Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice.

PubMed

Waisberg, Michael; Tarasenko, Tatyana; Vickers, Brandi K; Scott, Bethany L; Willcocks, Lisa C; Molina-Cruz, Alvaro; Pierce, Matthew A; Huang, Chiung-yu; Torres-Velez, Fernando J; Smith, Kenneth G C; Barillas-Mury, Carolina; Miller, Louis H; Pierce, Susan K; Bolland, Silvia

2011-01-18

Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease.

Self-Reactivities to the Non-Erythroid Alpha Spectrin Correlate with Cerebral Malaria in Gabonese Children

PubMed Central

Fesel, Constantin; Snounou, Georges; Rousselle, Jean-Claude; Lim, Pharat; Koko, Jean; Namane, Abdelkader; Cazenave, Pierre-André; Kombila, Maryvonne; Pied, Sylviane

2007-01-01

Background Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFα), with the manifestation of CM in Gabonese children. Methodology To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFα concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. Results/Conclusion The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFα concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM. PMID:17460756

Differences in Gene Transcriptomic Pattern of Plasmodium falciparum in Children with Cerebral Malaria and Asymptomatic Carriers

PubMed Central

Almelli, Talleh; Nuel, Grégory; Bischoff, Emmanuel; Aubouy, Agnès; Elati, Mohamed; Wang, Christian William; Dillies, Marie-Agnès; Coppée, Jean-Yves; Ayissi, Georges Nko; Basco, Leonardo Kishi; Rogier, Christophe; Ndam, Nicaise Tuikue; Deloron, Philippe; Tahar, Rachida

2014-01-01

The mechanisms underlying the heterogeneity of clinical malaria remain largely unknown. We hypothesized that differential gene expression contributes to phenotypic variation of parasites which results in a specific interaction with the host, leading to different clinical features of malaria. In this study, we analyzed the transcriptomes of isolates obtained from asymptomatic carriers and patients with uncomplicated or cerebral malaria. We also investigated the transcriptomes of 3D7 clone and 3D7-Lib that expresses severe malaria associated-variant surface antigen. Our findings revealed a specific up-regulation of genes involved in pathogenesis, adhesion to host cell, and erythrocyte aggregation in parasites from patients with cerebral malaria and 3D7-Lib, compared to parasites from asymptomatic carriers and 3D7, respectively. However, we did not find any significant difference between the transcriptomes of parasites from cerebral malaria and uncomplicated malaria, suggesting similar transcriptomic pattern in these two parasite populations. The difference between isolates from asymptomatic children and cerebral malaria concerned genes coding for exported proteins, Maurer's cleft proteins, transcriptional factor proteins, proteins implicated in protein transport, as well as Plasmodium conserved and hypothetical proteins. Interestingly, UPs A1, A2, A3 and UPs B1 of var genes were predominantly found in cerebral malaria-associated isolates and those containing architectural domains of DC4, DC5, DC13 and their neighboring rif genes in 3D7-lib. Therefore, more investigations are needed to analyze the effective role of these genes during malaria infection to provide with new knowledge on malaria pathology. In addition, concomitant regulation of genes within the chromosomal neighborhood suggests a common mechanism of gene regulation in P. falciparum. PMID:25479608

Coma in fatal adult human malaria is not caused by cerebral oedema.

PubMed

Medana, Isabelle M; Day, Nicholas P J; Sachanonta, Navakanit; Mai, Nguyen T H; Dondorp, Arjen M; Pongponratn, Emsri; Hien, Tran T; White, Nicholas J; Turner, Gareth D H

2011-09-17

The role of brain oedema in the pathophysiology of cerebral malaria is controversial. Coma associated with severe Plasmodium falciparum malaria is multifactorial, but associated with histological evidence of parasitized erythrocyte sequestration and resultant microvascular congestion in cerebral vessels. To determine whether these changes cause breakdown of the blood-brain barrier and resultant perivascular or parenchymal cerebral oedema, histology, immunohistochemistry and image analysis were used to define the prevalence of histological patterns of oedema and the expression of specific molecular pathways involved in water balance in the brain in adults with fatal falciparum malaria. The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection. The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02). Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water

Lactate transport and receptor actions in cerebral malaria

PubMed Central

Mariga, Shelton T.; Kolko, Miriam; Gjedde, Albert; Bergersen, Linda H.

2014-01-01

Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM. PMID:24904266

Prevention of murine cerebral malaria by low-dose cyclosporin A.

PubMed Central

Grau, G E; Gretener, D; Lambert, P H

1987-01-01

The effects of cyclosporin A (CsA) were investigated in an experimental model of cerebral malaria. In this model, Plasmodium berghei ANKA-infected CBA/Ca mice develop a clinically and histologically characterized neurological syndrome which is considered to be the result of immunopathological reactions mediated by L3T4+ T cells. It was shown that CsA displayed a strong protective effect on neurological complications when given at a dose 1 mg/kg/day for 5 consecutive days (Days 4-8), which had no effect on the parasite. Paradoxically, this protection against neurological complications was not seen when parasiticidal doses were used during this limited 5-day period. A similar protective effect was observed with two CsA derivatives, C5-34 and H7-94. The mechanisms by which CsA and the two derivatives could prevent murine cerebral malaria are unknown but can be related to exquisite effects on some lymphocyte functions. In view of these results, it might be conceivable to investigate the benefits of using low doses of CsA in man, in conjunction with the classical antiparasite therapy, for the management of cerebral malaria. PMID:3327806

Prevention of murine cerebral malaria by low-dose cyclosporin A.

PubMed

Grau, G E; Gretener, D; Lambert, P H

1987-08-01

The effects of cyclosporin A (CsA) were investigated in an experimental model of cerebral malaria. In this model, Plasmodium berghei ANKA-infected CBA/Ca mice develop a clinically and histologically characterized neurological syndrome which is considered to be the result of immunopathological reactions mediated by L3T4+ T cells. It was shown that CsA displayed a strong protective effect on neurological complications when given at a dose 1 mg/kg/day for 5 consecutive days (Days 4-8), which had no effect on the parasite. Paradoxically, this protection against neurological complications was not seen when parasiticidal doses were used during this limited 5-day period. A similar protective effect was observed with two CsA derivatives, C5-34 and H7-94. The mechanisms by which CsA and the two derivatives could prevent murine cerebral malaria are unknown but can be related to exquisite effects on some lymphocyte functions. In view of these results, it might be conceivable to investigate the benefits of using low doses of CsA in man, in conjunction with the classical antiparasite therapy, for the management of cerebral malaria.

Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria.

PubMed

Small, Dylan S; Taylor, Terrie E; Postels, Douglas G; Beare, Nicholas Av; Cheng, Jing; MacCormick, Ian Jc; Seydel, Karl B

2017-06-07

Cerebral malaria (CM) can be classified as retinopathy-positive or retinopathy-negative, based on the presence or absence of characteristic retinal features. While malaria parasites are considered central to the pathogenesis of retinopathy-positive CM, their contribution to retinopathy-negative CM is largely unknown. One theory is that malaria parasites are innocent bystanders in retinopathy-negative CM and the etiology of the coma is entirely non-malarial. Because hospitals in malaria-endemic areas often lack diagnostic facilities to identify non-malarial causes of coma, it has not been possible to evaluate the contribution of malaria infection to retinopathy-negative CM. To overcome this barrier, we studied a natural experiment involving genetically inherited traits, and find evidence that malaria parasitemia does contribute to the pathogenesis of retinopathy-negative CM. A lower bound for the fraction of retinopathy-negative CM that would be prevented if malaria parasitemia were to be eliminated is estimated to be 0.93 (95% confidence interval: 0.68, 1).

Proteomic profiling of the brain of mice with experimental cerebral malaria.

PubMed

Moussa, Ehab; Huang, Honglei; Ahras, Malika; Lall, Amar; Thezenas, Marie L; Fischer, Roman; Kessler, Benedikt M; Pain, Arnab; Billker, Oliver; Casals-Pascual, Climent

2018-05-30

Cerebral malaria (CM) is a severe neurological complication of malaria infection in both adults and children. In pursuit of effective treatment of CM, clinical studies, postmortem analysis and animal models have been employed to understand the pathology and identify effective interventions. In this study, a shotgun proteomics analysis was conducted to profile the proteomic signature of the brain tissue of mice with experimental cerebral malaria (ECM) in order to further understand the underlying pathology. To identify CM-associated response, proteomic signatures of the brains of C57/Bl6N mice infected with P. berghei ANKA that developed neurological syndrome were compared to those of mice infected with P. berghei NK65 that developed equally high parasite burdens without neurological signs, and to those of non-infected mice. The results show that the CM-associated response in mice that developed neurological signs comprise mainly acute-phase reaction and coagulation cascade activation, and indicate the leakage of plasma proteins into the brain parenchyma. Cerebral malaria (CM) remains a major cause of death in children. The majority of these deaths occur in sub-Saharan Africa. Even with adequate access to treatment, mortality remains high and neurological sequelae can be found in up to 20% of survivors. No adjuvant treatment to date has been shown to reduce mortality and the pathophysiology of CM is largely unknown. Experimental cerebral malaria (ECM) is a well-established model that may contribute to identify and test druggable targets. In this study we have identified the disruption of the blood-brain barrier following inflammatory and vascular injury as a mechanism of disease. In this study we report a number of proteins that could be validated as potential biomarkers of ECM. Further studies, will be required to validate the clinical relevance of these biomarkers in human CM. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroimmunological Blood Brain Barrier Opening in Experimental Cerebral Malaria

PubMed Central

Baer, Kerstin; Mikolajczak, Sebastian A.; Kappe, Stefan H. I.; Frevert, Ute

2012-01-01

Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological

Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria

PubMed Central

Small, Dylan S; Taylor, Terrie E; Postels, Douglas G; Beare, Nicholas AV; Cheng, Jing; MacCormick, Ian JC; Seydel, Karl B

2017-01-01

Cerebral malaria (CM) can be classified as retinopathy-positive or retinopathy-negative, based on the presence or absence of characteristic retinal features. While malaria parasites are considered central to the pathogenesis of retinopathy-positive CM, their contribution to retinopathy-negative CM is largely unknown. One theory is that malaria parasites are innocent bystanders in retinopathy-negative CM and the etiology of the coma is entirely non-malarial. Because hospitals in malaria-endemic areas often lack diagnostic facilities to identify non-malarial causes of coma, it has not been possible to evaluate the contribution of malaria infection to retinopathy-negative CM. To overcome this barrier, we studied a natural experiment involving genetically inherited traits, and find evidence that malaria parasitemia does contribute to the pathogenesis of retinopathy-negative CM. A lower bound for the fraction of retinopathy-negative CM that would be prevented if malaria parasitemia were to be eliminated is estimated to be 0.93 (95% confidence interval: 0.68, 1). DOI: http://dx.doi.org/10.7554/eLife.23699.001 PMID:28590246

A quantitative brain map of experimental cerebral malaria pathology.

PubMed

Strangward, Patrick; Haley, Michael J; Shaw, Tovah N; Schwartz, Jean-Marc; Greig, Rachel; Mironov, Aleksandr; de Souza, J Brian; Cruickshank, Sheena M; Craig, Alister G; Milner, Danny A; Allan, Stuart M; Couper, Kevin N

2017-03-01

The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.

A quantitative brain map of experimental cerebral malaria pathology

PubMed Central

Schwartz, Jean-Marc; Greig, Rachel; Mironov, Aleksandr; de Souza, J. Brian; Cruickshank, Sheena M.; Craig, Alister G.; Milner, Danny A.; Allan, Stuart M.

2017-01-01

The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM. PMID:28273147

Association between measures of vitamin A and the ocular fundus findings in cerebral malaria.

PubMed

Lewallen, S; Taylor, T E; Molyneux, M E; Semba, R D; Wills, B A; Courtright, P

1998-03-01

To investigate the relationship between serum vitamin A levels and conjunctival impression cytology and retinal whitening present in Malawian children with cerebral malaria. Standard retinal examination and conjunctival impression cytology were performed at hospital admission on 101 consecutively admitted children with cerebral malaria. Blood samples were drawn from 56 children at 24 hours, frozen at -20 degrees C, and transported for assessment of vitamin A levels by high-performance liquid chromatography. Associations among fundus findings and vitamin A measurements were sought. The whitening of the retina that we have previously described in children with cerebral malaria was found to be associated with a mean+/-SD serum vitamin A level of 0.29+/-0.1 micromol/L, compared with a mean vitamin A level of 0.41+/-0.2 micromol/L in children without retinal whitening. Children with retinal whitening were 2.77 (95% CI, 1.06-7.3) times more likely to have abnormal conjunctival impression cytology results than those without whitening. No child had any clinical or ophthalmologic evidence of chronic vitamin A deficiency. The retinal whitening described in children with cerebral malaria is associated with low serum vitamin A levels and with abnormal conjunctival impression cytology results and may be due to acute vitamin A deficiency at the tissue level.

Mechanisms of murine cerebral malaria: Multimodal imaging of altered cerebral metabolism and protein oxidation at hemorrhage sites

PubMed Central

Hackett, Mark J.; Aitken, Jade B.; El-Assaad, Fatima; McQuillan, James A.; Carter, Elizabeth A.; Ball, Helen J.; Tobin, Mark J.; Paterson, David; de Jonge, Martin D.; Siegele, Rainer; Cohen, David D.; Vogt, Stefan; Grau, Georges E.; Hunt, Nicholas H.; Lay, Peter A.

2015-01-01

Using a multimodal biospectroscopic approach, we settle several long-standing controversies over the molecular mechanisms that lead to brain damage in cerebral malaria, which is a major health concern in developing countries because of high levels of mortality and permanent brain damage. Our results provide the first conclusive evidence that important components of the pathology of cerebral malaria include peroxidative stress and protein oxidation within cerebellar gray matter, which are colocalized with elevated nonheme iron at the site of microhemorrhage. Such information could not be obtained previously from routine imaging methods, such as electron microscopy, fluorescence, and optical microscopy in combination with immunocytochemistry, or from bulk assays, where the level of spatial information is restricted to the minimum size of tissue that can be dissected. We describe the novel combination of chemical probe–free, multimodal imaging to quantify molecular markers of disturbed energy metabolism and peroxidative stress, which were used to provide new insights into understanding the pathogenesis of cerebral malaria. In addition to these mechanistic insights, the approach described acts as a template for the future use of multimodal biospectroscopy for understanding the molecular processes involved in a range of clinically important acute and chronic (neurodegenerative) brain diseases to improve treatment strategies. PMID:26824064

Impact of methylene blue and atorvastatin combination therapy on the apparition of cerebral malaria in a murine model.

PubMed

Dormoi, Jérome; Briolant, Sébastien; Desgrouas, Camille; Pradines, Bruno

2013-04-15

Proveblue®, a methylene blue dye that complies with European Pharmacopoeia and contains limited organic impurities and heavy metals of recognized toxicity, showed in vitro synergy against Plasmodium falciparum when combined with atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase. The objective of this study was to evaluate the in vivo efficacy of Proveblue® when combined with atorvastatin in a murine model of experimental cerebral malaria. Forty female C57Bl6/N mice were divided into four groups (control, atorvastatin 40 mg/kg for seven days, Proveblue® 10 mg/kg for five days and atorvastatin combined with Proveblue®), infected with Plasmodium berghei ANKA parasites by intraperitoneal inoculation and observed for 45 days. Treatment with atorvastatin alone did not demonstrate an effect significantly different from no treatment (p = 0.0573). All the mice treated by atorvastatin alone died. Treatment with Proveblue® or a combination of Proveblue® and atorvastatin was significantly increased survival of cerebral malaria (p = 0.0011 and 0.0002, respectively). Although there was only one death in the atorvastatin and Proveblue® combination treatment group (10%) versus two deaths (22%) with Proveblue® treatment, the effect on cerebral malaria was not significant (p = 0.283). The present work demonstrated, for the first time, the high efficacy of Proveblue® in preventing cerebral malaria. Atorvastatin alone or in combination appears to possess limited use for preventing cerebral malaria. Combination of atorvastatin with lower doses of Proveblue® (<10 mg/kg/day) should be evaluated to show potential synergistic effects in cerebral malaria prevention.

Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study*.

