Exchange transfusion combined with artesunate (ET-AS) as a safe and effective therapy in severe P. falciparum malaria: a case series.

BACKGROUND: the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series aims to describe the efficacy and safety of the exchange transfusion combined with artesunate (ET-AS) regimen in severe P. falciparum malaria. Eight patients diagnosed with severe P. falciparum malaria were included. All patients underwent ET using the COBE Spectra system. The aimed for a post-exchange hematocrit of 30%. Half the estimated blood volume was removed and replaced using fresh frozen plasma. The regimen was well-tolerated without complications. The parasite clearance time ranged from 1 ~ 5 days. Five patients with cerebral malaria exhibited full improved consciousness within 3 days, while patient2 with hemolysis improved on day 2. Liver function improved within 1 ~ 6 days, and patient 1 and patient 6 showed improvements renal function on days 18 and 19, respectively. The length of intensive care unit stay range from 2 ~ 10 days, and all patients treated with ET-AS remained in the hospital for 3 ~ 19 days. CONCLUSIONS: these preliminary results suggest that ET-AS regimens are a safe and effective therapy for severe P. falciparum malaria and can benefit patients in clinical settings.

Whole Blood Transfusion for Severe Malarial Anemia in a High Plasmodium falciparum Transmission Setting.

BACKGROUND: Severe malaria resulting from Plasmodium falciparum infection is the leading parasitic cause of death in children worldwide, and severe malarial anemia (SMA) is the most common clinical presentation. The evidence in support of current blood transfusion guidelines for patients with SMA is limited. METHODS: We conducted a retrospective cohort study of 911 hospitalized children with SMA in a holoendemic region of Zambia to examine the association of whole blood transfusion with in-hospital survival. Data were analyzed in adjusted logistic regression models using multiple imputation for missing data. RESULTS: The median age of patients was 24 months (interquartile range, 16-30) and overall case fatality was 16%. Blood transfusion was associated with 35% reduced odds of death in children with SMA (odds ratio, 0.65; 95% confidence interval, .52-.81; P = .0002) corresponding to a number-needed-to-treat (NNT) of 14 patients. Children with SMA complicated by thrombocytopenia were more likely to benefit from transfusion than those without thrombocytopenia (NNT = 5). Longer storage time of whole blood was negatively associated with survival and with the posttransfusion rise in the platelet count but was not associated with the posttransfusion change in hemoglobin concentration. CONCLUSIONS: Whole blood given to pediatric patients with SMA was associated with improved survival, mainly among those with thrombocytopenia who received whole blood stored for <4 weeks. These findings point to a potential use for incorporating thrombocytopenia into clinical decision making and management of severe malaria, which can be further assessed in prospective studies, and underline the importance of maintaining reliable blood donation networks in areas of high malaria transmission.

Dengue and Plasmodium falciparum Coinfection With Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-old Boy: A Clinical Conundrum.

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem disease wherein there is an exaggerated immune system activation following a trigger such as infection, malignancy, or autoimmune diseases. Here we report a case of a 3-year-old boy who presented to us with fever, was diagnosed with dengue fever, and treatment started for the same. Clinical response was poor to treatment and high-grade fever persisted. Subsequent evaluation showed Plasmodium falciparum malaria and treatment was initiated with antimalarial drugs. Further clinical deterioration with poor trend of laboratory values over the next few days prompted evaluation for HLH; workup was positive satisfying the HLH-2004 criteria and IV dexamethasone was started. The child gradually improved and was discharged with normal counts on follow-up over the next 3 months. This article emphasizes on the importance of high degree of suspicion, early workup, and initiation of treatment for HLH for a better outcome.

Predictors of treatment failures of plasmodium falciparum malaria in Vietnam: a 4-year single-centre retrospective study.

