Cerebral Malaria Presenting With Shock in an Adolescent: A Case Report

Substantial misdiagnosis of severe malaria in African children

Definition of hyperparasitemia in severe falciparum malaria should be updated

This case report presents a critical clinical scenario involving a 55-year-old patient who developed severe Plasmodium falciparum malaria with renal complications despite receiving doxycycline prophylaxis while traveling in a malaria-endemic region. The case emphasizes the potential failure of doxycycline prophylaxis and highlights the importance of considering malaria in patients with a history of travel to endemic areas, even if they have adhered to prophylactic treatment. The patient's clinical presentation included fever, extreme fatigue, and loss of consciousness, leading to hospitalization. Laboratory findings revealed severe anemia, elevated liver enzymes, and impaired renal function, consistent with the criteria for severe malaria. The diagnosis was confirmed by the presence of Plasmodium falciparum parasites on thin blood smears. Due to limited access to parenteral antimalarial medications in Kosovo, the patient received oral artemether-lumefantrine, resulting in clinical improvement. Supportive care and dialysis played a vital role in the patient's recovery. This case report underscores the need for increased awareness of prophylaxis failure, the challenges of managing severe malaria in non-endemic countries, and the importance of timely and appropriate interventions to improve outcomes in severe malaria cases, particularly those with renal involvement.

Countries race to contain resistance to key antimalarial

258 The Optic Nerve Sheath Diameter in Cerebral Infections

Cerebral Malaria: A Vasculopathy

Cutting edge discussions of management, policy, and program issues in emergency care

Clinical manifestations of malaria are nonspecific and range from asymptomatic to severe. The clinical presentations reflect complex interactions between the host, the environment, and the parasites. Signs and symptoms include fever, headache, muscle pain, abdominal pain, anorexia, nausea, vomiting, hepatosplenomegaly, jaundice and dark urine. In mild malaria, these signs and symptoms cannot differentiate malaria from common cold, influenza or other systemic diseases. Fever and malaise in malaria are believed to result from the release of endogenous cytokines [e. g. interleukin 1, 6 and 8 (IL-1, IL-6, IL-8) and tumor necrotic factor-α (TNF-α)] in response to parasite antigens. Other signs and symptoms of malaria are also associated with the rupture of parasitized red cells. In severe malaria, the clinical manifestations included cerebral malaria, pulmonary edema, renal failure, anaemia, and jaundice. Signs and symptoms of cerebral malaria are as follow alteration of consciousness, coma, dysconjugated eyeballs and convulsions. Among fatal cases, 80% died within the first 48 hrs of admission while the rest, death resulted from complications such as acute renal failure, pulmonary edema, bacterial infection, and lactic acidosis. 92% of the survivors had completed recovery. Treatment of multidrug resistant falciparum malaria in Thailand is complicated. New antimalarial drugs have been investigated at the Hospital for Tropical Diseases in the recent years. Artemisinine derivatives such as artesunate, artemether, arteether, dihydroartemisinin are also tested at the Bangkok Hospital for Tropical Diseases. Artesunate and artemether alone with a total dose of 600 to 750 mg produced cure rates of 80 to 95%. Artesunate suppositories have been proved successfully for the treatment of severe malaria. The artemisinin derivatives when used in combination with mefloquine cure rates improved to 95-100%. Dihydroartemisinin alone with a total dose of 480 mg given over 5 days gave a cure rate of 90%. At present, studies with the combination of artemisinin derivatives plus mefloquine in various doses and duration of treatment are being investigated. Until proven otherwise, the drug combinations are still recommended for all adult patients suffering from acute uncomplicated falciparum malaria contracted in multidrug resistant areas.In severe malaria, the choice of antimalarial chemotherapy depends on the clinical severity, the drug sensitivity of the parasites, and the availability and preparation of the drug. Quinine is widely available drug. Qinghaosu and its derivatives have been used successfully in treating both uncomplicated and severe falciparum malaria. Their effectiveness in eliminating the parasites have been extensively documented, however, the recrudescent rate is rather high (10-30%). In treating severe malaria, early diagnosis and early treatment are vital and the aim is to save patient's life. Prompt administration of an adequate and effective antimalarial drug is needed once the diagnosis is made. Other symptomatic and supportive treatment includes careful monitoring of fluid intake and urine output, frequent observations for complications with appropriate treatment and good nursing care.