PubMed

Conroy, Andrea L; Glover, Simon J; Hawkes, Michael; Erdman, Laura K; Seydel, Karl B; Taylor, Terrie E; Molyneux, Malcolm E; Kain, Kevin C

2012-03-01

To investigate the relationship among the angiopoietin-Tie-2 system, retinopathy, and mortality in children with cerebral malaria. A case-control study of retinopathy-positive vs. retinopathy-negative children with clinically defined cerebral malaria. Queen Elizabeth Central Hospital in Blantyre, Malawi. One hundred fifty-five children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ≤ 2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study. None. Clinical and laboratory parameters were recorded at admission and funduscopic examinations were performed. Admission levels of angiopoietin-1, angiopoietin-2, and a soluble version of their cognate receptor were measured by enzyme-linked immunosorbent assay. We show that angiopoietin-1 levels are decreased and angiopoietin-2 and soluble Tie-2 levels are increased in children with cerebral malaria who had retinopathy compared with those who did not. Angiopoietin-2 and soluble Tie-2 were independent predictors of retinopathy (adjusted odds ratio [95% CI], angiopoietin-2, 4.3 [1.3-14.6], p = .019; soluble Tie-2, 9.7 [2.1-45.8], p = .004). Angiopoietin-2 and soluble Tie-2 were positively correlated with the number of hemorrhages, the severity or retinal whitening, and the extent of capillary whitening observed on funduscopic examination (p < .05 after adjustment for multiple comparisons). Angiopoietin-2 and soluble Tie-2 levels were elevated in children with cerebral malaria who subsequently died and angiopoetin-2 was an independent predictor of death (adjusted odds ratio: 3.9 [1.2-12.7], p = .024). When combined with clinical parameters, angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees. These results provide insights into mechanisms of endothelial activation in cerebral malaria and indicate that the angiopoietin-Tie-2 axis is associated with retinopathy and

PCR negative cerebral malaria in a traveller returning from Mumbai.

PubMed

Bhome, Rohan; Bhome, Rahul

2011-08-11

The incidence of imported malaria to the UK is significant. The authors report a case of a healthy young man diagnosed with PCR negative cerebral malaria, a week after returning from Mumbai. The patient presented with acute confusion and vomiting. His condition deteriorated quickly warranting intubation, ventilation and transfer to intensive therapy unit. Extensive investigation did not find an underlying cause. Antimalarial treatment was initiated based on clinical suspicion despite a negative malarial screen. A rapid response to treatment followed such that the patient was extubated within 24 h. This case highlights the need for the UK Health Protection Agency to review its risk classification of malaria for travellers to Mumbai. Additionally, clinicians should promptly initiate antimalarial treatment in an unwell traveller returning from an endemic area when there is a high clinical suspicion even in the absence of a positive initial malaria screen.

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia.

PubMed

Opi, D Herbert; Swann, Olivia; Macharia, Alexander; Uyoga, Sophie; Band, Gavin; Ndila, Carolyne M; Harrison, Ewen M; Thera, Mahamadou A; Kone, Abdoulaye K; Diallo, Dapa A; Doumbo, Ogobara K; Lyke, Kirsten E; Plowe, Christopher V; Moulds, Joann M; Shebbe, Mohammed; Mturi, Neema; Peshu, Norbert; Maitland, Kathryn; Raza, Ahmed; Kwiatkowski, Dominic P; Rockett, Kirk A; Williams, Thomas N; Rowe, J Alexandra

2018-04-25

Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One ( CR1 ) gene, named Sl2 and McC b , occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McC b and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McC b polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α + thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies. © 2018, Opi et al.

Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria

PubMed Central

Dende, Chaitanya; Meena, Jairam; Nagarajan, Perumal; Panda, Amulya K.; Rangarajan, Pundi N.; Padmanaban, Govindarajan

2015-01-01

Malaria afflicts around 200 million people annually, with a mortality number close to 600,000. The mortality rate in Human Cerebral Malaria (HCM) is unacceptably high (15–20%), despite the availability of artemisinin-based therapy. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. Migration of T cells and parasite-infected RBCs (pRBCs) into the brain are both necessary to precipitate the disease. We have been able to simultaneously target both these parameters of ECM. Curcumin alone was able to reverse all the parameters investigated in this study that govern inflammatory responses, CD8+ T cell and pRBC sequestration into the brain and blood brain barrier (BBB) breakdown. But the animals eventually died of anemia due to parasite build-up in blood. However, arteether-curcumin (AC) combination therapy even after the onset of symptoms provided complete cure. AC treatment is a promising therapeutic option for HCM. PMID:26227888

Self-reactivities to the non-erythroid alpha spectrin correlate with cerebral malaria in Gabonese children.

PubMed

Guiyedi, Vincent; Chanseaud, Youri; Fesel, Constantin; Snounou, Georges; Rousselle, Jean-Claude; Lim, Pharat; Koko, Jean; Namane, Abdelkader; Cazenave, Pierre-André; Kombila, Maryvonne; Pied, Sylviane

2007-04-25

Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFalpha), with the manifestation of CM in Gabonese children. To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFalpha concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFalpha concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM.

Suppression of experimental cerebral malaria by disruption of malate:quinone oxidoreductase.

PubMed

Niikura, Mamoru; Komatsuya, Keisuke; Inoue, Shin-Ichi; Matsuda, Risa; Asahi, Hiroko; Inaoka, Daniel Ken; Kita, Kiyoshi; Kobayashi, Fumie

2017-06-12

Aspartate, which is converted from oxaloacetate (OAA) by aspartate aminotransferase, is considered an important precursor for purine salvage and pyrimidine de novo biosynthesis, and is thus indispensable for the growth of Plasmodium parasites at the asexual blood stages. OAA can be produced in malaria parasites via two routes: (i) from phosphoenolpyruvate (PEP) by phosphoenolpyruvate carboxylase (PEPC) in the cytosol, or (ii) from fumarate by consecutive reactions catalyzed by fumarate hydratase (FH) and malate:quinone oxidoreductase (MQO) in the mitochondria of malaria parasites. Although PEPC-deficient Plasmodium falciparum and Plasmodium berghei (rodent malaria) parasites show a growth defect, the mutant P. berghei can still cause experimental cerebral malaria (ECM) with similar dynamics to wild-type parasites. In contrast, the importance of FH and MQO for parasite viability, growth and virulence is not fully understood because no FH- and MQO-deficient P. falciparum has been established. In this study, the role of FH and MQO in the pathogenicity of asexual-blood-stage Plasmodium parasites causing cerebral malaria was examined. First, FH- and MQO-deficient parasites were generated by inserting a luciferase-expressing cassette into the fh and mqo loci in the genome of P. berghei ANKA strain. Second, the viability of FH-deficient and MQO-deficient parasites that express luciferase was determined by measuring luciferase activity, and the effect of FH or MQO deficiency on the development of ECM was examined. While the viability of FH-deficient P. berghei was comparable to that of control parasites, MQO-deficient parasites exhibited considerably reduced viability. FH activity derived from erythrocytes was also detected. This result and the absence of phenotype in FH-deficient P. berghei parasites suggest that fumarate can be metabolized to malate by host or parasite FH in P. berghei-infected erythrocytes. Furthermore, although the growth of FH- and MQO

Efficacy and safety evaluation of a novel trioxaquine in the management of cerebral malaria in a mouse model.

PubMed

Odhiambo, Onyango C; Wamakima, Hannah N; Magoma, Gabriel N; Kirira, Peter G; Malala, Bonface J; Kimani, Francis T; Muregi, Francis W

2017-07-03

The emergence of multidrug-resistant strains of Plasmodium falciparum poses a great threat of increased fatalities in cases of cerebral and other forms of severe malaria infections in which parenteral artesunate monotherapy is the current drug of choice. The study aimed to investigate in a mouse model of human cerebral malaria whether a trioxaquine chemically synthesized by covalent linking of a 4,7-dichloroquinoline pharmacophore to artesunate through a recent drug development approach termed 'covalent bitherapy' could improve the curative outcomes in cerebral malaria infections. Human cerebral malaria rodent model, the C57BL/6 male mice were infected intraperitoneally (ip) with Plasmodium berghei ANKA and intravenously (iv) treated with the trioxaquine from day 8 post-infection (pi) at 12.5 and 25 mg/kg, respectively, twice a day for 3 days. Treatments with the trioxaquine precursors (artesunate and 4,7-dichloroquine), and quinine were also included as controls. In vivo safety evaluation for the trioxaquine was done according to Organization for Economic Co-operation and Development (OECD) guidelines 423, where female Swiss albino mice were orally administered with either 300 or 2000 mg/kg of the trioxaquine and monitored for signs of severity, and or mortality for 14 days post-treatment. The trioxaquine showed a potent and a rapid antiplasmodial activity with 80% parasite clearance in the first 24 h for the two dosages used. Long-term parasitaemia monitoring showed a total parasite clearance as the treated mice survived beyond 60 days post-treatment, with no recrudescence observed. Artesunate treated mice showed recrudescence 8 days post-treatment, with all mice in this group succumbing to the infection. Also, 4,7-dichloroquinoline and quinine did not show any significant parasitaemia suppression in the first 24 h post-treatment, with the animals succumbing to the infection. Covalent bitherapy proves to be a viable source of urgently needed new anti

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria.

PubMed

Alkaitis, Matthew S; Wang, Honghui; Ikeda, Allison K; Rowley, Carol A; MacCormick, Ian J C; Chertow, Jessica H; Billker, Oliver; Suffredini, Anthony F; Roberts, David J; Taylor, Terrie E; Seydel, Karl B; Ackerman, Hans C

2016-12-15

 Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endothelium-dependent vasodilation. Increased conversion of arginine to ornithine by parasites or host arginase is a proposed mechanism of arginine depletion.  We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope-labeled tracers measured by quadrupole time-of-flight liquid chromatography-mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice.  Children with cerebral malaria and P. berghei-infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice.  Simultaneous arginine and ornithine depletion in malaria parasite-infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Disentangling complex parasite interactions: Protection against cerebral malaria by one helminth species is jeopardized by co-infection with another.

PubMed

Abbate, Jessica L; Ezenwa, Vanessa O; Guégan, Jean-François; Choisy, Marc; Nacher, Mathieu; Roche, Benjamin

2018-05-01

Multi-species interactions can often have non-intuitive consequences. However, the study of parasite interactions has rarely gone beyond the effects of pairwise combinations of species, and the outcomes of multi-parasite interactions are poorly understood. We investigated the effects of co-infection by four gastrointestinal helminth species on the development of cerebral malaria among Plasmodium falciparum-infected patients. We characterized associations among the helminth parasite infra-community, and then tested for independent (direct) and co-infection dependent (indirect) effects of helminths on cerebral malaria risk. We found that infection by Ascaris lumbricoides and Trichuris trichiura were both associated with direct reductions in cerebral malaria risk. However, the benefit of T. trichiura infection was halved in the presence of hookworm, revealing a strong indirect effect. Our study suggests that the outcome of interactions between two parasite species can be significantly modified by a third, emphasizing the critical role that parasite community interactions play in shaping infection outcomes.

Plasmodium falciparum cerebral malaria complicated by disseminated intravascular coagulation and symmetrical peripheral gangrene: case report and review.

PubMed

Liechti, M E; Zumsteg, V; Hatz, C F R; Herren, T

2003-09-01

The case of a 56-year-old female tourist who survived cerebral Plasmodium falciparum malaria with disseminated intravascular coagulation and symmetrical peripheral gangrene, ultimately requiring amputation of her left-sided fingertips and toes, is reported. While symmetrical peripheral gangrene has been described rarely in Asian, African, and American patients with Plasmodium falciparum malaria and disseminated intravascular coagulation, no such case has been reported in travelers returning from endemic areas.

CXCL4 and CXCL10 Predict Risk of Fatal Cerebral Malaria

PubMed Central

Wilson, Nana O.; Jain, Vidhan; Roberts, Christina E.; Lucchi, Naomi; Joel, Pradeep K.; Singh, Mrigendra P.; Nagpal, Avinash C.; Dash, Aditya P.; Udhayakumar, Venkatachalam; Singh, Neeru; Stiles, Jonathan K.

2011-01-01

Plasmodium falciparum in a subset of patients can lead to a diffuse encephalopathy known as cerebral malaria (CM). Despite treatment, mortality caused by CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM involves alterations in cytokine and chemokine expression, local inflammation, vascular injury and repair processes. These diverse factors have limited the rate of discovery of prognostic predictors of fatal CM. Identification of reliable early predictors of CM severity will enable clinicians to adjust this risk with appropriate management of CM. Recent studies revealed that elevated levels of CXCL10 expression in cerebrospinal fluid and peripheral blood plasma independently predicted severe and fatal CM. CXCR3, a promiscuous receptor of CXCL10, plays an important role in pathogenesis of mouse model of CM. In this study the role of corresponding CXCR3 ligands (CXCL11, CXCL10, CXCL9 & CXCL4) in fatal or severe CM was evaluated by comparing their levels in 16 healthy control (HC), 26 mild malaria (MM), 26 cerebral malaria survivors (CMS) and 12 non-survivors (CMNS) using enzyme linked immunosorbent assay (ELISA). Levels of CXCL4 and CXCL10 were significantly elevated in CMNS patients (p < 0.05) when compared with HC, MM and CMS. Elevated plasma levels of CXCL10 and CXCL4 were tightly associated with CM mortality. Receiver Operating Characteristic (ROC) curve analysis revealed that CXCL4 and CXCL10 can discriminate CMNS from MM (p < 0.0001) and CMS (p < 0.0001) with an area under the curve (AUC) = 1. These results suggest that CXCL4 and CXCL10 play a prominent role in pathogenesis of CM associated death and may be used as functional or surrogate biomarkers for predicting CM severity. PMID:21508508

CXCL4 and CXCL10 predict risk of fatal cerebral malaria.

PubMed

Wilson, Nana O; Jain, Vidhan; Roberts, Christina E; Lucchi, Naomi; Joel, Pradeep K; Singh, Mrigendra P; Nagpal, Avinash C; Dash, Aditya P; Udhayakumar, Venkatachalam; Singh, Neeru; Stiles, Jonathan K

2011-01-01

Plasmodium falciparum in a subset of patients can lead to a diffuse encephalopathy known as cerebral malaria (CM). Despite treatment, mortality caused by CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM involves alterations in cytokine and chemokine expression, local inflammation, vascular injury and repair processes. These diverse factors have limited the rate of discovery of prognostic predictors of fatal CM. Identification of reliable early predictors of CM severity will enable clinicians to adjust this risk with appropriate management of CM. Recent studies revealed that elevated levels of CXCL10 expression in cerebrospinal fluid and peripheral blood plasma independently predicted severe and fatal CM. CXCR3, a promiscuous receptor of CXCL10, plays an important role in pathogenesis of mouse model of CM. In this study the role of corresponding CXCR3 ligands (CXCL11, CXCL10, CXCL9 & CXCL4) in fatal or severe CM was evaluated by comparing their levels in 16 healthy control (HC), 26 mild malaria (MM), 26 cerebral malaria survivors (CMS) and 12 non-survivors (CMNS) using enzyme linked immunosorbent assay (ELISA). Levels of CXCL4 and CXCL10 were significantly elevated in CMNS patients (p < 0.05) when compared with HC, MM and CMS. Elevated plasma levels of CXCL10 and CXCL4 were tightly associated with CM mortality. Receiver Operating Characteristic (ROC) curve analysis revealed that CXCL4 and CXCL10 can discriminate CMNS from MM (p < 0.0001) and CMS (p <0.0001) with an area under the curve (AUC)=1. These results suggest that CXCL4 and CXCL10 play a prominent role in pathogenesis of CM associated death and may be used as functional or surrogate biomarkers for predicting CM severity.

Murine AIDS Protects Mice Against Experimental Cerebral Malaria: Down-Regulation by Interleukin 10 a T-Helper Type 1 CD4^+ Cell-Mediated Pathology

NASA Astrophysics Data System (ADS)

Eckwalanga, Michel; Marussig, Myriam; Dias Tavares, Marisa; Bouanga, Jean Claude; Hulier, Elisabeth; Henriette Pavlovitch, Jana; Minoprio, Paola; Portnoi, Denis; Renia, Laurent; Mazier, Dominique

1994-08-01

The retrovirus LP-BM5 murine leukemia virus induces murine AIDS in C57BL/6 mice that has many similarities with human AIDS; Plasmodium berghei ANKA causes experimental cerebral malaria in the same strain of mice. The outcome of malaria infection was studied in mice concurrently infected with the two pathogens. The retrovirus significantly reduced the gravity of the neurological manifestations associated with Plasmodium berghei ANKA infection. The protection against experimental cerebral malaria induced by murine AIDS increased with duration of viral infection and, hence, with the severity of the immunodeficiency. Interleukin 10, principally from splenic T cells, was shown to play a crucial role in this protection.

Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria

PubMed Central

El-Assaad, Fatima; Combes, Valery; Grau, Georges Emile Raymond

2014-01-01

Cerebral malaria (CM) is characterized by a dysregulated immune response that results in endothelial membrane destabilization and increased microparticle (MP) production. Citicoline (CTC) is a membrane stabilizer used for the treatment of neurological disorders. We evaluated the efficacy of CTC as adjunct therapy to aid recovery from experimental CM. We show that CTC reduces MP production in vitro; in combination with artesunate in vivo, confers partial protection against CM; and prolongs survival. PMID:24165175

Spectral reflectance of the ocular fundus as a diagnostic marker for cerebral malaria

NASA Astrophysics Data System (ADS)

Liu, Xun; Rice, David A.; Khoobehi, Bahram

2012-03-01

The challenge of correctly identifying malaria infection continues to impede our efforts to control this disease. Recent studies report highly specific retinal changes in severe malaria patients; these retinal changes may represent a very useful diagnostic indicator for this disease. To further explore the ocular manifestations of malaria, we used hyperspectral imaging to study retinal changes caused by Plasmodium berghei ANKA parasitization in a mouse model. We collected the spectral reflectance of the ocular fundus from hyperspectral images of the mouse eye. The blood oxygen sensitive spectral region was normalized for variances in illumination, and used to calculate relative values that correspond to oxygenated hemoglobin levels. Oxygen hemoglobin levels are markedly lower in parasitized mice, indicating that hemoglobin digestion by P. berghei may be detected using spectral reflectance. Furthermore, the ocular reflectance of parasitized mice was abnormally elevated between 660nm and 750nm, suggesting fluorescence in this region. While the source of this fluorescence is not yet clear, its presence correlates strongly with P. Berghei parasitization, and may indicate the presence of hemozoin deposits in the retinal vasculature. The pathology of severe malaria still presents many questions for clinicians and scientists, and our understanding of cerebral malaria has been generally confined to clinical observation and postmortem examination. As the retina represents a portion of the central nervous system that can be easily examined noninvasively, our technique may provide the basis for an automated tool to detect and examine severe malaria via retinal changes.

Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

PubMed Central

Nacer, Adéla; Movila, Alexandru; Sohet, Fabien; Girgis, Natasha M.; Gundra, Uma Mahesh; Loke, P'ng; Daneman, Richard; Frevert, Ute

2014-01-01

Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8+ T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45hi CD8+ T cells, ICAM-1+ macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8+ T cells and ICAM+ macrophages, causes a severe restriction in

Differential plasma microvesicle and brain profiles of microRNA in experimental cerebral malaria.

PubMed

Cohen, Amy; Zinger, Anna; Tiberti, Natalia; Grau, Georges E R; Combes, Valery

2018-05-11

Cerebral malaria (CM) is a fatal complication of Plasmodium infection, mostly affecting children under the age of five in the sub-Saharan African region. CM pathogenesis remains incompletely understood, although sequestered infected red blood cells, inflammatory cells aggregating in the cerebral blood vessels, and the microvesicles (MV) that they release in the circulation, have been implicated. Plasma MV numbers increase in CM patients and in the murine model, where blocking their release, genetically or pharmacologically, protects against brain pathology, suggesting a role of MV in CM neuropathogenesis. In this work, the microRNA (miRNA) cargo of MV is defined for the first time during experimental CM with the overarching hypothesis that this characterization could help understand CM pathogenesis. The change in abundance of miRNA was studied following infection of CBA mice with Plasmodium berghei ANKA strain (causing experimental CM), and Plasmodium yoelii, which causes severe malaria without cerebral complications, termed non-CM (NCM). miRNA expression was analyzed using microarrays to compare MV from healthy (NI) and CM mice, yielding several miRNA of interest. The differential expression profiles of these selected miRNA (miR-146a, miR-150, miR-193b, miR-205, miR-215, miR-467a, and miR-486) were analyzed in mouse MV, MV-free plasma, and brain tissue by quantitative reverse transcription PCR (RT-qPCR). Two miRNA-miR-146a and miR-193b-were confirmed as differentially abundant in MV from CM mice, compared with NCM and NI mice. These miRNA have been shown to play various roles in inflammation, and their dysregulation during CM may be critical for triggering the neurological syndrome via regulation of their potential downstream targets. These data suggest that, in the mouse model at least, miRNA may have a regulatory role in the pathogenesis of severe malaria.

Correlation of hemorrhage, axonal damage, and blood-tissue barrier disruption in brain and retina of Malawian children with fatal cerebral malaria.

PubMed

Greiner, Jesse; Dorovini-Zis, Katerina; Taylor, Terrie E; Molyneux, Malcolm E; Beare, Nicholas A V; Kamiza, Steve; White, Valerie A

2015-01-01

The retinal and brain histopathological findings in children who died from cerebral malaria (CM) have been recently described. Similar changes occur in both structures, but the findings have not been directly compared in the same patients. In this study, we compared clinical retinal findings and retinal and cerebral histopathological changes in a series of patients in Blantyre, Malawi, who died of CM. The features systematically compared in the same patient were: (1) clinical, gross and microscopic retinal hemorrhages with microscopic cerebral hemorrhages, (2) retinal and cerebral hemorrhage-associated and -unassociated axonal damage, and fibrinogen leakage, and (3) differences in the above features between the pathological categories of CM without microvascular pathology (CM1) and CM with microvascular pathology (CM2) in retina and brain. Forty-seven patients were included: seven CM1, 28 CM2, and 12 controls. In the 35 malaria cases retinal and cerebral pathology correlated in all features except for non-hemorrhage associated fibrinogen leakage. Regarding CM1 and CM2 cases, the only differences were in the proportion of patients with hemorrhage-associated cerebral pathology, and this was expected, based on the definitions of CM1 and CM2. The retina did not show this difference. Non-hemorrhage associated pathology was similar for the two groups. As postulated, histopathological features of hemorrhages, axonal damage and non-hemorrhage associated fibrinogen leakage correlated in the retina and brain of individual patients, although the difference in hemorrhages between the CM1 and CM2 groups was not consistently observed in the retina. These results help to underpin the utility of ophthalmoscopic examination and fundus findings to help in diagnosis and assessment of cerebral malaria patients, but may not help in distinguishing between CM1 and CM2 patients during life.

The pathogenesis of pediatric cerebral malaria: eye exams, autopsies, and neuroimaging.

PubMed

Taylor, Terrie E; Molyneux, Malcolm E

2015-04-01

Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuroimaging studies, which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed. © 2015 New York Academy of Sciences.

Supraorbital Postmortem Brain Sampling for Definitive Quantitative Confirmation of Cerebral Sequestration of Plasmodium falciparum Parasites

PubMed Central

Milner, Danny A.; Valim, Clarissa; Luo, Robert; Playforth, Krupa B.; Kamiza, Steve; Molyneux, Malcolm E.; Seydel, Karl B.; Taylor, Terrie E.

2012-01-01

Background The conventional clinical case definition of cerebral malaria (CM) is imprecise but specificity is improved by a definitive clinical feature such as retinopathy or confirming sequestration of parasites in a post-mortem examination of the brain. A full autopsy is often not possible, since it is costly and may encounter resistance of the deceased's family. Methods We have assessed the use of a cytological smear of brain tissue, obtained post-mortem by supraorbital sampling, for the purpose of quantifying cerebral sequestration in children with fatal malaria in Blantyre, Malawi. We have compared this method to histological quantification of parasites at autopsy. Results The number of parasites present on cytological smears correlated with the proportion of vessels parasitized as assessed by histology of fixed and stained brain tissue. Use of cytological results in addition to the standard clinical case definition increases the specificity of the clinical case definition alone from 48.3% to 100% with a minimal change in sensitivity. Conclusions Post-mortem supraorbital sampling of brain tissue improves the specificity of the diagnosis of fatal cerebral malaria and provides accurate quantitative estimates of cerebral sequestration. This tool can be of great value in clinical, pathogenetic, and epidemiological research studies on cerebral malaria. PMID:22291197

The spectrum of retinopathy in adults with Plasmodium falciparum malaria

PubMed Central

Maude, Richard J.; Beare, Nicholas A.V.; Sayeed, Abdullah Abu; Chang, Christina C.; Charunwatthana, Prakaykaew; Faiz, M. Abul; Hossain, Amir; Yunus, Emran Bin; Hoque, M. Gofranul; Hasan, Mahtab Uddin; White, Nicholas J.; Day, Nicholas P.J.; Dondorp, Arjen M.

2009-01-01

Summary A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied. Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P = 0.039), bacterial sepsis (0/5, 0%; P = 0.038) or healthy controls (0/18, 0%; P < 0.001). The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed. The severity of retinal whitening correlated with admission venous plasma lactate (P = 0.046), suggesting that retinal ischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to study malarial retinopathy. PMID:19344925

The spectrum of retinopathy in adults with Plasmodium falciparum malaria.

PubMed

Maude, Richard J; Beare, Nicholas A V; Abu Sayeed, Abdullah; Chang, Christina C; Charunwatthana, Prakaykaew; Faiz, M Abul; Hossain, Amir; Yunus, Emran Bin; Hoque, M Gofranul; Hasan, Mahtab Uddin; White, Nicholas J; Day, Nicholas P J; Dondorp, Arjen M

2009-07-01

A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied. Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P=0.039), bacterial sepsis (0/5, 0%; P=0.038) or healthy controls (0/18, 0%; P<0.001). The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed. The severity of retinal whitening correlated with admission venous plasma lactate (P=0.046), suggesting that retinal ischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to study malarial retinopathy.

Indocyanine Green Liposomes for Diagnosis and Therapeutic Monitoring of Cerebral Malaria.

PubMed

Portnoy, Emma; Vakruk, Natalia; Bishara, Ameer; Shmuel, Miriam; Magdassi, Shlomo; Golenser, Jacob; Eyal, Sara

2016-01-01

Cerebral malaria (CM) is a major cause of death of Plasmodium falciparum infection. Misdiagnosis of CM often leads to treatment delay and mortality. Conventional brain imaging technologies are rarely applicable in endemic areas. Here we address the unmet need for a simple, non-invasive imaging methodology for early diagnosis of CM. This study presents the diagnostic and therapeutic monitoring using liposomes containing the FDA-approved fluorescent dye indocyanine green (ICG) in a CM murine model. Increased emission intensity of liposomal ICG was demonstrated in comparison with free ICG. The Liposomal ICG's emission was greater in the brains of the infected mice compared to naïve mice and drug treated mice (where CM was prevented). Histological analyses suggest that the accumulation of liposomal ICG in the cerebral vasculature is due to extensive uptake mediated by activated phagocytes. Overall, liposomal ICG offers a valuable diagnostic tool and a biomarker for effectiveness of CM treatment, as well as other diseases that involve inflammation and blood vessel occlusion.

The pathogenesis of pediatric cerebral malaria: eye exams, autopsies and neuro-imaging

PubMed Central

Taylor, Terrie E.; Molyneux, Malcolm E.

2015-01-01

Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuro-imaging studies which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed. PMID:25708306

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

PubMed Central

Sam-Agudu, Nadia A.; Greene, Jennifer A.; Opoka, Robert O.; Kazura, James W.; Boivin, Michael J.; Zimmerman, Peter A.; Riedesel, Melissa A.; Bergemann, Tracy L.; Schimmenti, Lisa A.; John, Chandy C.

2010-01-01

Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at −1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at −1237 or the G allele at 1174 had higher levels of IFN-γ than those without these alleles (P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-γ levels in children with UM or altered TNF-α levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection. PMID:20348497

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

PubMed Central

Ssentongo, Paddy; Robuccio, Anna E.; Thuku, Godfrey; Sim, Derek G.; Nabi, Ali; Bahari, Fatemeh; Shanmugasundaram, Balaji; Billard, Myles W.; Geronimo, Andrew; Short, Kurt W.; Drew, Patrick J.; Baccon, Jennifer; Weinstein, Steven L.; Gilliam, Frank G.; Stoute, José A.; Chinchilli, Vernon M.; Read, Andrew F.; Gluckman, Bruce J.; Schiff, Steven J.

2017-01-01

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP. PMID:28272506

Interleukin 6 production in experimental cerebral malaria: modulation by anticytokine antibodies and possible role in hypergammaglobulinemia

PubMed Central

1990-01-01

The production of Interleukin 6 (IL-6) was studied during experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. IL-6 is present in the serum of mice with ECM, the highest concentrations being observed in mice with full-blown neurological syndrome. High IL-6 levels were also observed, however, in the absence of pathology in nonlethal malaria infection. These data suggest that IL- 6 is produced in large amounts during malaria infection, but does not play a major role in the pathogenesis of ECM. A modulation of IL-6 production in ECM was achieved by in vivo treatment with other anticytokine antibodies: antibodies to interferon (IFN-gamma) or to tumor necrosis factor (TNF) abolished the rise of IL-6, while anti-IL-3 and anti-granulocyte/macrophage colony-stimulating factor antibodies only partially prevented this rise, suggesting that the two cytokines IFN-gamma and TNF are important intermediates in IL-6 production. Passive immunization against IL-6 did not prevent ECM, but significantly reduced serum IgG levels in malaria-infected mice. Thus, by its effects on B cells, IL-6 may be involved in hypergammaglobulinemia and immune-complex diseases, e.g., glomerulonephritis observed during malaria infection. PMID:2121890

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

PubMed Central

Basu-Roy, Upal; Ty, Maureen; Alique, Matilde; Fernandez-Arias, Cristina; Movila, Alexandru; Gomes, Pollyanna; Edagha, Innocent; Wassmer, Samuel C.; Walther, Thomas

2016-01-01

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised. PMID:27643439

Activated Neutrophils Are Associated with Pediatric Cerebral Malaria Vasculopathy in Malawian Children

PubMed Central

Feintuch, Catherine Manix; Saidi, Alex; Seydel, Karl; Chen, Grace; Goldman-Yassen, Adam; Mita-Mendoza, Neida K.; Kim, Ryung S.; Frenette, Paul S.; Taylor, Terrie

2016-01-01

ABSTRACT Most patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of <0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

PubMed Central

2014-01-01

Cerebral malaria (CM) is a life-threatening complication of falciparum malaria, associated with high mortality rates, as well as neurological impairment in surviving patients. Despite disease severity, the etiology of CM remains elusive. Interestingly, although the Plasmodium parasite is sequestered in cerebral microvessels, it does not enter the brain parenchyma: so how does Plasmodium induce neuronal dysfunction? Several independent research groups have suggested a mechanism in which increased blood–brain barrier (BBB) permeability might allow toxic molecules from the parasite or the host to enter the brain. However, the reported severity of BBB damage in CM is variable depending on the model system, ranging from mild impairment to full BBB breakdown. Moreover, the factors responsible for increased BBB permeability are still unknown. Here we review the prevailing theories on CM pathophysiology and discuss new evidence from animal and human CM models implicating BBB damage. Finally, we will review the newly-described role of matrix metalloproteinases (MMPs) and BBB integrity. MMPs comprise a family of proteolytic enzymes involved in modulating inflammatory response, disrupting tight junctions, and degrading sub-endothelial basal lamina. As such, MMPs represent potential innovative drug targets for CM. PMID:24467887

MALARIAL RETINOPATHY: A NEWLY ESTABLISHED DIAGNOSTIC SIGN IN SEVERE MALARIA

PubMed Central

BEARE, NICHOLAS A. V.; TAYLOR, TERRIE E.; HARDING, SIMON P.; LEWALLEN, SUSAN; MOLYNEUX, MALCOLM E.

2008-01-01

Severe malaria is commonly misdiagnosed in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. The detection of malarial retinopathy is a candidate diagnostic test for cerebral malaria. Malarial retinopathy consists of a set of retinal abnormalities that is unique to severe malaria and common in children with cerebral malaria. Its presence and severity are related to risk of death and length of coma in survivors. A large, prospective autopsy study of children dying with cerebral malaria in Malawi found that malarial retinopathy was better than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma. However, visualization has to date relied on specialist examination techniques. Further studies are planned to evaluate the usefulness of funduscopy by general clinicians in a variety of settings across Africa. Studies of the retina and retinal blood vessels provide an unparalleled opportunity to visualize an infected microvasculature and its effect on neural tissue in vivo. This report reviews current knowledge of malarial retinopathy, including its use as a diagnostic test in the comatose child, and its value as a tool for research into the pathophysiology of cerebral malaria. PMID:17123967

Nanocurcumin is superior to native curcumin in preventing degenerative changes in Experimental Cerebral Malaria.

PubMed

Dende, Chaitanya; Meena, Jairam; Nagarajan, Perumal; Nagaraj, Viswanathan Arun; Panda, Amulya Kumar; Padmanaban, Govindarajan

2017-08-30

Curcumin has many pharmacological activities despite its poor bioavailability and in vivo stability. Here, we show that a nanoformulated curcumin (PLGA-curcumin) has better therapeutic index than native curcumin in preventing the onset of neurological symptoms and delaying the death of mice in experimental cerebral malaria. Oral PLGA-curcumin was at least as effective as native curcumin at a 15-fold lower concentration in preventing the breakdown of blood-brain barrier and inhibition of brain mRNAs for inflammatory cytokines, chemokine receptor CXCR3 and its ligand CXCL10, with an increase in the anti-inflammatory cytokine IL-10. This was also reflected in serum cytokine and chemokine levels. At equivalent concentrations, a single oral dose of PLGA-curcumin was more effective in inhibiting serum IFNγ levels and enhancing IL-10 levels than native curcumin. Even at low concentrations, PLGA-curcumin was superior to native curcumin in inhibiting the sequestration of parasitized-RBCs and CD8 + T cells in the brain. A single oral dose of 5 mg PLGA-curcumin containing 350 μg of curcumin resulted in 3-4 fold higher concentration and prolonged presence of curcumin in the brain than that obtained with 5 mg of native curcumin, indicating better bioavailability of PLGA-curcumin. PLGA-curcumin has potential as an adjunct drug to treat human cerebral malaria.

Cerebrospinal fluid Plasmodium falciparum histidine-rich protein-2 in pediatric cerebral malaria.