BACKGROUND: Drug-resistant falciparum malaria is an increasing public health burden. This study examined the magnitude of Plasmodium falciparum infection and the patterns and predictors of treatment failure in Vietnam. METHODS: Medical records of all 443 patients with malaria infection admitted to the Hospital for Tropical Diseases between January 2015 and December 2018 were used to extract information on demographics, risk factors, symptoms, laboratory tests, treatment, and outcome. RESULTS: More than half (59.8%, 265/443, CI 55.1-64.4%) of patients acquired Plasmodium falciparum infection of whom 21.9% (58/265, CI 17.1-27.4%) had severe malaria, while 7.2% (19/265, CI 4.6-10.9%) and 19.2% (51/265, CI 14.7-24.5%) developed early treatment failure (ETF) and late treatment failure (LTF) respectively. Among 58 patients with severe malaria, 14 (24.1%) acquired infection in regions where artemisinin resistance has been documented including Binh Phuoc (11 patients), Dak Nong (2 patients) and Gia Lai (1 patient). Under treatment with intravenous artesunate, the median (IQR) parasite half-life of 11 patients coming from Binh Phuoc was 3 h (2.3 to 8.3 h), two patients coming from Dak Nong was 2.8 and 5.7 h, and a patient coming from Gia Lai was 6.5 h. Most patients (98.5%, 261/265) recovered completely. Four patients with severe malaria died. Severe malaria was statistically associated with receiving treatment at previous hospitals (P < 0.001), hepatomegaly (P < 0.001) and number of inpatient days (P < 0.001). Having severe malaria was a predictor of ETF (AOR 6.96, CI 2.55-19.02, P < 0.001). No predictor of LTF was identified. CONCLUSIONS: Plasmodium falciparum remains the prevalent malaria parasite. Despite low mortality rate, severe malaria is not rare and is a significant predictor of ETF. To reduce the risk for ETF, studies are needed to examine the effectiveness of combination therapy including parenteral artesunate and a parenteral partner drug for severe malaria. The study alerts the possibility of drug-resistant malaria in Africa and other areas in Vietnam, which are known as non-endemic areas of anti-malarial drug resistance. A more comprehensive study using molecular technique in these regions is required to completely understand the magnitude of drug-resistant malaria and to design appropriate control strategies.

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein.

BACKGROUND: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. METHODS: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. RESULTS: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. CONCLUSION: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

Malaria elimination using the 1-3-7 approach: lessons from Sampov Loun, Cambodia.

BACKGROUND: Cambodia has targeted malaria elimination within its territory by 2025 and is developing a model elimination package of strategies and interventions designed to achieve this goal. METHODS: Cambodia adopted a simplified 1-3-7 surveillance model in the Sampov Loun operational health district in western Cambodia beginning in July 2015. The 1-3-7 approach targets reporting of confirmed cases within one day, investigation of specific cases within three days, and targeted control measures to prevent further transmission within seven days. In Sampov Loun, response measures included reactive case detection (testing of co-travelers, household contacts and family members, and surrounding households with suspected malaria cases), and provision of health education, and insecticide-treated nets. Day 28 follow up microscopy was conducted for all confirmed P. falciparum and P. falciparum-mixed-species malaria cases to assess treatment efficacy. RESULTS: The number of confirmed malaria cases in the district fell from 519 in 2015 to 181 in 2017, and the annual parasite incidence (API) in the district fell from 3.21 per 1000 population to 1.06 per 1000 population. The last locally transmitted case of malaria in Sampov Loun was identified in March 2016. In response to the 408 index cases identified, 1377 contacts were screened, resulting in the identification of 14 positive cases. All positive cases occurred among index case co-travelers. CONCLUSION: The experience of the 1-3-7 approach in Sampov Loun indicates that the basic essential malaria elimination package can be feasibly implemented at the operational district level to achieve the goal of malaria elimination in Cambodia and has provided essential information that has led to the refinement of this package.

Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein.

Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine against Plasmodium falciparum that contains 19 NANP repeats followed by a thrombospondin repeat domain. Although RTS,S has undergone extensive clinical testing and has progressed through phase III clinical trials, continued efforts are underway to enhance its efficacy and duration of protection. Here, we determined that two monoclonal antibodies (mAbs 311 and 317), isolated from a recent controlled human malaria infection trial exploring a delayed fractional dose, inhibit parasite development in vivo by at least 97%. Crystal structures of antibody fragments (Fabs) 311 and 317 with an (NPNA)3 peptide illustrate their different binding modes. Notwithstanding, one and three of the three NPNA repeats adopt similar well-defined type I ß-turns with Fab311 and Fab317, respectively. Furthermore, to explore antibody binding in the context of P. falciparum CSP, we used negative-stain electron microscopy on a recombinant shortened CSP (rsCSP) construct saturated with Fabs. Both complexes display a compact rsCSP with multiple Fabs bound, with the rsCSP-Fab311 complex forming a highly organized helical structure. Together, these structural insights may aid in the design of a next-generation malaria vaccine.

Differential impact of malaria control interventions on P. falciparum and P. vivax infections in young Papua New Guinean children.

INTRODUCTION: As malaria transmission declines, understanding the differential impact of intensified control on Plasmodium falciparum relative to Plasmodium vivax and identifying key drivers of ongoing transmission is essential to guide future interventions. METHODS: Three longitudinal child cohorts were conducted in Papua New Guinea before (2006/2007), during (2008) and after scale-up of control interventions (2013). In each cohort, children aged 1-5 years were actively monitored for infection and illness. Incidence of malaria episodes, molecular force of blood-stage infections (molFOB) and population-averaged prevalence of infections were compared across the cohorts to investigate the impact of intensified control in young children and the key risk factors for malaria infection and illness in 2013. RESULTS: Between 2006 and 2008, P. falciparum infection prevalence, molFOB, and clinical malaria episodes reduced by 47%, 59% and 69%, respectively, and a further 49%, 29% and 75% from 2008 to 2013 (prevalence 41.6% to 22.1% to 11.2%; molFOB: 3.4 to 1.4 to 1.0 clones/child/year; clinical episodes incidence rate (IR) 2.6 to 0.8 to IR 0.2 episodes/child/year). P. vivax clinical episodes declined at rates comparable to P. falciparum between 2006, 2008 and 2013 (IR 2.5 to 1.1 to 0.2), while P. vivax molFOB (2006, 9.8; 2008, 12.1) and prevalence (2006, 59.6%; 2008, 65.0%) remained high in 2008. However, in 2013, P. vivax molFOB (1.2) and prevalence (19.7%) had also substantially declined. In 2013, 89% of P. falciparum and 93% of P. vivax infections were asymptomatic, 62% and 47%, respectively, were sub-microscopic. Area of residence was the major determinant of malaria infection and illness. CONCLUSION: Intensified vector control and routine case management had a differential impact on rates of P. falciparum and P. vivax infections but not clinical malaria episodes in young children. This suggests comparable reductions in new mosquito-derived infections but a delayed impact on P. vivax relapsing infections due to a previously acquired reservoir of hypnozoites. This demonstrates the need to strengthen implementation of P. vivax radical cure to maximise impact of control in co-endemic areas. The high heterogeneity of malaria in 2013 highlights the importance of surveillance and targeted interventions to accelerate towards elimination.

Comparison of immunogenicity and safety outcomes of a malaria vaccine FMP013/ALFQ in rhesus macaques (Macaca mulatta) of Indian and Chinese origin.

