome Trust–Mahidol University–Oxford Tropical Medicine Programme, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand, Telephone: +66 2 3549172, Fax: +66 2 3549169 and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, U.K, E-mail: ca.serdemport@dkcin.