PubMed

Thakur, Kiran T; Vareta, Jimmy; Carson, Kathryn A; Kampondeni, Samuel; Potchen, Michael J; Birbeck, Gretchen L; MacCormick, Ian; Taylor, Terrie; Sullivan, David J; Seydel, Karl B

2018-03-23

Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM. Patients included in the study were admitted (2009-2013) to the Pediatric Research Ward (Queen Elizabeth Central Hospital, Blantyre, Malawi) meeting World Health Organization criteria for CM with findings of malarial retinopathy. Enzyme-linked immunosorbent assay was used to determine plasma and CSF PfHRP-2 levels. Wilcoxon rank-sum tests and multivariable logistic regression analysis assessed the association of clinical and radiographic characteristics with the primary outcome of death during hospitalization. In this cohort of 94 patients, median age was 44 (interquartile range 29-62) months, 53 (56.4%) patients were male, 6 (7%) were HIV-infected, and 10 (11%) died during hospitalization. Elevated concentrations of plasma lactate (p = 0.005) and CSF PfHRP-2 (p = 0.04) were significantly associated with death. On multivariable analysis, higher PfHRP-2 in the CSF was associated with death (odds ratio 9.00, 95% confidence interval 1.44-56.42) while plasma PfHRP-2 was not (odds ratio 2.05, 95% confidence interval 0.45-9.35). Elevation of CSF, but not plasma PfHRP-2, is associated with death in this paediatric CM cohort. PfHRP-2 egress into the CSF may represent alteration of blood brain barrier permeability related to the sequestration of parasitized erythrocytes in the cerebral microvasculature.

Reversibility of Retinal Microvascular Changes in Severe Falciparum Malaria

PubMed Central

Maude, Richard J.; Kingston, Hugh W. F.; Joshi, Sonia; Mohanty, Sanjib; Mishra, Saroj K.; White, Nicholas J.; Dondorp, Arjen M.

2014-01-01

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted. PMID:24935949

Annona muricata modulate brain-CXCL10 expression during cerebral malaria phase

NASA Astrophysics Data System (ADS)

Djamiatun, Kis; Matug, Sumia M. A.; Prasetyo, Awal; Wijayahadi, Noor; Nugroho, Djoko

2017-02-01

Cerebral malaria (CM) contributes in malaria mortality. People in endemic region get benefices by using A. muricata-leaf extract (AME) before qualified for receiving standard anti-malaria, because AME restrains malaria infection and modulate immune responses. CXCL10 expressed by astrocytes limit brain inflammation. Vascular leakage was found in the brain of experimental CM. Additionally, biomarker related with vascular leakage, angiopoietin-2 (Ang-2) levels increase in CM-patients. Objectives of this study were to determine the efficacy of ethanolic-AME in regulating brain-CXCL10-expression and Ang-2 levels during CM-phase. The study was post-test-only-control-group design. Thirty Swiss-mice were randomly divided in 6 groups. C+ and C- groups were PbA-inoculated and healthy-mice, respectively. X1 and X2 groups were healthy-mice treated with AME 100 and 150 mg/Kg BW/day, respectively. X3 and X4 groups were PbA-inoculated and received either dose mentioned above. CXCL10 was stained by IHC, and determined by Allred score. Plasma-Ang-2 was measured by elisa-method. Kruskal-Wallis-test showed the difference of CXCL10-expression among the studied groups (p=0.003). CXCL10-expression of C+ group was lower than healthy-mice which were C-, X1 and X2 groups (p=0.008, p=0.045, and p=0.012). CXCL10-expression of X3 was comparable to healthy mice (C-, X1 and X2), and was higher than C+ and X4 groups (p=0.012 and p=0.028). CXCL10-expression of X4 group was lower than C- and X2 groups (p=0.011 and p=0.016). Kruskal-Wallis-test showed no difference of Ang-2-levels among 6 groups (p = 0.175). The conclusion is A. muricata influences brain-CXCL10 expression during CM phase, but has no association with Ang-2 levels during CM phase.

Malaria Pathogenesis

NASA Astrophysics Data System (ADS)

Miller, Louis H.; Good, Michael F.; Milon, Genevieve

1994-06-01

Malaria is a disease caused by repeated cycles of growth of the parasite Plasmodium in the erythrocyte. Various cellular and molecular strategies allow the parasite to evade the human immune response for many cycles of parasite multiplication. Under certain circumstances Plasmodium infection causes severe anemia or cerebral malaria; the expression of disease is influenced by both parasite and host factors, as exemplified by the exacerbation of disease during pregnancy. This article provides an overview of malaria pathogenesis, synthesizing the recent field, laboratory, and epidemiological data that will lead to the development of strategies to reduce mortality and morbidity.

CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature

PubMed Central

Swanson, Phillip A.; Hart, Geoffrey T.; Russo, Matthew V.; Nayak, Debasis; Yazew, Takele; Peña, Mirna; Khan, Shahid M.; Pierce, Susan K.; McGavern, Dorian B.

2016-01-01

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen

Reversibility of retinal microvascular changes in severe falciparum malaria.

PubMed

Maude, Richard J; Kingston, Hugh W F; Joshi, Sonia; Mohanty, Sanjib; Mishra, Saroj K; White, Nicholas J; Dondorp, Arjen M

2014-09-01

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted. © The American Society of Tropical Medicine and Hygiene.

Background norepinephrine primes astrocytic calcium responses to subsequent norepinephrine stimuli in the cerebral cortex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nuriya, Mutsuo; Keio Advanced Research Center for Water Biology and Medicine, Keio University, Shinjuku, Tokyo, 160-8582; Graduate School of Environment and Information Sciences, Yokohama National University, Yokohama, Kanagawa, 240-8501

Norepinephrine (NE) levels in the cerebral cortex are regulated in two modes; the brain state is correlated with slow changes in background NE concentration, while salient stimuli induce transient NE spikes. Previous studies have revealed their diverse neuromodulatory actions; however, the modulatory role of NE on astrocytic activity has been poorly characterized thus far. In this study, we evaluated the modulatory action of background NE on astrocytic responses to subsequent stimuli, using two-photon calcium imaging of acute murine cortical brain slices. We find that subthreshold background NE significantly augments calcium responses to subsequent pulsed NE stimulation in astrocytes. This primingmore » effect is independent of neuronal activity and is mediated by the activation of β-adrenoceptors and the downstream cAMP pathway. These results indicate that background NE primes astrocytes for subsequent calcium responses to NE stimulation and suggest a novel gliomodulatory role for brain state-dependent background NE in the cerebral cortex. - Highlights: • Background NE augments the responsiveness of astrocytes to subsequent NE stimulation. • The priming effect is independent of neuronal activity and mediated by βadrenoceptor. • Background subthreshold NE may play gliomodulatory roles in the cerebral cortex.« less

Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor.

PubMed Central

Grau, G E; Heremans, H; Piguet, P F; Pointaire, P; Lambert, P H; Billiau, A; Vassalli, P

1989-01-01

Experimental cerebral malaria (ECM), a lethal hyperacute neurological syndrome associated with high blood levels of tumor necrosis factor, develops in genetically susceptible (CBA/Ca) mice 7 days after infection with Plasmodium berghei ANKA strain. Injections of neutralizing monoclonal antibody against recombinant murine interferon gamma, not later than 4 days after infection, markedly reduced the incidence of ECM and the elevation in serum levels of tumor necrosis factor. This treatment prevented the cerebral lesions (plugging of brain vessels by monocytes, lymphocytes, and parasitized erythrocytes). In contrast, the extent of macrophage infiltration in lymphoid organs (which is a characteristic feature of mice developing ECM), as well as the course of infection, remained unaffected by the antibody treatment. Protected mice died at a later time of severe anemia and overwhelming parasitemia, the usual outcome of P. berghei infection in mice that are not susceptible to ECM. The present data indicate that interferon gamma constitutes an important link in the cytokine network that leads to brain vessel inflammation in experimental malaria. It is proposed that interferon gamma released by activated CD4+ T cells acts by augmenting both production and action of tumor necrosis factor. PMID:2501793

Plasmodium vivax Hospitalizations in a Monoendemic Malaria Region: Severe Vivax Malaria?

PubMed Central

Quispe, Antonio M.; Pozo, Edwar; Guerrero, Edith; Durand, Salomón; Baldeviano, G. Christian; Edgel, Kimberly A.; Graf, Paul C. F.; Lescano, Andres G.

2014-01-01

Severe malaria caused by Plasmodium vivax is no longer considered rare. To describe its clinical features, we performed a retrospective case control study in the subregion of Luciano Castillo Colonna, Piura, Peru, an area with nearly exclusive vivax malaria transmission. Severe cases and the subset of critically ill cases were compared with a random set of uncomplicated malaria cases (1:4). Between 2008 and 2009, 6,502 malaria cases were reported, including 106 hospitalized cases, 81 of which fit the World Health Organization definition for severe malaria. Of these 81 individuals, 28 individuals were critically ill (0.4%, 95% confidence interval = 0.2–0.6%) with severe anemia (57%), shock (25%), lung injury (21%), acute renal failure (14%), or cerebral malaria (11%). Two potentially malaria-related deaths occurred. Compared with uncomplicated cases, individuals critically ill were older (38 versus 26 years old, P < 0.001), but similar in other regards. Severe vivax malaria monoinfection with critical illness is more common than previously thought. PMID:24752683

A new hypothesis on the manifestation of cerebral malaria: the secret is in the liver.

PubMed

Martins, Yuri Chaves; Daniel-Ribeiro, Cláudio Tadeu

2013-11-01

Despite the abundance of information on cerebral malaria (CM), the pathogenesis of this disease is not completely understood. At present, two nonexclusive dominant hypotheses exist to explain how the neurological syndrome manifests: the sequestration (or mechanical) hypothesis and the inflammatory hypothesis. The sequestration hypothesis states that sequestration of Plasmodium falciparum-parasitized red blood cells (pRBCs) to brain capillary endothelia causes obstruction of capillary blood flow followed by brain tissue anoxia and coma. The inflammatory hypothesis postulates that P. falciparum infection releases toxic molecules in the circulation, inducing an imbalanced systemic inflammatory response that leads to coagulopathy, brain endothelial cell dysfunction, accumulation of leukocytes in the brain microcirculation, blood brain barrier (BBB) leakage, cerebral vasoconstriction, edema, and coma. However, both hypotheses, even when considered together, are not sufficient to fully explain the pathogenesis of CM. Here, we propose that the development of acute liver failure (ALF) together with BBB breakdown are the necessary and sufficient conditions for the genesis of CM. ALF is characterized by coagulopathy and hepatic encephalopathy (HE) in a patient without pre-existing liver disease. Signs of hepatic dysfunction have been shown to occur in 2.5-40% of CM patients. In addition, recent studies with murine models demonstrated that mice presenting experimental cerebral malaria (ECM) had hepatic damage and brain metabolic changes characteristic of HE. However, the occurrence of CM in patients with mild or without apparent hepatocellular liver damage and the presence of liver damage in non-CM murine models indicate that the development of ALF during malaria infection is not the single factor responsible for neuropathology. To solve this problem, we also propose that BBB breakdown contributes to the pathogenesis of CM and synergizes with hepatic failure to cause

Protective or pathogenic effects of vascular endothelial growth factor (VEGF) as potential biomarker in cerebral malaria.

PubMed

Canavese, Miriam; Spaccapelo, Roberta

2014-03-01

Cerebral malaria (CM) is the major lethal complication of Plasmodium falciparum infection. It is characterized by persistent coma along with symmetrical motor signs. Several clinical, histopathological, and laboratory studies have suggested that cytoadherence of parasitized erythrocytes, neural injury by malarial toxin, and excessive inflammatory cytokine production are possible pathogenic mechanisms. Although the detailed pathophysiology of CM remains unsolved, it is thought that the binding of parasitized erythrocytes to the cerebral endothelia of microvessels, leading to their occlusion and the consequent angiogenic dysregulation play a key role in the disease pathogenesis. Recent evidences showed that vascular endothelial growth factor (VEGF) and its receptor-related molecules are over-expressed in the brain tissues of CM patients, as well as increased levels of VEGF are detectable in biologic samples from malaria patients. Whether the modulation of VEGF is causative agent of CM mortality or a specific phenotype of patients with susceptibility to fatal CM needs further evaluation. Currently, there is no biological test available to confirm the diagnosis of CM and its complications. It is hoped that development of biomarkers to identify patients and potential risk for adverse outcomes would greatly enhance better intervention and clinical management to improve the outcomes. We review and discuss here what it is currently known in regard to the role of VEGF in CM as well as VEGF as a potential biomarker.

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

PubMed

Clarke, Geraldine M; Rockett, Kirk; Kivinen, Katja; Hubbart, Christina; Jeffreys, Anna E; Rowlands, Kate; Jallow, Muminatou; Conway, David J; Bojang, Kalifa A; Pinder, Margaret; Usen, Stanley; Sisay-Joof, Fatoumatta; Sirugo, Giorgio; Toure, Ousmane; Thera, Mahamadou A; Konate, Salimata; Sissoko, Sibiry; Niangaly, Amadou; Poudiougou, Belco; Mangano, Valentina D; Bougouma, Edith C; Sirima, Sodiomon B; Modiano, David; Amenga-Etego, Lucas N; Ghansah, Anita; Koram, Kwadwo A; Wilson, Michael D; Enimil, Anthony; Evans, Jennifer; Amodu, Olukemi K; Olaniyan, Subulade; Apinjoh, Tobias; Mugri, Regina; Ndi, Andre; Ndila, Carolyne M; Uyoga, Sophie; Macharia, Alexander; Peshu, Norbert; Williams, Thomas N; Manjurano, Alphaxard; Sepúlveda, Nuno; Clark, Taane G; Riley, Eleanor; Drakeley, Chris; Reyburn, Hugh; Nyirongo, Vysaul; Kachala, David; Molyneux, Malcolm; Dunstan, Sarah J; Phu, Nguyen Hoan; Quyen, Nguyen Ngoc; Thai, Cao Quang; Hien, Tran Tinh; Manning, Laurens; Laman, Moses; Siba, Peter; Karunajeewa, Harin; Allen, Steve; Allen, Angela; Davis, Timothy Me; Michon, Pascal; Mueller, Ivo; Molloy, Síle F; Campino, Susana; Kerasidou, Angeliki; Cornelius, Victoria J; Hart, Lee; Shah, Shivang S; Band, Gavin; Spencer, Chris Ca; Agbenyega, Tsiri; Achidi, Eric; Doumbo, Ogobara K; Farrar, Jeremy; Marsh, Kevin; Taylor, Terrie; Kwiatkowski, Dominic P

2017-01-09

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.

Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice.

PubMed

Blank, Jannike; Behrends, Jochen; Jacobs, Thomas; Schneider, Bianca E

2016-02-01

Cerebral malaria (CM) is the most severe complication of human infection with Plasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM is Plasmodium berghei ANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome of PbANKA infection in mice previously infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodent Plasmodium parasites in experimental coinfection models. We found that concomitant M. tuberculosis infection did not change the clinical course of PbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected with PbANKA. Our data suggest that M. tuberculosis coinfection is not able to change the outcome of PbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected with M. tuberculosis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

PPARγ Agonists Improve Survival and Neurocognitive Outcomes in Experimental Cerebral Malaria and Induce Neuroprotective Pathways in Human Malaria

PubMed Central

Serghides, Lena; Friedel, Miriam; Cui, Cheryl; Ho, Keith T.; Mount, Howard T. J.; Sled, John G.; Kain, Kevin C.

2014-01-01

Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM. PMID:24603727

Minocycline prevents cerebral malaria, confers neuroprotection and increases survivability of mice during Plasmodium berghei ANKA infection.

PubMed

Apoorv, Thittayil Suresh; Babu, Phanithi Prakash

2017-02-01

Cerebral malaria (CM) is a neurological complication arising due to Plasmodium falciparum or Plasmodium vivax infection. Minocycline, a semi-synthetic tetracycline, has been earlier reported to have a neuroprotective role in several neurodegenerative diseases. In this study, we investigated the effect of minocycline treatment on the survivability of mice during experimental cerebral malaria (ECM). The currently accepted mouse model, C57BL/6 mice infected with Plasmodium berghei ANKA, was used for the study. Infected mice were treated with an intra-peritoneal dose of minocycline hydrochloride, 45mg/kg daily for ten days that led to parasite clearance in blood, brain, liver and spleen on 7th day post-infection; and the mice survived until experiment ended (90days) without parasite recrudescence. Evans blue extravasation assay showed that blood-brain barrier integrity was maintained by minocycline. The tumor necrosis factor-alpha protein level and caspase activity, which is related to CM pathogenesis, was significantly reduced in the minocycline-treated group. Fluoro-Jade® C and hematoxylin-eosin staining of the brains of minocycline group revealed a decrease in degenerating neurons and absence of hemorrhages respectively. Minocycline treatment led to decrease in gene expressions of inflammatory mediators like interferon-gamma, CXCL10, CCL5, CCL2; receptors CXCR3 and CCR2; and hence decrease in T-cell-mediated cerebral inflammation. We also proved that this reduction in gene expressions is irrespective of the anti-parasitic property of minocycline. The distinct ability of minocycline to modulate gene expressions of CXCL10 and CXCR3 makes it effective than doxycycline, a tetracycline used as chemoprophylaxis. Our study shows that minocycline is highly effective in conferring neuroprotection during ECM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome.