BACKGROUND: Indian-origin rhesus (InR) are preferred for research, but strict export restrictions continue to limit their use. Chinese-origin rhesus (ChR), although easier to procure, are genetically distinct from InR and differ in their immune response to infectious agents, such as the Simian Immunodeficiency Virus. The most advanced malaria vaccine, RTS,S (GlaxoSmithKline), is based on the circumsporozoite protein (CSP) of Plasmodium falciparum. The efficacy of RTS,S vaccine in the field remains low and short-lived; efforts are underway to improve CSP-based vaccines. Rhesus models can accelerate preclinical down-selection of the next generation of malaria vaccines. This study was used to determine if the safety and immunogenicity outcomes following vaccination with a CSP vaccine would differ in the InR and ChR models, given the genetic differences between the two sub-populations of rhesus. METHODS: The FMP013 vaccine, was composed of nearly full-length soluble P. falciparum CSP produced in Escherichia coli and was adjuvanted with the Army liposomal formulation (ALFQ). Three doses of the vaccine were administered in InR and ChR (n = 6) at 1-month intervals and the antibody and T cell responses were assessed. RESULTS: Local and systemic toxicity profile of FMP013 vaccine in InR and ChR were similar and they revealed that the FMP013 vaccine was safe and caused only mild and transient inflammatory adverse reactions. Following the first 2 vaccines, there was a slower acquisition of antibodies to the CSP repeat region in ChR. However after the 3rd vaccination the titers in the two models were comparable. The ChR group repeat-specific antibodies had higher avidity and ChR group showed higher inhibition of liver stage development activity compared to InR. There was no difference in T-cell responses to the FMP013 vaccine between the two models. CONCLUSIONS: A difference in the quality of serological responses was detected between the two sub-populations of rhesus. However, both models confirmed that FMP013/ALFQ vaccine was safe, highly immunogenic, elicited functional antibodies and T-cell responses. Overall, the data suggests that rhesus of Indian and Chinese origins can be interchangeably used to compare the safety and immunogenicity of next-generation of malaria vaccines and adjuvants.

Prevalence and clinical outcomes of Plasmodium falciparum and intestinal parasitic infections among children in Kiryandongo refugee camp, mid-Western Uganda: a cross sectional study.

BACKGROUND: The prevalence of Plasmodium falciparum and Intestinal Parasitic Infections (IPIs) - with the corresponding pathogenesis among children remain uncertain. This study aimed at determining the prevalence and the outcomes (including anaemia) of the respective infections and co-infections. Anaemia is a condition in which the number of red blood cells transporting oxygen to the various body parts is not sufficient to meet the needs of the body. METHODS: This was a cross sectional study conducted among 476-refugee camp school children. Kato-Katz technique was used to screen stool samples for intestinal parasites. Microscopy was used for malaria testing while the portable Haemoglobin (Hb) calorimeter was used to measure haemoglobin concentration. RESULTS: The overall prevalence of the mixed infections was 63.03%. Plasmodium falciparum was most prevalent of the single infections 262(55.04%) followed by Taenia spp. 14 (2.9%), Schistosoma mansoni 12(2.5%), Giardia lamblia 7 (2.9%), Trichuris trichiura 2(0.4%), Hookworm 2(0.4%) and Strongyloides stercoralis 1(0.2%). The odds of developing simple or uncomplicated malaria infection or anaemia was 14 times higher in individuals with dual co-infection with Plasmodium falciparum + Taenia sp. compared to single parasitic infection (Odds = 14.13, P = 0.019). Co-infection with Plasmodium falciparum + Taenia spp, was a strong predictor of Malaria and anaemia. CONCLUSION: This study shows that Plasmodium falciparum and Taenia spp. co-infections is a stronger predictor of malaria and anaemia. The prevalence of malaria and anaemia remains higher than the other regions in Uganda outside restricted settlements. The findings of this study underline the need for pragmatic intervention programmes to reduce burden of the co-infections in the study area and similar settlements.

Red blood cell exchange in treatment of severe cerebral P. falciparum malaria: A case report.

INTRODUCTION: Red blood cells exchange transfusion has been demonstrated to be helpful in treatment of sever P. falciparum malaria. However, no large scale randomized controlled trials have been completed to date and the CDC does not recommend RBC exchange transfusions as standard of care. We present a case of severe cerebral malaria in a patient with extremely high parasitemia and severe altered mental status who improved rapidly with automated RBC exchange. REPORT: Seventy-two year old female presented with 1 day history of weakness, altered mental status, malaise, and cyclic sweats after returning from a trip to Sierra Leone. Thick and Thin Smears demonstrated P. falciparum rings present and Quantitative malaria screen demonstrated 53.33% parasitemia. Patient was started on quinidine and doxycycline but continued to deteriorate. Automated RBC exchange transfusion was performed within 24 hours of admission and resulted in rapid improvement in symptomology. Repeat thick and thin smears revealed undetectable parasite load. CONCLUSION: Automated RBC exchange may improve outcomes in severe P. falciparum malaria when presenting parasite loads are very high.