Malaria is a vector-borne disease that is still responsible for high human morbidity and mortality. Of the five Plasmodium species that can cause malaria in humans, Plasmodium falciparum is regarded the most virulent species. The most fundamental component of sustained control and eradication efforts is the development of effective drugs for malaria treatment and prophylaxis. Plasmodium falciparum’s sexual stages (gametocytes) are not associated with malarial pathogenesis or the clinical symptoms, but they are responsible for the transmission of the disease from human hosts to mosquitos. As such, the development of gametocytocidal interventions that targets the transmission stage to break the disease’s lifecycle forms the basis of efforts towards malaria elimination and eradication. However, despite the importance of this developmental stage, the biology and pharmacology of gametocytes are still very poorly understood. This thesis has set out to gain a better understanding of the identity of gametocyte-active antimalarials and a deeper understanding of the mechanisms underpinning the activity. Using a newly generated luciferase-reporting transgenic line, pharmacodynamic gametocyte studies could be performed to help characterise the activity of selected known reference antimalarials, new potential gametocyte inhibitors in pre-clinical development as well as newly developed fully synthetic compounds designed against the sexual stages. This novel assay revealed that the efficacy of active tested compounds is highly stage-specific. Of all the tested reference antimalarial drugs, MB and DHA were the most potent antimalarial across all gametocyte stages and importantly they were active at clinically relevant levels. These observations were progressed further, developing a time- dependent killing assay that was performed with different concentrations of targeted drug over discrete time intervals to determine the drug’s kill rate. These parameters were then used to simulate the PK/PD relationship of the drug in order to estimate gametocyte clearance profiles during the human treatment period (Chapter 3 and 4). A main focus of the thesis was conducted to better understand the mechanism of drug activity of the 8-aminoquinolines against gametocytes. The ability of a series of 8-aminoquinolines (primaquine as the parent drug, synthesised metabolites in chapter 5, three novel analogues and tafenoquine in (chapter 6) to interact with CYP2D6 was tested by measuring their ability to specifically inhibit the metabolism of fluorescently-tagged tracer substrate by recombinant human CYP 2D6. Reaction products from the CYP metabolites and HLM were then used to test firstly their ability to kill gametocytes, and then to establish their ability to generate hydrogen peroxides and finally measure their haemolytic toxicity. At 10 µM, primaquine CYP metabolites showed activity against the gametocytes that was higher than that of the parent drugs, with the exception of tafenoquine which, interestingly, demonstrated good activity and haemolytic toxicity as a parent drug. These analyses are presented and discussed in the context of strategies that aim at the discovery and development of new transmission-reducing antimalarial drugs.

A survey to examine the extent of use of plants (herbal medicine) in the management of malaria was carried out in Ido/Osi Local Government Area (LGA) of Ekiti State, Nigeria. Pretested and structured questionnaires were administered to assess the knowledge, attitude and practice (KAP) of the people in the management of malaria with herbal medicines. Results showed that only 67.6% attributed the cause of malaria to mosquito bites and 88.1% identified malaria’s symptoms. Majority of the respondents (74.3%) use herbal medicine to treat malaria while 66.0% use modern medicine. Only 34.2% of the respondents among those who use both herbal and modern medicines combine the medicines at a time to treat malaria. Up to thirty-nine plants were mentioned to be used in herbal anti-malarial recipes in the area. As the number of respondents (67.6%) who knew the cause of malaria is not appreciable enough, there is need for more enlightenment programmes in the area. Since the respondents claimed that the plants they use cure malaria is an indication that some of these plants could possess antimalarial properties. Key words: Herbs, malaria, knowledge, attitude and practice (KAP), Ekiti, anti-malarials.

Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin–irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3–4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality.