PubMed

Matsubara, Ryuma; Aonuma, Hiroka; Kojima, Mikiko; Tahara, Michiru; Andrabi, Syed Bilal Ahmad; Sakakibara, Hitoshi; Nagamune, Kisaburo

2015-01-01

The apicomplexan parasite Toxoplasma gondii produces the plant hormone abscisic acid, but it is unclear if phytohormones are produced by the malaria parasite Plasmodium spp., the most important parasite of this phylum. Here, we report detection of salicylic acid, an immune-related phytohormone of land plants, in P. berghei ANKA and T. gondii cell lysates. However, addition of salicylic acid to P. falciparum and T. gondii culture had no effect. We transfected P. falciparum 3D7 with the nahG gene, which encodes a salicylic acid-degrading enzyme isolated from plant-infecting Pseudomonas sp., and established a salicylic acid-deficient mutant. The mutant had a significantly decreased concentration of parasite-synthesized prostaglandin E2, which potentially modulates host immunity as an adaptive evolution of Plasmodium spp. To investigate the function of salicylic acid and prostaglandin E2 on host immunity, we established P. berghei ANKA mutants expressing nahG. C57BL/6 mice infected with nahG transfectants developed enhanced cerebral malaria, as assessed by Evans blue leakage and brain histological observation. The nahG-transfectant also significantly increased the mortality rate of mice. Prostaglandin E2 reduced the brain symptoms by induction of T helper-2 cytokines. As expected, T helper-1 cytokines including interferon-γ and interleukin-2 were significantly elevated by infection with the nahG transfectant. Thus, salicylic acid of Plasmodium spp. may be a new pathogenic factor of this threatening parasite and may modulate immune function via parasite-produced prostaglandin E2.

Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome

PubMed Central

Matsubara, Ryuma; Aonuma, Hiroka; Kojima, Mikiko; Tahara, Michiru; Andrabi, Syed Bilal Ahmad; Sakakibara, Hitoshi; Nagamune, Kisaburo

2015-01-01

The apicomplexan parasite Toxoplasma gondii produces the plant hormone abscisic acid, but it is unclear if phytohormones are produced by the malaria parasite Plasmodium spp., the most important parasite of this phylum. Here, we report detection of salicylic acid, an immune-related phytohormone of land plants, in P. berghei ANKA and T. gondii cell lysates. However, addition of salicylic acid to P. falciparum and T. gondii culture had no effect. We transfected P. falciparum 3D7 with the nahG gene, which encodes a salicylic acid-degrading enzyme isolated from plant-infecting Pseudomonas sp., and established a salicylic acid-deficient mutant. The mutant had a significantly decreased concentration of parasite-synthesized prostaglandin E2, which potentially modulates host immunity as an adaptive evolution of Plasmodium spp. To investigate the function of salicylic acid and prostaglandin E2 on host immunity, we established P. berghei ANKA mutants expressing nahG. C57BL/6 mice infected with nahG transfectants developed enhanced cerebral malaria, as assessed by Evans blue leakage and brain histological observation. The nahG-transfectant also significantly increased the mortality rate of mice. Prostaglandin E2 reduced the brain symptoms by induction of T helper-2 cytokines. As expected, T helper-1 cytokines including interferon-γ and interleukin-2 were significantly elevated by infection with the nahG transfectant. Thus, salicylic acid of Plasmodium spp. may be a new pathogenic factor of this threatening parasite and may modulate immune function via parasite-produced prostaglandin E2. PMID:26466097

Plasmodium vivax hospitalizations in a monoendemic malaria region: severe vivax malaria?

PubMed

Quispe, Antonio M; Pozo, Edwar; Guerrero, Edith; Durand, Salomón; Baldeviano, G Christian; Edgel, Kimberly A; Graf, Paul C F; Lescano, Andres G

2014-07-01

Severe malaria caused by Plasmodium vivax is no longer considered rare. To describe its clinical features, we performed a retrospective case control study in the subregion of Luciano Castillo Colonna, Piura, Peru, an area with nearly exclusive vivax malaria transmission. Severe cases and the subset of critically ill cases were compared with a random set of uncomplicated malaria cases (1:4). Between 2008 and 2009, 6,502 malaria cases were reported, including 106 hospitalized cases, 81 of which fit the World Health Organization definition for severe malaria. Of these 81 individuals, 28 individuals were critically ill (0.4%, 95% confidence interval = 0.2-0.6%) with severe anemia (57%), shock (25%), lung injury (21%), acute renal failure (14%), or cerebral malaria (11%). Two potentially malaria-related deaths occurred. Compared with uncomplicated cases, individuals critically ill were older (38 versus 26 years old, P < 0.001), but similar in other regards. Severe vivax malaria monoinfection with critical illness is more common than previously thought. © The American Society of Tropical Medicine and Hygiene.

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

PubMed Central

Clarke, Geraldine M; Rockett, Kirk; Kivinen, Katja; Hubbart, Christina; Jeffreys, Anna E; Rowlands, Kate; Jallow, Muminatou; Conway, David J; Bojang, Kalifa A; Pinder, Margaret; Usen, Stanley; Sisay-Joof, Fatoumatta; Sirugo, Giorgio; Toure, Ousmane; Thera, Mahamadou A; Konate, Salimata; Sissoko, Sibiry; Niangaly, Amadou; Poudiougou, Belco; Mangano, Valentina D; Bougouma, Edith C; Sirima, Sodiomon B; Modiano, David; Amenga-Etego, Lucas N; Ghansah, Anita; Koram, Kwadwo A; Wilson, Michael D; Enimil, Anthony; Evans, Jennifer; Amodu, Olukemi K; Olaniyan, Subulade; Apinjoh, Tobias; Mugri, Regina; Ndi, Andre; Ndila, Carolyne M; Uyoga, Sophie; Macharia, Alexander; Peshu, Norbert; Williams, Thomas N; Manjurano, Alphaxard; Sepúlveda, Nuno; Clark, Taane G; Riley, Eleanor; Drakeley, Chris; Reyburn, Hugh; Nyirongo, Vysaul; Kachala, David; Molyneux, Malcolm; Dunstan, Sarah J; Phu, Nguyen Hoan; Quyen, Nguyen Ngoc; Thai, Cao Quang; Hien, Tran Tinh; Manning, Laurens; Laman, Moses; Siba, Peter; Karunajeewa, Harin; Allen, Steve; Allen, Angela; Davis, Timothy ME; Michon, Pascal; Mueller, Ivo; Molloy, Síle F; Campino, Susana; Kerasidou, Angeliki; Cornelius, Victoria J; Hart, Lee; Shah, Shivang S; Band, Gavin; Spencer, Chris CA; Agbenyega, Tsiri; Achidi, Eric; Doumbo, Ogobara K; Farrar, Jeremy; Marsh, Kevin; Taylor, Terrie; Kwiatkowski, Dominic P

2017-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations. DOI: http://dx.doi.org/10.7554/eLife.15085.001 PMID:28067620

Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria.

PubMed

Bastos, Marcele F; Kayano, Ana Carolina A V; Silva-Filho, João Luiz; Dos-Santos, João Conrado K; Judice, Carla; Blanco, Yara C; Shryock, Nathaniel; Sercundes, Michelle K; Ortolan, Luana S; Francelin, Carolina; Leite, Juliana A; Oliveira, Rafaella; Elias, Rosa M; Câmara, Niels O S; Lopes, Stefanie C P; Albrecht, Letusa; Farias, Alessandro S; Vicente, Cristina P; Werneck, Claudio C; Giorgio, Selma; Verinaud, Liana; Epiphanio, Sabrina; Marinho, Claudio R F; Lalwani, Pritesh; Amino, Rogerio; Aliberti, Julio; Costa, Fabio T M

2018-03-20

Cerebral malaria (CM) is a multifactorial syndrome involving an exacerbated proinflammatory status, endothelial cell activation, coagulopathy, hypoxia, and accumulation of leukocytes and parasites in the brain microvasculature. Despite significant improvements in malaria control, 15% of mortality is still observed in CM cases, and 25% of survivors develop neurologic sequelae for life-even after appropriate antimalarial therapy. A treatment that ameliorates CM clinical signs, resulting in complete healing, is urgently needed. Previously, we showed a hyperbaric oxygen (HBO)-protective effect against experimental CM. Here, we provide molecular evidence that HBO targets brain endothelial cells by decreasing their activation and inhibits parasite and leukocyte accumulation, thus improving cerebral microcirculatory blood flow. HBO treatment increased the expression of aryl hydrocarbon receptor over hypoxia-inducible factor 1-α (HIF-1α), an oxygen-sensitive cytosolic receptor, along with decreased indoleamine 2,3-dioxygenase 1 expression and kynurenine levels. Moreover, ablation of HIF-1α expression in endothelial cells in mice conferred protection against CM and improved survival. We propose that HBO should be pursued as an adjunctive therapy in CM patients to prolong survival and diminish deleterious proinflammatory reaction. Furthermore, our data support the use of HBO in therapeutic strategies to improve outcomes of non-CM disorders affecting the brain.-Bastos, M. F., Kayano, A. C. A. V., Silva-Filho, J. L., Dos-Santos, J. C. K., Judice, C., Blanco, Y. C., Shryock, N., Sercundes, M. K., Ortolan, L. S., Francelin, C., Leite, J. A., Oliveira, R., Elias, R. M., Câmara, N. O. S., Lopes, S. C. P., Albrecht, L., Farias, A. S., Vicente, C. P., Werneck, C. C., Giorgio, S., Verinaud, L., Epiphanio, S., Marinho, C. R. F., Lalwani, P., Amino, R., Aliberti, J., Costa, F. T. M. Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen

The GPI transamidase complex subunit PbGPI16 of Plasmodium berghei is important for inducing experimental cerebral malaria.

PubMed

Liu, Qingyang; Zhao, Yan; Zheng, Li; Zhu, Xiaotong; Cui, Liwang; Cao, Yaming

2018-05-21

In animal models of experimental cerebral malaria (ECM), the glycosylphosphatidylinositols (GPIs) and GPI anchors are the major factors that induce nuclear factor kappa B (NF-κB) activation and proinflammatory responses, which contribute to malaria pathogenesis. GPIs and GPI anchors are transported to the cell surface via a process called GPI transamidation, which involves the GPI transamidase (GPI-T) complex. In this study, we showed that GPI16, one of the GPI-T subunits, is highly conserved among Plasmodium species. Genetic knockout of pbgpi16 ( Δpbgpi16 ) in the rodent malaria parasite Plasmodium berghei ANKA strain led to a significant reduction of the amount of GPIs in the membranes of merozoites as well as surface display of several GPI-anchored merozoite surface proteins. Compared with the wild-type parasites, Δpbgpi16 parasites in C57BL/6 mice caused much less NF-κB activation and elicited a substantially attenuated T helper type 1 response. As a result, Δpbgpi16 -infected mice displayed much less severe brain pathology and considerably fewer Δpbgpi16 -infected mice died from ECM. This study corroborated the GPI toxin as a significant inducer of ECM and further suggested that vaccines against parasite GPIs may be a promising strategy to limit the severity of malaria. Copyright © 2018 American Society for Microbiology.

[Severe Plasmodium falciparum malaria. Description of 5 cases].

PubMed

Espinosa, G; Tortajada, C; Gascón, J; Miquel, R; Nicolás, J M; Nadal, P; Corachán, M

1997-09-01

In the last few years a considerable number of imported malaria has been reported in Spain, probably due the increased tourism to areas with endemic malaria, particularly with P. falciparum. This is the species more frequently associated with severe complications and the only one capable of causing cerebral malaria. In this report we review five cases of malaria which required intensive care because of their severity. None of the patients had received chemoprophylaxis. In all cases the admission criterion to the intensive care unit was the organic failure of one or more systems (renal failure and disseminated intravascular coagulation [DIC] mainly) or the presence of changes in the central nervous system. Parasitemia at admission was higher than 5% in all patients. One patient died on account of cerebral malaria. Only one patient had severe complications not directly associated with malaria. In patients who already have severity criteria, a negative parasitemia test during the clinical course does not necessarily implies a clinical improvement nor does it exclude the emergence of complications. On the other hand, a low parasitemic degree is never a contraindication for admission to the intensive care unit when severity criteria are present.

Severe imported malaria in an intensive care unit: a review of 59 cases

PubMed Central

2012-01-01

Background In view of the close relationship of Portugal with African countries, particularly former Portuguese colonies, the diagnosis of malaria is not a rare thing. When a traveller returns ill from endemic areas, malaria should be the number one suspect. World Health Organization treatment guidelines recommend that adults with severe malaria should be admitted to an intensive care unit (ICU). Methods Severe cases of malaria in patients admitted to an ICU were reviewed retrospectively (1990-2011) and identification of variables associated with in-ICU mortality performed. Malaria prediction score (MPS), malaria score for adults (MSA), simplified acute physiology score (SAPSII) and a score based on WHO's malaria severe criteria were applied. Statistical analysis was performed using StataV12. Results Fifty nine patients were included in the study, all but three were adults; 47 (79,6%) were male; parasitaemia on admission, quantified in 48/59 (81.3%) patients, was equal or greater than 2% in 47 of them (97.9%); the most common complications were thrombocytopaenia in 54 (91.5%) patients, associated with disseminated intravascular coagulation (DIC) in seven (11.8%), renal failure in 31 (52.5%) patients, 18 of which (30.5%) oliguric, shock in 29 (49.1%) patients, liver dysfunction in 27 (45.7%) patients, acidaemia in 23 (38.9%) patients, cerebral dysfunction in 22 (37.2%) patients, 11 of whom with unrousable coma, pulmonary oedema/ARDS in 22 (37.2%) patients, hypoglycaemia in 18 (30.5%) patients; 29 (49.1%) patients presented five or more dysfunctions. The case fatality rate was 15.2%. Comparing the four scores, the SAPS II and the WHO score were the most sensitive to death prediction. In the univariate analysis, death was associated with the SAPS II score, cerebral malaria, acute renal and respiratory failure, DIC, spontaneous bleeding, acidosis and hypoglycaemia. Age, partial immunity to malaria, delay in malaria diagnosis and the level of parasitaemia were not

Background norepinephrine primes astrocytic calcium responses to subsequent norepinephrine stimuli in the cerebral cortex.

PubMed

Nuriya, Mutsuo; Takeuchi, Miyabi; Yasui, Masato

2017-01-29

Norepinephrine (NE) levels in the cerebral cortex are regulated in two modes; the brain state is correlated with slow changes in background NE concentration, while salient stimuli induce transient NE spikes. Previous studies have revealed their diverse neuromodulatory actions; however, the modulatory role of NE on astrocytic activity has been poorly characterized thus far. In this study, we evaluated the modulatory action of background NE on astrocytic responses to subsequent stimuli, using two-photon calcium imaging of acute murine cortical brain slices. We find that subthreshold background NE significantly augments calcium responses to subsequent pulsed NE stimulation in astrocytes. This priming effect is independent of neuronal activity and is mediated by the activation of β-adrenoceptors and the downstream cAMP pathway. These results indicate that background NE primes astrocytes for subsequent calcium responses to NE stimulation and suggest a novel gliomodulatory role for brain state-dependent background NE in the cerebral cortex. Copyright © 2016 Elsevier Inc. All rights reserved.

Case Report: A Case of Severe Cerebral Malaria Managed with Therapeutic Hypothermia and Other Modalities for Brain Edema.

PubMed

Gad, AbdAllah; Ali, Sajjad; Zahoor, Talal; Azarov, Nick

2018-04-01

Malarial infections are uncommon in the United States and almost all reported cases stem from recent travelers coming from endemic countries. Cerebral malaria (CM) is a severe form of the disease usually affecting children and individuals with limited immunity. Despite proper management, mortality from CM can reach up to 25%, especially when it is associated with brain edema. Inefficient management of the edema may result in brain herniation and death. Uniform guidelines for management of CM-associated brain edema are lacking. In this report, we present a case of CM with associated severe brain edema that was successfully managed using a unique combination of therapeutic hypothermia, hypertonic saline, mannitol, and hyperventilation along with the antimalarial drugs quinidine and doxycycline. Our use of hypothermia was based on its proven benefit for improving neurological outcomes in post-cardiac arrest patients and previous in vitro research, suggesting its potential inhibitory role on malaria growth.

Automated Detection of Malarial Retinopathy in Digital Fundus Images for Improved Diagnosis in Malawian Children with Clinically Defined Cerebral Malaria.