Emerging roles for hemostatic dysfunction in malaria pathogenesis.

Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum-infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.

Therapeutic plasma exchange in the treatment of complicated Plasmodium falciparum malaria: A case report.

Severe falciparum malaria is associated with multiple organ dysfunction and a high rate of fatal outcome. Malaria is a world-wide disease in tropical areas through the bites of vector mosquitoes. Parasitic protozoans introduced by the mosquito's saliva to the blood travel to the liver then mature and reproduce. In humans, malaria is caused by Plasmodium falciparum, P. malariae, P. ovale, P. vivax, and P. knowlesi, and P. falciparum causes most deaths. Typical malaria symptoms include fever, chills, fatigue, headache, nausea, and vomiting. In severe cases, it can cause jaundice, seizures, coma, or death. Jaundice, caused by intravascular hemolysis is a usual complication of malaria, especially in patients with P. falciparum infection. The use of exchange transfusion in malaria is not currently advocated by the Centers of Disease Control and Prevention (CDC) of the United States of America. The role of therapeutic plasma exchange as an adjunctive therapy in malaria has not been widely discussed in the literature. Here, we present a 23-year-old patient with jaundice, acute renal failure, and cerebral involvement who was successfully treated with plasma exchange and hemodialysis.

Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.

Tetrahydrobiopterin (BH4) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH2), which inhibits NOS. Depending on BH4 availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH4/BH2 ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH4 deficiency. The primary three biopterin metabolites (BH4, BH2 and B0 [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH4 was decreased (median 0.16 »mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH2 was increased in SM (median 0.91 »mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH4/BH2 ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH4/BH2 ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH2 in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.

A report of cerebral malaria treated with automated red blood cell exchange.

BACKGROUND: Adjunctive automated whole blood or red blood cell exchange (RBCEx) can rapidly decrease malarial hyperparasitemia. Several case reports and series suggest improvement in clinical symptomatology; however, recent Centers of Disease Control and Prevention (CDC) recommendations concluded that RBCEx has no efficacy as an adjunctive therapy. We present a case of mental status changes secondary to cerebral malaria treated with automated RBCEx resulting in rapid and dramatic neurologic improvement. CASE REPORT: An 84-year-old Somali woman presented with a 3-day history of altered mental status, spiking fevers, chills, bilateral leg pain and weakness, and intermittent diarrhea. Her travel history included a recent trip to Kenya for 1 month without antimalarial chemoprophylaxis. During the hospital stay, her health declined, and she became obtunded. Physical examination revealed fever, tachypnea, hypertension, hypoxia, and no response to verbal or physical stimuli. Her hemoglobin decreased from 12.6 to 6.5 g/dL with 12% intraerythrocytic parasitemia by thin smear. Intraerythrocytic trophozoites and banana-shaped gametocytes were present consistent with Plasmodium falciparum. An emergent 1.5-volume RBC mass automated RBCEx and quinidine infusion decreased her parasitemia to 2%. The patient's mental status improved throughout the procedure, and after the 2½-hour procedure, the patient was alert, oriented, and speaking coherently. The patient continued to receive quinidine and artesunate 1 day later from CDC. CONCLUSION: Automated RBCEx transfusion reduced the parasite burden and restored neurologic functioning in a patient with cerebral malaria while awaiting definitive treatment with artesunate.

An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia.