There are many studies about global efforts to prevent, manage and control malaria. What is lacking, however, are studies about the relations between scientific interventions and the broader societal dimensions of malaria. In response to this situation the study brings together insights from human and non-human geographies, science and postcolonial studies as well as entomology. Malaria is a disease that emerges out of an encounter between three species: Plasmodium parasite, Anopheles mosquito and human. Accordingly, the object of scholarly attention of this thesis is the encounter itself - the fragile but potentially destructive moment when the lives of three distinct and very much alive species intersect. More concretely, malaria control in Ghana happens in a space where lively mosquitoes meet gold-mining companies, fast evolving parasites encounter enthusiastic vaccine developers and where poor people still struggle to pay for antimalarial drugs. The theoretical and empirical chapters interrogate malaria as a complex interspecies encounter. I examine the agency of human, parasite and mosquito in constituting and (re)defining the disease. Of particular importance to the analysis are practices that constitute malaria and its control interventions. Ultimately, the thesis advocates new inventive spatial topologies in conceptualizing malaria and practicing its control. I argue that human and non-human practices are profoundly intermingled and together constitute the disease. Malaria is articulated in enmeshed ecologies. Reading malaria in this way documents how humans co-exist with micro-organisms, and problematises the ecological conditions as well as social and political configurations of malaria in a postcolonial world.

High transmission rate and drug resistance have been implicated in the spread and re-emergence of malaria in areas where the disease had been eradicated. The objective of this study was to determine the prevalence of falciparum malaria and pre-disposing factors to malaria among patients presenting with fever in selected State Hospitals in Ogun State, Southwestern Nigeria. Four thousand and sixty six patients were recruited into this study. Scientific and Ethical clearance was obtained for this study. Blood samples were collected for malaria screening from the subjects. Structured questionnaires were administered to patients and parents of infants to determine the factors that could lead to the development of drug resistance by the parasite in the study population. Out of 4066 subjects screened during the study period, 61.1% were positive for falciparum malaria. Highest prevalence of 70.8% was recorded in children 1-5 years, also the group with highest parasitemia (1080). The study showed that 24.6% of the patient visited hospitals for treatment, 12% use local healers while 25.0% bought antimalarial drugs without prescription. Moreover, some subjects use more than one method in their management of malaria. Those who combined antimalarial drugs with traditional medicine from local healers were 17.4%. Only 18% of the sample population used insecticide treated mosquito nets, 42.3% used window and door nets, while 13% did not employ any mosquito preventive method. Uncontrolled use of drugs and exposure of parasites to the drugs should be monitored in areas where the parasite is still sensitive to the drug.

Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380.

A community-based household survey was conducted to investigate the ownership and utilization of malaria control commodities in the Federal Capital Territory (FCT), Nigeria, using a multifaceted four-phase operational research. The main objectives were to investigate access to and utilization of health services in the capital of the country, to evaluate Insecticide-treated nets (ITN)/long lasting insecticidal nets (LLIN) household coverage including ownership and usage and to assess progress towards achieving LLIN target in the FCT. A multifaceted four-phase operational research, consisting of a community-based household survey describing ownership and use of LLINs, a review of hospital records on malaria disease, the prevalence of malaria among children under the age of five years and use of sulphadoxine-pyrimethamine as intermittent preventive treatment in pregnancy (IPTp), was used to investigate the extent of access to health services and utilization of malaria control strategies adopted in the FCT with reference to the Roll Back Malaria initiative. Of the 585 households surveyed, only 158 (27%) reported ownership of LLINs and 427 (73%) not owning LLIN (χ² = 3.83, p < 0.05). Only 2% of adults, 7% under-fives and 19% of pregnant women, respectively slept under LLINs the night before survey. Urban under-fives were 12 times more likely to seek treatment for malaria than their semi-urban counterparts (χ² = 13.2, p = 0.0002, OR = 12.3, CI = 2.47, 61.35). There was no significant difference in the proportion of women in urban, semi-urban and rural location, who took antimalaria medication during last pregnancy or those who did not.Information, education and communication targeting health promotion on the use of LLIN in FCT could have a salutary impact on the well-being of rural, semi-urban and urban dwellers in Federal Capital Territory, Abuja, Nigeria. Key words: Community, household, malaria, long lasting insecticidal nets, Federal Capital Territory, area councils, economic burden, gross domestic product.