PubMed

Joshi, Vinayak; Agurto, Carla; Barriga, Simon; Nemeth, Sheila; Soliz, Peter; MacCormick, Ian J; Lewallen, Susan; Taylor, Terrie E; Harding, Simon P

2017-02-15

Cerebral malaria (CM), a complication of malaria infection, is the cause of the majority of malaria-associated deaths in African children. The standard clinical case definition for CM misclassifies ~25% of patients, but when malarial retinopathy (MR) is added to the clinical case definition, the specificity improves from 61% to 95%. Ocular fundoscopy requires expensive equipment and technical expertise not often available in malaria endemic settings, so we developed an automated software system to analyze retinal color images for MR lesions: retinal whitening, vessel discoloration, and white-centered hemorrhages. The individual lesion detection algorithms were combined using a partial least square classifier to determine the presence or absence of MR. We used a retrospective retinal image dataset of 86 pediatric patients with clinically defined CM (70 with MR and 16 without) to evaluate the algorithm performance. Our goal was to reduce the false positive rate of CM diagnosis, and so the algorithms were tuned at high specificity. This yielded sensitivity/specificity of 95%/100% for the detection of MR overall, and 65%/94% for retinal whitening, 62%/100% for vessel discoloration, and 73%/96% for hemorrhages. This automated system for detecting MR using retinal color images has the potential to improve the accuracy of CM diagnosis.

Automated Detection of Malarial Retinopathy in Digital Fundus Images for Improved Diagnosis in Malawian Children with Clinically Defined Cerebral Malaria

NASA Astrophysics Data System (ADS)

Joshi, Vinayak; Agurto, Carla; Barriga, Simon; Nemeth, Sheila; Soliz, Peter; MacCormick, Ian J.; Lewallen, Susan; Taylor, Terrie E.; Harding, Simon P.

2017-02-01

Cerebral malaria (CM), a complication of malaria infection, is the cause of the majority of malaria-associated deaths in African children. The standard clinical case definition for CM misclassifies ~25% of patients, but when malarial retinopathy (MR) is added to the clinical case definition, the specificity improves from 61% to 95%. Ocular fundoscopy requires expensive equipment and technical expertise not often available in malaria endemic settings, so we developed an automated software system to analyze retinal color images for MR lesions: retinal whitening, vessel discoloration, and white-centered hemorrhages. The individual lesion detection algorithms were combined using a partial least square classifier to determine the presence or absence of MR. We used a retrospective retinal image dataset of 86 pediatric patients with clinically defined CM (70 with MR and 16 without) to evaluate the algorithm performance. Our goal was to reduce the false positive rate of CM diagnosis, and so the algorithms were tuned at high specificity. This yielded sensitivity/specificity of 95%/100% for the detection of MR overall, and 65%/94% for retinal whitening, 62%/100% for vessel discoloration, and 73%/96% for hemorrhages. This automated system for detecting MR using retinal color images has the potential to improve the accuracy of CM diagnosis.

Cerebral malaria in mice: demonstration of cytoadherence of infected red blood cells and microrheologic correlates.

PubMed

Kaul, D K; Nagel, R L; Llena, J F; Shear, H L

1994-04-01

To understand the microcirculatory events during cerebral malaria, we have studied the lethal strain of rodent Plasmodia, Plasmodium yoelii 17XL, originally described by Yoeli and Hargreaves in 1974. The virulence of P. yoelii 17XL is caused by intravascular sequestration of infected red blood cells (IRBCs), especially in the brain vessels and capillaries. This mouse model resembles human P. falciparum infection more closely than P. berghei ANKA infection since it shows little, if any, inflammation of the brain. In vivo microcirculatory studies on cytoadherence of IRBCs were performed using the cremaster muscle preparation, which is an easily accessible vasculature for intravital observations. Ex vivo assay of cytoadherence was carried out in the artificially perfused mesocecum preparation of the rat. The results in either preparation demonstrated cytoadherence of IRBCs that was restricted to postcapillary venules. Furthermore, the in vivo measurements showed the prevalence of cytoadherence in small-diameter (< 40 microns) venules in accordance with the local wall shear rates. The parasitized animals demonstrated significantly reduced red blood cell velocities and wall shear rates in the small-diameter postcapillary venules of the cremaster. The relationship between cytoadherence and venular wall shear rates was also reflected in the inverse correlation between the number of adhered cells and the venular diameter in the ex vivo mesocecum preparation. In the ex vivo preparation, cytoadherence of IRBCs was accompanied by a higher peripheral resistance. Transmission electron microscopy of the cremaster muscle and brain tissues showed a tight association of IRBCs with the endothelium of small venules. These observations demonstrate that cytoadherence of P. yoelii 17XL-infected mouse red blood cells is very similar to that of P. falciparum-infected cells. Thus, this model should allow a detailed analysis of the molecular mechanisms involved in the generation of cerebral

IL-33-mediated protection against experimental cerebral malaria is linked to induction of type 2 innate lymphoid cells, M2 macrophages and regulatory T cells.

PubMed

Besnard, Anne-Gaelle; Guabiraba, Rodrigo; Niedbala, Wanda; Palomo, Jennifer; Reverchon, Flora; Shaw, Tovah N; Couper, Kevin N; Ryffel, Bernhard; Liew, Foo Y

2015-02-01

Cerebral malaria (CM) is a complex parasitic disease caused by Plasmodium sp. Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to the development of cerebral pathology. Using the blood-stage PbA (Plasmodium berghei ANKA) model of infection, we show here that administration of the pro-Th2 cytokine, IL-33, prevents the development of experimental cerebral malaria (ECM) in C57BL/6 mice and reduces the production of inflammatory mediators IFN-γ, IL-12 and TNF-α. IL-33 drives the expansion of type-2 innate lymphoid cells (ILC2) that produce Type-2 cytokines (IL-4, IL-5 and IL-13), leading to the polarization of the anti-inflammatory M2 macrophages, which in turn expand Foxp3 regulatory T cells (Tregs). PbA-infected mice adoptively transferred with ILC2 have elevated frequency of M2 and Tregs and are protected from ECM. Importantly, IL-33-treated mice deleted of Tregs (DEREG mice) are no longer able to resist ECM. Our data therefore provide evidence that IL-33 can prevent the development of ECM by orchestrating a protective immune response via ILC2, M2 macrophages and Tregs.

IL-33-Mediated Protection against Experimental Cerebral Malaria Is Linked to Induction of Type 2 Innate Lymphoid Cells, M2 Macrophages and Regulatory T Cells

PubMed Central

Besnard, Anne-Gaelle; Guabiraba, Rodrigo; Niedbala, Wanda; Palomo, Jennifer; Reverchon, Flora; Shaw, Tovah N.; Couper, Kevin N.; Ryffel, Bernhard; Liew, Foo Y.

2015-01-01

Cerebral malaria (CM) is a complex parasitic disease caused by Plasmodium sp. Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to the development of cerebral pathology. Using the blood-stage PbA (Plasmodium berghei ANKA) model of infection, we show here that administration of the pro-Th2 cytokine, IL-33, prevents the development of experimental cerebral malaria (ECM) in C57BL/6 mice and reduces the production of inflammatory mediators IFN-γ, IL-12 and TNF-α. IL-33 drives the expansion of type-2 innate lymphoid cells (ILC2) that produce Type-2 cytokines (IL-4, IL-5 and IL-13), leading to the polarization of the anti-inflammatory M2 macrophages, which in turn expand Foxp3 regulatory T cells (Tregs). PbA-infected mice adoptively transferred with ILC2 have elevated frequency of M2 and Tregs and are protected from ECM. Importantly, IL-33-treated mice deleted of Tregs (DEREG mice) are no longer able to resist ECM. Our data therefore provide evidence that IL-33 can prevent the development of ECM by orchestrating a protective immune response via ILC2, M2 macrophages and Tregs. PMID:25659095

Rabies Encephalitis in Malaria-Endemic Area, Malawi, Africa

PubMed Central

Mallewa, Macpherson; Fooks, Anthony R.; Banda, Daniel; Chikungwa, Patrick; Mankhambo, Limangeni; Molyneux, Elizabeth; Molyneux, Malcolm E.

2007-01-01

In a malaria-endemic area of Africa, rabies was an important cause of fatal central nervous system infection, responsible for 14 (10.5%) of 133 cases. Four patients had unusual clinical manifestations, and rabies was only diagnosed postmortem. Three (11.5%) of 26 fatal cases were originally attributed to cerebral malaria. PMID:17370529

A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration.

PubMed

Mejia, Pedro; Treviño-Villarreal, J Humberto; Reynolds, Justin S; De Niz, Mariana; Thompson, Andrew; Marti, Matthias; Mitchell, James R

2017-11-09

Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

Health, human rights, and malaria control: historical background and current challenges.

PubMed

Brentlinger, Paula E

2006-01-01

Malaria, a parasitic infection, causes hundreds of millions of disease episodes and more than a million deaths every year, nearly all of them occurring in the poorer and more vulnerable sectors of the world's developing countries. In spite of the great burden of suffering caused by malaria, the human rights implications of this disease have not been well described. This article summarizes important associations between the spread of malaria and human rights abuses (such as those associated with slavery and armed conflict) and between poverty, socio-economic inequity, and access to malaria-control measures. The author concludes that malaria control merits inclusion as a core element in global strategies to achieve progressive realization of the right to health.

High plasma levels of soluble intercellular adhesion molecule (ICAM)-1 are associated with cerebral malaria.

PubMed

Adukpo, Selorme; Kusi, Kwadwo A; Ofori, Michael F; Tetteh, John K A; Amoako-Sakyi, Daniel; Goka, Bamenla Q; Adjei, George O; Edoh, Dominic A; Akanmori, Bartholomew D; Gyan, Ben A; Dodoo, Daniel

2013-01-01

Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM. Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p<0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p>0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies

Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study

PubMed Central

Conroy, Andrea L.; Glover, Simon J.; Hawkes, Michael; Erdman, Laura K.; Seydel, Karl B.; Taylor, Terrie E.; Molyneux, Malcolm E.; Kain, Kevin C.

2011-01-01

Objective To investigate the relationship between the angiopoietin-Tie-2 system, retinopathy and mortality in children with cerebral malaria (CM). Design Case-control study of retinopathy positive versus retinopathy negative children with clinically defined CM. Setting Queen Elizabeth Central Hospital in Blantyre, Malawi. Subjects 155 children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ≤2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study. Measurements Clinical and laboratory parameters were recorded at admission and fundoscopic exams were performed. Admission levels of angiopoietin-1, angiopoietin-2 and a soluble version of their cognate receptor (sTie-2) were measured by ELISA. Main results We show that angiopoietin-1 levels are decreased and angiopoietin-2 and sTie-2 levels are increased in children with CM who had retinopathy compared to those who did not. Angiopoietin-2 and sTie-2 were independent predictors of retinopathy (adjusted Odds ratio (95% CI): angiopoietin-2, 4.3 (1.3-14.6), p=0.019; sTie-2, 9.7 (2.1-45.8), p=0.004). Angiopoietin-2 and sTie-2 were positively correlated with the number of hemorrhages, the severity of retinal whitening and the extent of capillary whitening observed on fundoscopic exam (p<0.05 following adjustment for multiple comparisons). Angiopoietin-2 and sTie-2 levels were elevated in children with CM who subsequently died and Angiopoetin-2 was an independent predictor of death (adjusted Odds ratio: 3.9 (1.2-12.7), p=0.024). When combined with clinical parameters, Angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees. Conclusions These results provide insights into mechanisms of endothelial activation in CM and indicate that the angiopoietin-Tie-2 axis is associated with retinopathy and mortality in pediatric CM. PMID:22343839

The antimicrobial molecule trappin-2/elafin has anti-parasitic properties and is protective in vivo in a murine model of cerebral malaria

PubMed Central

Roussilhon, Christian; Bang, Gilles; Bastaert, Fabien; Solhonne, Brigitte; Garcia-Verdugo, Ignacio; Peronet, Roger; Druilhe, Pierre; Sakuntabhai, Anavaj; Mecheri, Salaheddine; Sallenave, Jean-Michel

2017-01-01

According to the WHO, and despite reduction in mortality rates, there were an estimated 438 000 malaria deaths in 2015. Therefore new antimalarials capable of limiting organ damage are still required. We show that systemic and lung adenovirus (Ad)-mediated over-expression of trappin-2 (T-2) an antibacterial molecule with anti-inflammatory activity, increased mice survival following infection with the cerebral malaria-inducing Plasmodium berghei ANKA (PbANKA) strain. Systemically, T-2 reduced PbANKA sequestration in spleen, lung, liver and brain, associated with a decrease in pro-inflammatory cytokines (eg TNF-α in spleen and lung) and an increase in IL-10 production in the lung. Similarly, local lung instillation of Ad-T-2 resulted in a reduced organ parasite sequestration and a shift towards an anti-inflammatory/repair response, potentially implicating monocytes in the protective phenotype. Relatedly, we demonstrated in vitro that human monocytes incubated with Plasmodium falciparum-infected red blood cells (Pf-iRBCs) and IgGs from hyper-immune African human sera produced T-2 and that the latter colocalized with merozoites and inhibited Pf multiplication. This array of data argues for the first time for the potential therapeutic usefulness of this host defense peptide in human malaria patients, with the aim to limit acute lung injury and respiratory distress syndrom often observed during malaria episodes. PMID:28181563

Complement receptor 1 variants confer protection from severe malaria in Odisha, India.

PubMed

Panda, Aditya K; Panda, Madhumita; Tripathy, Rina; Pattanaik, Sarit S; Ravindran, Balachandran; Das, Bidyut K

2012-01-01

In Plasmodium falciparum infection, complement receptor-1 (CR1) on erythrocyte's surface and ABO blood group play important roles in formation of rosettes which are presumed to be contributory in the pathogenesis of severe malaria. Although several studies have attempted to determine the association of CR1 polymorphisms with severe malaria, observations remain inconsistent. Therefore, a case control study and meta-analysis was performed to address this issue. Common CR1 polymorphisms (intron 27 and exon 22) and blood group were typed in 353 cases of severe malaria (SM) [97 cerebral malaria (CM), 129 multi-organ dysfunction (MOD), 127 non-cerebral severe malaria (NCSM)], 141 un-complicated malaria and 100 healthy controls from an endemic region of Odisha, India. Relevant publications for meta-analysis were searched from the database. The homozygous polymorphisms of CR1 intron 27 and exon 22 (TT and GG) and alleles (T and G) that are associated with low expression of CR1 on red blood cells, conferred significant protection against CM, MOD and malaria deaths. Combined analysis showed significant association of blood group B/intron 27-AA/exon 22-AA with susceptibility to SM (CM and MOD). Meta-analysis revealed that the CR1 exon 22 low expression polymorphism is significantly associated with protection against severe malaria. The results of the present study demonstrate that common CR1 variants significantly protect against severe malaria in an endemic area.

To report a case of unilateral proliferative retinopathy following noncerebral malaria with Plasmodium falciparum in Southern India.

PubMed

Verma, Aditya; Krishna, M S

2015-01-01

The retinopathy in association with malaria fever described so far includes retinal hemorrhages, vessel changes, retinal discoloration/whitening and papilledema. Malaria retinopathy has been mostly described in severe cases, associated with Plasmodium falciparum, correlating the patho-physiology of retinal and cerebral manifestations. We report an unusual case of proliferative retinopathy as a manifestation of malaria fever, caused by P. falciparum with no cerebral involvement. The patient had features of unilateral retinal vascular occlusion with proliferative changes and vitreous hemorrhage. To the best of our knowledge, such a case has never been reported so far in the literature. This report highlights the possible occurrence of severe proliferative changes associated with malaria fever, which if diagnosed early can prevent possible blindness.

Life-saving rectal artesunate for complicated malaria in children.

PubMed

Pengsaa, Krisana; Sirivichayakul, Chukiat; Na-Bangchang, Kesara; Thaiarporn, Itthipon; Chaivisuth, Anong; Wongsuwan, Amnaj; Attanath, Phanorsri; Pojjaroen-Anant, Chanathep; Wisetsing, Pataraporn; Chanthavanich, Pornthep; Sabchareon, Arunee

2005-05-01

We report the effectiveness of two regimens of rectal artesunate formulation in treating 13 Thai children with cerebral/complicated falciparum malaria. The drug was given at an initial dose of 40 mg/kg bodyweight, in 3 or 4 divided doses in the first 24 hours, followed by 10 mg/kg bodyweight once daily for three consecutive days. Mefloquine, at a dose of 15 mg/kg bodyweight was given orally at 72 hours after the initial dose of artesunate, followed by 10 mg/kg bodyweight 6 hours later. Three cases with cerebral malaria gained consciousness within 20 hours of artesunate administration. The median time required for reduction of parasitemia by 90% of the initial value (P90) in 13 children was 11.2 hours. No recrudescence was observed in any of the patients during the 28-day follow-up period. Plasma concentrations of artesunate and dihydroartemisinin (active plasma metabolite of artesunate) measured in two patients who received the high initial dose regimen (20 mg/ kg bodyweight) suggested rapid absorption and adequate plasma concentrations of both compounds following the administration of artesunate via the rectal route. Further studies for the optimized regimen of rectal artesunate in the treatment of cerebral/complicated childhood falciparum malaria in areas of multidrug resistance are warranted.

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators.

PubMed

Schmidt, Kim E; Kuepper, Janina M; Schumak, Beatrix; Alferink, Judith; Hofmann, Andrea; Howland, Shanshan W; Rénia, Laurent; Limmer, Andreas; Specht, Sabine; Hoerauf, Achim

2018-01-01

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4-6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions.

MRI findings in a cohort of brain injured survivors of pediatric cerebral malaria.