BACKGROUND: In 2012, the World Health Organization recommended the addition of single low-dose primaquine (SLDPQ, 0.25 mg base/kg body weight) to artemisinin combination therapies to block the transmission of Plasmodium falciparum without testing for glucose-6-phosphate dehydrogenase deficiency. The targeted group was non-pregnant patients aged ≥ 1 year (later changed to ≥ 6 months) with acute uncomplicated falciparum malaria, primarily in countries with artemisinin-resistant P. falciparum (ARPf). No dosing regimen was suggested, leaving malaria control programmes and clinicians in limbo. Therefore, we designed a user-friendly, age-based SLDPQ regimen for Cambodia, the country most affected by ARPf. METHODS: By reviewing primaquine's pharmacology, we defined a therapeutic dose range of 0.15-0.38 mg base/kg (9-22.5 mg in a 60-kg adult) for a therapeutic index of 2.5. Primaquine doses (1-20 mg) were tested using a modelled, anthropometric database of 28,138 Cambodian individuals (22,772 healthy, 4119 with malaria and 1247 with other infections); age distributions were: 0.5-4 years (20.0 %, n = 5640), 5-12 years (9.1 %, n = 2559), 13-17 years (9.1 %, n = 2550), and ≥ 18 years (61.8 %, n = 17,389). Optimal age-dosing groups were selected according to calculated mg base/kg doses and proportions of individuals receiving a therapeutic dose. RESULTS: Four age-dosing bands were defined: (1) 0.5-4 years, (2) 5-9 years, (3) 10-14 years, and (4) ≥15 years to receive 2.5, 5, 7.5, and 15 mg of primaquine base, resulting in therapeutic doses in 97.4 % (5494/5640), 90.5 % (1511/1669), 97.7 % (1473/1508), and 95.7 % (18,489/19,321) of individuals, respectively. Corresponding median (1st-99th centiles) mg base/kg doses of primaquine were (1) 0.23 (0.15-0.38), (2) 0.29 (0.18-0.45), (3) 0.27 (0.15-0.39), and (4) 0.29 (0.20-0.42). CONCLUSIONS: This age-based SLDPQ regimen could contribute substantially to malaria elimination and requires urgent evaluation in Cambodia and other countries with similar anthropometric characteristics. It guides primaquine manufacturers on suitable tablet strengths and doses for paediatric-friendly formulations. Development of similar age-based dosing recommendations for Africa is needed.

AN IMPORTED CASE OF COMPLICATED FALCIPARUM MALARIA.

The paper describes a clinical case of imported severe Pfalciparum malaria in a French citizen treated at the clinic of the Research Institute of Epidemiology, Microbiology, and Infectious Disdases, Ministry of the Republic of Uzbekistan. Due to the fact that the patient with tropical malaria sought medical advice too late, the disease was complicated by grade I malaria-induced coma, acute renal failure- in an oliguric phase, severe anemia, and disseminated intravascular coagulation syndrome. Thanks to effective etiopathogenetic and pathogenetic therapy, the patient recovered and returned to his motherland.

Establishing communication mechanism for malaria prevention in Baiga tribal villages in Baiga Chak area of Dindori district, Madhya Pradesh.

BACKGROUND & OBJECTIVES: Malaria is a serious public health concern in several parts of India, particularly in tribal areas of Madhya Pradesh (MP). Dindori district inhabitated by Baiga tribe, contributes about 15 per cent to the total malaria burden in MP. The tribal and other local inhabitants believe in magico-religious treatment of malaria and use modern health facilities only as second line of treatment. The present study was planned in the villages of one of the particularly vulnerable tribal group of MP, the Baigas. The objective of the study was to generate awareness and utilization of health services for malaria by establishing a communication strategy using local students and unemployed youths as agents of change. METHODS: The study was undertaken in 47 villages and the need based IEC (information, education and communication) intervention was evaluated within four months of initiation by adopting before and after with control design. For both baseline and resurvey the households covered each time were 2350. RESULTS: The baseline data generated revealed that around 53 per cent of the people in the study villages were aware of malaria. Among the non Baigas, 59 per cent were aware of malaria, while among the Baigas it was 49 per cent. IEC intervention could raise the level of awareness to malaria significantly with a net intervention effect of 23 per cent. The IEC intervention also improved the utilization of modern health services significantly. INTERPRETATION & CONCLUSIONS: The IEC strategy designed by using local children and youths was effective as the malaria was on decline in the study area. The same strategy with necessary modifications may be replicated in other areas pandemic for malaria.