PubMed

Kampondeni, Sam D; Potchen, Michael J; Beare, Nicholas A V; Seydel, Karl B; Glover, Simon J; Taylor, Terrie E; Birbeck, Gretchen L

2013-03-01

Abstract. A prospective cohort study of retinopathy-confirmed cerebral malaria (CM) survivors identified 42 of 132 with neurologic sequelae. The 38 survivors with sequelae who were alive when magnetic resonance imaging (MRI) technology became available underwent brain MRIs. Common MRI abnormalities included periventricular T2 signal changes (53%), atrophy (47%), subcortical T2 signal changes (18%), and focal cortical defects (16%). The χ(2) tests assessed the relationship between chronic MRI findings, acute clinical and demographic data, and outcomes. Children who were older at the time of CM infection (P = 0.01) and those with isolated behavioral problems (P = 0.02) were more likely to have a normal MRI. Acute focal seizures were associated with atrophy (P = 0.05). Acute papilledema was associated with subcortical T2 signal changes (P = 0.02). Peripheral retinal whitening (P = 0.007) and a higher admission white blood cell count (P = 0.02) were associated with periventricular T2 signal changes. Chronic MRI findings suggest seizures, increased intracranial pressure, and microvascular ischemia contribute to clinically relevant structural brain injury in CM.

Treatment of Malaria

DTIC Science & Technology

1986-04-01

is trans- ferred by classical Mendelian inheritance during sexual reproduction of the parasite in the anopheline vector (Beale et al, 1978; Walliker...evaluation of parasite counts in capillary blood, bone marrow and intradermal smears in patients with cerebral malaria. XI Inter - national Congress for...1978) Concentration of parasiti /ed erythrocytes in mnalaria diagnosis, Transactionis olft’e IRoal Seiiity of Tropical .edricine an’ tmid giene 72: 552

Plasmodium berghei ANKA (PbA) infection of C57BL/6J mice: a model of severe malaria.

PubMed

de Oca, Marcela Montes; Engwerda, Christian; Haque, Ashraful

2013-01-01

The term "severe malaria" refers to a wide spectrum of syndromes in Plasmodium-infected humans including cerebral malaria (CM), respiratory distress, severe anemia, liver dysfunction, and hypoglycemia. Mouse models have been employed to further our understanding of the pathology and immune responses that occur during Plasmodium infection. Evidence of brain, liver, lung, and spleen pathology, as well as anemia and tissue-sequestration of parasites, has been reported in various strains of inbred mice. While no single mouse model mimics all the various clinical manifestations of severe malaria in humans, here we describe a detailed protocol for Plasmodium berghei ANKA infection of C57BL/6J mice. For many years, this model has been referred to as "experimental cerebral malaria," but in fact recapitulates many of the symptoms and pathologies observed in most severe malaria syndromes.

Inpatient mortality in children with clinically diagnosed malaria as compared with microscopically confirmed malaria.

PubMed

Opoka, Robert O; Xia, Zongqi; Bangirana, Paul; John, Chandy C

2008-04-01

Inpatient treatment for malaria without microscopic confirmation of the diagnosis occurs commonly in sub-Saharan Africa. Differences in mortality in children who are tested by microscopy for Plasmodium falciparum infection as compared with those not tested are not well characterized. A retrospective chart review was conducted of all children up to 15 years of age admitted to Mulago Hospital, Kampala, Uganda from January 2002 to July 2005, with a diagnosis of malaria and analyzed according to microscopy testing for P. falciparum. A total of 23,342 children were treated for malaria during the study period, 991 (4.2%) of whom died. Severe malarial anemia in 7827 (33.5%) and cerebral malaria in 1912 (8.2%) were the 2 common causes of malaria-related admissions. Children who did not receive microscopy testing had a higher case fatality rate than those with a positive blood smear (7.5% versus 3.2%, P < 0.001). After adjustment for age, malaria complications, and comorbid conditions, children who did not have microscopy performed or had a negative blood smear had a higher risk of death than those with a positive blood smear [odds ratio (OR): 3.49, 95% confidence interval (CI): 2.88-4.22, P < 0.001; and OR: 1.59, 95% CI: 1.29-1.96, P < 0.001, respectively]. Diagnosis of malaria in the absence of microscopic confirmation is associated with significantly increased mortality in hospitalized Ugandan children. Inpatient diagnosis of malaria should be supported by microscopic or rapid diagnostic test confirmation.

Developmental outcomes in Malawian children with retinopathy-positive cerebral malaria.

PubMed

Boivin, Michael J; Gladstone, Melissa J; Vokhiwa, Maclean; Birbeck, Gretchen L; Magen, Jed G; Page, Connie; Semrud-Clikeman, Margaret; Kauye, Felix; Taylor, Terrie E

2011-03-01

To assess children with retinopathy-positive cerebral malaria (CM) for neurocognitive sequelae. Participants were selected from an ongoing exposure-control study. Eighty-three Malawian children averaging 4.4 years of age and diagnosed with retinopathy-positive CM were compared to 95 controls. Each child was classified as delayed or not using age-based norms for the Malawi Developmental Assessment Tool (MDAT) for developmental delay on the total scale and for the domains of gross motor, fine motor, language and social skills. Groups were also compared on the Achenbach Child Behaviour Checklist (CBCL) (1.5-5 years). Children with retinopathy-positive CM were delayed, relative to the comparison group, on MDAT total development (P = 0.028; odds ratio or OR = 2.13), with the greatest effects on language development (P = 0.003; OR = 4.93). The two groups did not differ significantly on the Achenbach CBCL internalizing and externalizing symptoms total scores. Stepwise regression demonstrated that coma duration, seizures while in hospital, platelet count and lactate level on admission were predictive of assessment outcomes for the children with retinopathy-positive CM. Children who suffer retinopathy-positive CM at preschool age are at greater risk of developmental delay, particularly with respect to language development. This confirms previous retrospective study findings with school-age children evaluated years after acute illness. The MDAT and the Achenbach CBCL proved sensitive to clinical indicators of severity of malarial illness. © 2010 Blackwell Publishing Ltd.

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators

PubMed Central

Alferink, Judith; Hofmann, Andrea; Howland, Shanshan W.; Rénia, Laurent; Limmer, Andreas; Specht, Sabine; Hoerauf, Achim

2018-01-01

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4–6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions. PMID:29438386

The effects of hypoxia on the ERG in paediatric cerebral malaria.

PubMed

Lochhead, J; Movaffaghy, A; Falsini, B; Harding, S; Riva, C; Molyneux, M

2010-02-01

Cerebral malaria (CM) is a disease of high mortality worldwide. It can be associated with malarial retinopathy (MR) resulting from impaired perfusion within the retinal microvasculature. Areas of capillary non-perfusion (CNP) appear white (retinal whitening) on ophthalmoloscopy. In this study, electrophysiological investigations were performed to investigate the physiological consequences of these hypoxic and ischaemic changes. Children admitted with CM were assessed for inclusion in the study. Those with MR underwent further detailed fundus assessment to quantify retinal whitening and were then designated a severity score. Electrophysiological recordings were performed using a miniganzfeldt stimulator with calibration to the International Society for Clinical Electrophysiology of Visual (ISCEV) standards. ERG data were then analysed with respect to presence of MR and also graded disease severity. Thirty-one children were recruited with a diagnosis of CM, 20 had MR (group 1), and 11 had absent MR (group 2). Statistical analyses of these two groups showed a significant relationship between reduced single flash cone b wave amplitude (CBWA) and increased severity of retinal whitening/CNP (P<0.05). Cone and maximal response b : a wave ratios remained >1 in all subjects. Retinal whitening/CNP in MR is associated with significant changes in ERG cone b wave function. The relatively high b : a ratio is compatible with the high frequency of MR resolution without sequelae.

Visual outcomes in children in Malawi following retinopathy of severe malaria.

PubMed

Beare, N A V; Southern, C; Kayira, K; Taylor, T E; Harding, S P

2004-03-01

To investigate whether retinal changes in children with severe malaria affect visual acuity 1 month after systemic recovery. All children with severe malaria admitted to a research ward in Malawi during one malaria season were examined by direct and indirect ophthalmoscopy. Visual acuity was tested in those attending follow up by Cardiff cards, Sheridan-Gardiner single letters, or Snellen chart. 96 (68%) children attended follow up, of whom 83 (86%) had visual acuity measured. Cardiff cards were used in 47 (57%) children, and Sheridan-Gardiner letters or Snellen chart in 29 (35%). There was no significant difference in the mean logMAR visual acuity between groups with or without macular whitening (0.14 versus 0.16, p = 0.55). There was no trend for worse visual acuity with increasing severity of macular whitening (p = 0.52) including patients in whom the fovea was involved (p = 0.32). Six (4.2%) children had cortical blindness after cerebral malaria, and all six had other neurological sequelae. Ophthalmoscopy during the acute illness revealed no abnormalities in four of these children. Retinal changes in severe malaria, in particular macular whitening, do not appear to affect visual acuity at 1 month. This supports the hypothesis that retinal whitening is due to reversible intracellular oedema in response to relative hypoxia, caused by sequestered erythrocytes infected by Plasmodium falciparum. Impaired visual functioning after cerebral malaria is not attributable to retinal changes and appears to be a cortical phenomenon.

Cerebral malaria as a risk factor for the development of epilepsy and other long-term neurological conditions: a meta-analysis.

PubMed

Christensen, Stephanie S; Eslick, Guy D

2015-04-01

Cerebral malaria (CM) is the most common and severe acute neurological manifestation of Plasmodium falciparum malaria. Children living in malaria-endemic areas of sub-Saharan Africa are at the highest risk of developing CM, and the long-term effect of CM on neurological function is uncertain. We conducted a meta-analysis to quantitatively assess the association between CM and development of long-term neurological impairment. We performed a systematic search through PubMed (including MEDLINE; 1946 to December 2014) and EMBASE (1974 to January 2015) to identify relevant articles. Eligible studies assessed the association between CM and neurological sequelae and were included if they met the criteria allowing a complete extraction of data. Eight studies were included in the final analysis, and in total, 2005 individuals were analysed (cases: n=842, controls: n=1163), most of whom were children. CM was associated with an increased risk of epilepsy (OR 4.68, 95% CI: 2.52-8.70), an increased risk of intelligence quotient (IQ) impairment (OR 4.72, 95% CI: 0.78-28.49), an increased risk of neurodisabilities (OR 16.16, 95% CI: 1.34-195.45), and an increased risk of behavioural disorder (OR 8.47, 95% CI: 2.75-26.04). Our findings suggest that children who survive CM are at increased risk of long-term neurological adverse outcome, including epilepsy. This may present a major public health problem in terms of education and development in malaria-endemic areas. Measures to avoid neurological morbidity are warranted. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Improving cognitive outcome in cerebral malaria: insights from clinical and experimental research.

PubMed

de Miranda, Aline Silva; Brant, Fátima; Machado, Fabiana Simão; Rachid, Milene Alvarenga; Teixeira, Antônio Lúcio

2011-12-01

Cerebral Malaria (CM) is a clinical syndrome defined by the World Health Organization (WHO) as a potentially reversible diffuse encephalopathy characterized mainly by coma and the presence of asexual forms of Plasmodium falciparum parasites in peripheral blood smears in the absence of other causes of encephalopathy. A wide range of clinical manifestations follows the disease including cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM pathogenesis remain incompletely understood although vascular, immunological and metabolic changes have been described. The classical treatment of CM is based on the administration of antimalarial drugs, especially chloroquine and artemisinin derivates as artesunate. Even with treatment, 15 to 20% of children with CM die and approximately 10 to 17% of those who survive remain with significant long-term cognitive impairment. In this context, neuroprotective and adjuvant therapies have been recently investigated in clinical and experimental studies of CM in an attempt to improve cognitive outcome. A poor understanding of pathophysiological mechanisms, properties of compounds used and patient selection have contributed to the lack of success of these interventions. This review discusses clinical aspects of cognitive sequelae, possible mechanisms involved in the brain injury, perspectives and limitations regarding the pharmacological strategies to improve cognitive outcome in CM.

Cerebral malaria and sequelar epilepsy: first matched case-control study in Gabon.

PubMed

Ngoungou, Edgard Brice; Koko, Jean; Druet-Cabanac, Michel; Assengone-Zeh-Nguema, Yvonne; Launay, Marylène Ndong; Engohang, Edouard; Moubeka-Mounguengui, Martine; Kouna-Ndouongo, Philomène; Loembe, Paul-Marie; Preux, Pierre-Marie; Kombila, Maryvonne

2006-12-01

Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas. The purpose of this article was to evaluate the relationship between CM and epilepsy in Gabon. A matched case-control study was carried out on a sample of subjects aged six months to 25 years and hospitalized between 1990 and 2004 in three hospitals in Libreville, Gabon. Cases were defined as patients suffering from epilepsy and confirmed by a neurologist. Controls were defined as patients without epilepsy. The exposure of interest was CM according to WHO criteria. In total, 296 cases and 296 controls were included. Of these, 36 (26 cases and 10 controls) had a CM history. The adjusted odds ratio (aOR) to develop epilepsy after CM was 3.9 [95% CI: 1.7-8.9], p<0.001. Additional risk factors were identified: family history of epilepsy: aOR=6.0 [95% CI: 2.6-14.1], p<0.0001, and febrile convulsions: aOR=9.2 [95% CI 4.0-21.1], p<0.0001. This first case-control study on that issue suggests that epilepsy-related CM is an underrecognized problem. It emphasizes the need for further studies to better evaluate the role of convulsions during CM.

Visual outcomes in children in Malawi following retinopathy of severe malaria

PubMed Central

Beare, N A V; Southern, C; Kayira, K; Taylor, T E; Harding, S P

2004-01-01

Aim: To investigate whether retinal changes in children with severe malaria affect visual acuity 1 month after systemic recovery. Methods: All children with severe malaria admitted to a research ward in Malawi during one malaria season were examined by direct and indirect ophthalmoscopy. Visual acuity was tested in those attending follow up by Cardiff cards, Sheridan-Gardiner single letters, or Snellen chart. Results: 96 (68%) children attended follow up, of whom 83 (86%) had visual acuity measured. Cardiff cards were used in 47 (57%) children, and Sheridan-Gardiner letters or Snellen chart in 29 (35%). There was no significant difference in the mean logMAR visual acuity between groups with or without macular whitening (0.14 versus 0.16, p = 0.55). There was no trend for worse visual acuity with increasing severity of macular whitening (p = 0.52) including patients in whom the fovea was involved (p = 0.32). Six (4.2%) children had cortical blindness after cerebral malaria, and all six had other neurological sequelae. Ophthalmoscopy during the acute illness revealed no abnormalities in four of these children. Conclusion: Retinal changes in severe malaria, in particular macular whitening, do not appear to affect visual acuity at 1 month. This supports the hypothesis that retinal whitening is due to reversible intracellular oedema in response to relative hypoxia, caused by sequestered erythrocytes infected by Plasmodium falciparum. Impaired visual functioning after cerebral malaria is not attributable to retinal changes and appears to be a cortical phenomenon. PMID:14977760

Intensive care in severe malaria: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine.

PubMed

Karnad, Dilip R; Nor, Mohd Basri Mat; Richards, Guy A; Baker, Tim; Amin, Pravin

2018-02-01

Severe malaria is common in tropical countries in Africa, Asia, Oceania and South and Central America. It may also occur in travelers returning from endemic areas. Plasmodium falciparum accounts for most cases, although P vivax is increasingly found to cause severe malaria in Asia. Cerebral malaria is common in children in Africa, manifests as coma and seizures, and has a high morbidity and mortality. In other regions, adults may also develop cerebral malaria but neurological sequelae in survivors are rare. Acute kidney injury, liver dysfunction, thrombocytopenia, disseminated intravascular coagulopathy (DIC) and acute respiratory distress syndrome (ARDS) are also common in severe malaria. Metabolic abnormalities include hypoglycemia, hyponatremia and lactic acidosis. Bacterial infection may coexist in patients presenting with shock or ARDS and this along with a high parasite load has a high mortality. Intravenous artesunate has replaced quinine as the antimalarial agent of choice. Critical care management as per severe sepsis is also applicable to severe malaria. Aggressive fluid boluses may not be appropriate in children. Blood transfusions may be required and treatment of seizures and raised intracranial pressure is important in cerebral malaria in children. Mortality in severe disease ranges from 8 to 30% despite treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

PubMed Central

Plewes, Katherine; Maude, Richard J.; Hanson, Josh; Herdman, M. Trent; Leopold, Stije J.; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M. Mahtab Uddin; Fanello, Caterina I.; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

2017-01-01

Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid

Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort.