Determinants of mortality, intensive care requirement and prolonged hospitalization in malaria - a tertiary care hospital based cohort study from South-Western India.

BACKGROUND: There is a remarkable dearth of literature on less pronounced outcomes in malaria, namely prolonged hospitalization and intensive care requirement. Limitations on routine clinical applicability of the World Health Organization's (WHO) guidelines for determination of severity in malaria does result in underestimation of the true burden of clinicians' perceived severity in malaria. This study was conducted to evaluate the clinico-laboratory and malarial severity features to determine their association with mortality, prolonged hospitalization and requirement of intensive care outcomes. METHODS: A tertiary care hospital based retrospective study was conducted from the year 2007 to 2011 among microscopically proven adult malaria patients. Logistic regression analysis was performed to determine the factors associated with mortality, more than seven days hospitalization, intensive care and other supportive requirements. RESULTS: Of a total of 922 malaria cases studied, more than seven days of hospitalization was the most frequent outcome (21.8% (201), 95% CI=19.1-24.5%) followed by intensive care requirement (8.6% (79), 95% CI=6.8-10.4%) and in-hospital mortality (1.2% (11), 95% CI=0.5-1.9%). Odds of mortality were significantly higher with cerebral malaria, pulmonary oedema/acute respiratory distress syndrome (PE/ARDS), liver dysfunction, severe anaemia, renal failure, respiratory distress, metabolic acidosis and leucocytosis. More than seven days hospitalization had inverse association with mortality. Plasmodium falciparum infection, more than three days of history of fever, haemoglobinuria, renal failure, shock, leucocytosis, severe thrombocytopaenia and every 10 mmHg fall in systolic blood pressure were the independent predictors of more than seven days of hospitalization. More than three days of history of fever, cerebral malaria, PE/ARDS, renal failure, metabolic acidosis, hyperparasitaemia, leucocytosis and severe thrombocytopaenia were independently associated factors with intensive care requirement. CONCLUSIONS: For routine clinical settings, severity definition for malaria needs to be redefined or modified from the existing WHO guidelines. Leucocytosis and severe thrombocytopaenia should be identified as severity determinant in malaria. Patients having more than three days history of fever, leucocytosis, severe thrombocytopaenia and renal failure are more likely to require either prolonged hospitalization and/or intensive care. PE/ARDS alone in Plasmodium vivax may result in mortality, whereas multiorgan involvement is common in P. falciparum related mortalities.

Production and characterization of monoclonal antibodies against substrate specific loop region of Plasmodium falciparum lactate dehydrogenase.

Plasmodial lactate dehydrogenase, terminal enzyme of the glycolytic pathway, has been shown to be biochemically, immunologically and structurally different from the mammalian enzyme. The substrate specific loop region of plasmodial lactate dehydrogenase (pLDH) has 5 amino acids insert (DKEWN) important for anti-malarial drug targeting. In the present study, we have produced six monoclonal antibodies, which are against three different epitopes of Plasmodium falciparum LDH (PfLDH). Two of these monoclonal antibodies (10C4D5 and 10D3G2) are against the substrate specific loop region of PfLDH (residues 98-109, AGFTKAPGKSDKEWNR). The 10C4D5 and 10D3G2 monoclonals bind to substrate specific loop region resulting in inhibition of PfLDH activity. A Microplate Sandwich ELISA was developed employing high affinity non-inhibitory (10A5H5, Kaff 1.272 ± 0.057 nM) and inhibitory (10C4D5, Kaff 0.306 ± 0.011 nM) monoclonal antibodies and evaluated using gossypol, a well known inhibitor of pLDH. The binding of gossypol to substrate specific loop region resulted in inhibition of binding of 10C4D5 monoclonal. This Microplate Sandwich ELISA can be utilized for identification of compounds inhibitory to PfLDH (binding to substrate specific loop region of parasite LDH) from combinatory chemical libraries or medicinal plants extracts. The Microplate Sandwich ELISA has also shown potential for specific diagnosis of malaria using finger prick blood samples.