PubMed

Idro, Richard; Kakooza-Mwesige, Angelina; Asea, Benjamin; Ssebyala, Keron; Bangirana, Paul; Opoka, Robert O; Lubowa, Samson K; Semrud-Clikeman, Margaret; John, Chandy C; Nalugya, Joyce

2016-03-31

Cerebral malaria (CM) and severe malarial anaemia (SMA) are associated with neuro-developmental impairment in African children, but long-term mental health disorders in these children are not well defined. A cohort of children previously exposed to CM (n = 173) or SMA (n = 99) had neurologic assessments performed and screening for behaviour difficulties using the Strengths and Difficulties Questionnaire (SDQ) a median of 21 months after the disease episode. These findings were compared to concurrently recruited community children (CC, n = 108). Participants with SDQ total difficulties score ≥ 17 had a mental health interview with the child and adolescent version of the Mini-International Neuropsychiatric Interview (MINI-KID) and a sample had brain magnetic resonance imaging (MRI). Fifty-five children had SDQ score ≥ 17. On the MINI-KID, these children were classified as having no difficulties (n = 18), behaviour difficulties only (n = 13) or a mental health disorder (n = 24). Behaviour difficulties were seen in similar frequencies in CM (3.5%), SMA (4.0%) and CC (2.8%). In contrast, mental health disorders were most frequent in CM (10.4%), followed by SMA (4.0%) and CC (1.8%). Externalizing disorders (conduct, oppositional defiance and attention deficit hyperactivity) were the most common mental health disorders. The median total coma duration was 72 (IQR 36.0-115.0) h in patients with mental health disorders compared to 48 (IQR 28.5-78.7) h in those without, p = 0.039. Independent risk factors for mental health disorder included neurologic deficit at discharge (OR 4.09 (95% CI 1.60, 10.5) and seizure recurrences during hospitalization, (OR 2.80, 95% CI 1.13, 6.97). Brain MRI findings consistent with small vessel ischaemic neural injury was seen in over half of these children. Cerebral malaria may predispose children to mental health disorders, possibly as a consequence of ischaemic neural injury. There is urgent need for programmes of follow-up, diagnosis and

Early home-based recognition of anaemia via general danger signs, in young children, in a malaria endemic community in north-east Tanzania

PubMed Central

Ringsted, Frank M; Bygbjerg, Ib C; Samuelsen, Helle

2006-01-01

Background Ethnographic studies from East Africa suggest that cerebral malaria and anaemia are not classified in local knowledge as malaria complications, but as illnesses in their own right. Cerebral malaria 'degedege' has been most researched, in spite of anaemia being a much more frequent complication in infants, and not much is known on how this is interpreted by caretakers. Anaemia is difficult to recognize clinically, even by health workers. Methods Ethnographic longitudinal cohort field study for 14 months, with monthly home-visits in families of 63 newborn babies, identified by community census, followed throughout April – November 2003 and during follow-up in April-May 2004. Interviews with care-takers (mostly mothers) and observational studies of infants and social environment were combined with three haemoglobin (Hb) screenings, supplemented with reports from mothers after health facility use. Results General danger signs, reported by mothers, e.g. infant unable to breast-feed or sit, too weak to be carried on back – besides of more alarming signs such as sleeping all time, loosing consciousness or convulsing – were well associated with actual or evolving moderate to severe anaemia (Hb ≤ 5–8 g/dl). By integrating the local descriptions of danger symptoms and signs, and comparing with actual or evolving low Hb, an algorithm to detect anaemia was developed, with significant sensitivity and specificity. For most danger signs, mothers twice as often took young children to traditional healers for herbal treatment, rather than having their children admitted to hospital. As expected, pallor was more rarely recognized by mothers, or primary reason for treatment seeking. Conclusion Mothers do recognize and respond to symptoms and danger signs related to development of anaemia, the most frequent complication of malaria in young children in malaria endemic areas. Mothers' observations and actions should be reconsidered and integrated in management of

Severe malaria - a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report

PubMed Central

2010-01-01

Background Zoonotic malaria caused by Plasmodium knowlesi is an important, but newly recognized, human pathogen. For the first time, post-mortem findings from a fatal case of knowlesi malaria are reported here. Case presentation A formerly healthy 40 year-old male became symptomatic 10 days after spending time in the jungle of North Borneo. Four days later, he presented to hospital in a state of collapse and died within two hours. He was hyponatraemic and had elevated blood urea, potassium, lactate dehydrogenase and amino transferase values; he was also thrombocytopenic and eosinophilic. Dengue haemorrhagic shock was suspected and a post-mortem examination performed. Investigations for dengue virus were negative. Blood for malaria parasites indicated hyperparasitaemia and single species P. knowlesi infection was confirmed by nested-PCR. Macroscopic pathology of the brain and endocardium showed multiple petechial haemorrhages, the liver and spleen were enlarged and lungs had features consistent with ARDS. Microscopic pathology showed sequestration of pigmented parasitized red blood cells in the vessels of the cerebrum, cerebellum, heart and kidney without evidence of chronic inflammatory reaction in the brain or any other organ examined. Brain sections were negative for intracellular adhesion molecule-1. The spleen and liver had abundant pigment containing macrophages and parasitized red blood cells. The kidney had evidence of acute tubular necrosis and endothelial cells in heart sections were prominent. Conclusions The overall picture in this case was one of systemic malaria infection that fit the WHO classification for severe malaria. Post-mortem findings in this case were unexpectedly similar to those that define fatal falciparum malaria, including cerebral pathology. There were important differences including the absence of coma despite petechial haemorrhages and parasite sequestration in the brain. These results suggest that further study of knowlesi malaria

Irf8-Regulated Genomic Responses Drive Pathological Inflammation during Cerebral Malaria

PubMed Central

Radovanovic, Irena; Tam, Mifong; MacMicking, John D.; Stevenson, Mary M.; Gros, Philippe

2013-01-01

Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8R294C) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We report that BXH2 are completely resistant to the development of cerebral malaria (ECM) following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes increased by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes (including the Irf8 transcription partner Irf1) confers protection against ECM. ECM-resistance in Irf8 and Irf1 mutants is associated with impaired myeloid and lymphoid cells function, including production of IL12p40 and IFNγ. We note strong overlap between genes bound and regulated by IRF8 during ECM and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. We report a common core of IRF8-bound genes forming a critical inflammatory host-response network. PMID:23853600

Epidemiology of malaria in pregnancy in central India.

PubMed Central

Singh, N.; Shukla, M. M.; Sharma, V. P.

1999-01-01

Analysis of three years of data from a malaria clinic operated by the Indian Council of Medical Research (ICMR) in the Government Medical College Hospital in Jabalpur, central India, showed a high malaria prevalence among pregnant women, which was statistically highly significant (P < 0.0001) compared with the situation among nonpregnant women. Cerebral malaria was a common complication of severe Plasmodium falciparum infection, with a high mortality during pregnancy, requiring immediate attention. The study also showed that malaria infection was more frequent in primigravidae, falling progressively with increasing parity. Mean parasite densities were significantly higher in pregnant women compared with nonpregnant women for both P. falciparum (P < 0.001; df = 137) and P. vivax (P < 0.05; df = 72) infection. Pregnant women with falciparum or vivax malaria were significantly more anaemic than noninfected pregnant women or infected nonpregnant women. The average weight of 155 neonates from infected mothers was 350 g less than that of 175 neonates from noninfected mothers. This difference in birth weight was statistically significant for both P. falciparum (P < 0.0001; df = 278) and P. vivax (P < 0.0001; df = 223) infection. Congenital malaria was not recorded. We conclude that pregnant women from this geographical area require systematic intervention owing to their high susceptibility to malaria during pregnancy and the puerperium. PMID:10444880

Performance of “VIKIA Malaria Ag Pf/Pan” (IMACCESS®), a new malaria rapid diagnostic test for detection of symptomatic malaria infections

PubMed Central

2012-01-01

Background Recently, IMACCESS® developed a new malaria test (VIKIA Malaria Ag Pf/Pan™), based on the detection of falciparum malaria (HRP-2) and non-falciparum malaria (aldolase). Methods The performance of this new malaria rapid diagnostic test (RDT) was assessed using 1,000 febrile patients seeking malaria treatment in four health centres in Cambodia from August to December 2011. The results of the VIKIA Malaria Ag Pf/Pan were compared with those obtained by microscopy, the CareStart Malaria™ RDT (AccessBio®) which is currently used in Cambodia, and real-time PCR (as “gold standard”). Results The best performances of the VIKIA Malaria Ag Pf/Pan™ test for detection of both Plasmodium falciparum and non-P. falciparum were with 20–30 min reading times (sensitivity of 93.4% for P. falciparum and 82.8% for non-P. falciparum and specificity of 98.6% for P. falciparum and 98.9% for non-P. falciparum) and were similar to those for the CareStart Malaria™ test. Conclusions This new RDT performs similarly well as other commercially available tests (especially the CareStart Malaria™ test, used as comparator), and conforms to the World Health Organization’s recommendations for RDT performance. It is a good alternative tool for the diagnosis of malaria in endemic areas. PMID:22920654

Comparison of Clinical Profile between P. vivax and P. falciparum Malaria in Children: A Tertiary Care Centre Perspective from India.

PubMed

Goyal, Jagdish Prasad; Makwana, Aarti M

2014-01-01

Background. Malaria is a one of the leading causes of morbidity and mortality in tropical countries. Plasmodium vivax (P. vivax) is usually thought to be causing benign malaria with low incidence of complications as compared to Plasmodium falciparum (P. falciparum). Methods. This retrospective observational study included malaria patients who were admitted to K.T. Children Hospital and P.D.U. Government Medical College, Rajkot, a tertiary care teaching hospital, Gujarat, western India, during the period January 2012 to December 2012. Inclusion criteria were patients in whom either P. falciparum or P. vivax was positive on rapid malaria antigen test and peripheral blood smear. Patients showing mixed infections were excluded from study. Results. A total of 79 subjects (mean age 5.4 ± 3.6 years) were included in the study. It consisted of 47 P. vivax and 32 P. falciparum cases. The P. vivax cases consisted of 33 (70.2%) males and 11 (19.8%) females while P. falciparum cases consisted of 14 (43.8%) males and 18 (56.2%) females. One patient of each P. vivax and P. falciparum expired. There was no statistical significant difference found between complications such as anemia, thrombocytopenia, liver and renal dysfunction, ARDS, and cerebral malaria between P. vivax and P. falciparum. Conclusion. We conclude that P. vivax monoinfection tends to have as similar course and complications as compared to malaria due to P. falciparum monoinfection.

X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria

PubMed Central

Doumbo, Ogobara K; Wellems, Thomas E; Diallo, Dapa A

2007-01-01

Background Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A− form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. Methods and Findings We conducted large case-control studies of the A− form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. Conclusions The A− form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is

Progress towards malaria control targets in relation to national malaria programme funding

PubMed Central

2013-01-01

Background Malaria control has been dramatically scaled up the past decade, mainly thanks to increasing international donor financing since 2003. This study assessed progress up to 2010 towards global malaria impact targets, in relation to Global Fund, other donor and domestic malaria programme financing over 2003 to 2009. Methods Assessments used domestic malaria financing reported by national programmes, and Global Fund/OECD data on donor financing for 90 endemic low- and middle-income countries, WHO estimates of households owning one or more insecticide-treated mosquito net (ITN) for countries in sub-Saharan Africa, and WHO-estimated malaria case incidence and deaths in countries outside sub-Saharan Africa. Results Global Fund and other donor funding is concentrated in a subset of the highest endemic African countries. Outside Africa, donor funding is concentrated in those countries with highest malaria mortality and case incidence rates over the years 2000 to 2003. ITN coverage in 2010 in Africa, and declines in case and death rates per person at risk over 2004 to 2010 outside Africa, were greatest in countries with highest donor funding per person at risk, and smallest in countries with lowest donor malaria funding per person at risk. Outside Africa, all-source malaria programme funding over 2003 to 2009 per case averted ($56-5,749) or per death averted ($58,000-3,900,000) over 2004 to 2010 tended to be lower (more favourable) in countries with higher donor malaria funding per person at risk. Conclusions Increases in malaria programme funding are associated with accelerated progress towards malaria control targets. Associations between programme funding per person at risk and ITN coverage increases and declines in case and death rates suggest opportunities to maximize the impact of donor funding, by strategic re-allocation to countries with highest continued need. PMID:23317000

NITRIC OXIDE FOR THE ADJUNCTIVE TREATMENT OF SEVERE MALARIA: HYPOTHESIS AND RATIONALE

PubMed Central

Hawkes, Michael; Opoka, Robert Opika; Namasopo, Sophie; Miller, Christopher; Conroy, Andrea L.; Serghides, Lena; Kim, Hani; Thampi, Nisha; Liles, W. Conrad; John, Chandy C.; Kain, Kevin C.

2011-01-01

We hypothesize that supplemental inhaled nitric oxide (iNO) will improve outcomes in children with severe malaria receiving standard antimalarial therapy. The rationale for the hypothesized efficacy of iNO rests on: (1) biological plausibility, based on known actions of NO in modulating endothelial activation; (2) pre-clinical efficacy data from animal models of experimental cerebral malaria; and (3) a human trial of the NO precursor L-arginine, which improved endothelial function in adults with severe malaria. iNO is an attractive new candidate for the adjunctive treatment of severe malaria, given its proven therapeutic efficacy in animal studies, track record of safety in clinical practice and numerous clinical trials, inexpensive manufacturing costs, and ease of administration in settings with limited healthcare infrastructure. We plan to test this hypothesis in a randomized controlled trial (ClinicalTrials.gov Identifier: NCT01255215). PMID:21745716

Congenital Malaria in China

PubMed Central

Liu, Xue; Culleton, Richard; Tao, Li; Xia, Hui; Gao, Qi

2014-01-01

Abstract Background Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria-endemic regions. It is recognized as a serious problem in Plasmodium falciparum–endemic sub-Saharan Africa, where recent data suggests that it is more common than previously believed. In such regions where malaria transmission is high, neonates may be protected from disease caused by congenital malaria through the transfer of maternal antibodies against the parasite. However, in low P. vivax–endemic regions, immunity to vivax malaria is low; thus, there is the likelihood that congenital vivax malaria poses a more significant threat to newborn health. Malaria had previously been a major parasitic disease in China, and congenital malaria case reports in Chinese offer valuable information for understanding the risks posed by congenital malaria to neonatal health. As most of the literature documenting congenital malaria cases in China are written in Chinese and therefore are not easily accessible to the global malaria research community, we have undertaken an extensive review of the Chinese literature on this subject. Methods/Principal Findings Here, we reviewed congenital malaria cases from three major searchable Chinese journal databases, concentrating on data from 1915 through 2011. Following extensive screening, a total of 104 cases of congenital malaria were identified. These cases were distributed mainly in the eastern, central, and southern regions of China, as well as in the low-lying region of southwest China. The dominant species was P. vivax (92.50%), reflecting the malaria parasite species distribution in China. The leading clinical presentation was fever, and other clinical presentations were anaemia, jaundice, paleness, diarrhoea, vomiting, and general weakness. With the exception of two cases, all patients were cured

Plasmodium falciparum-induced severe malaria with acute kidney injury and jaundice: a case report

NASA Astrophysics Data System (ADS)

Baswin, A.; Siregar, M. L.; Jamil, K. F.

2018-03-01

P. falciparum-induced severe malaria with life-threatening complications like acute kidney injury (AKI), jaundice, cerebral malaria, severe anemia, acidosis, and acute respiratory distress syndrome (ARDS). A 31-year-old soldier man who works in Aceh Singkil, Indonesia which is an endemic malaria area presented with a paroxysm of fever, shaking chills and sweats over four days, headache, arthralgia, abdominal pain, pale, jaundice, and oliguria. Urinalysis showed hemoglobinuria. Blood examination showed hemolytic anemia, thrombocytopenia, and hyperbilirubinemia. Falciparum malaria was then confirmed by peripheral blood smear, antimalarial medications were initiated, and hemodialysis was performed for eight times. The patient’s condition and laboratory results were quickly normalized. We report a case of P. falciparum-induced severe malaria with AKI and jaundice. The present case suggests that P. falciparum may induce severe malaria with life-threatening complications, early diagnosis and treatment is important to improve the quality of life of patients. Physicians must be alert for correct diagnosis and proper management of imported tropical malaria when patients have travel history in endemic areas.

VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

PubMed Central

Carapau, Daniel; Pena, Ana C.; Ataíde, Ricardo; Monteiro, Carla A. A.; Félix, Nuno; Costa-Silva, Artur; Marinho, Claudio R. F.; Dias, Sérgio; Mota, Maria M.

2010-01-01

The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. The most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. In addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. The similarities between the physiopathological lesions described here and the ones occurring in humans, as well as the demonstration that VEGF is a critical host factor in the onset of malaria-associated ALI in mice, not only offers important mechanistic insights into the processes underlying the pathology related with malaria but may also pave the way for interventional studies. PMID:20502682

Evaluation of the Clearview® malaria pLDH malaria rapid diagnostic test in a non-endemic setting

PubMed Central

2011-01-01

Background Malaria Rapid Diagnostic Tests (RDTs) are widely used to diagnose malaria. The present study evaluated a new RDT, the Clearview® Malaria pLDH test targeting the pan-Plasmodium antigen lactate dehydrogenase (pLDH). Methods The Clearview® Malaria pLDH test was evaluated on fresh samples obtained in returned international travellers using microscopy corrected by PCR as the reference method. Included samples were Plasmodium falciparum (139), Plasmodium vivax (22), Plasmodium ovale (20), Plasmodium malariae (7), and 102 negative. Results Overall sensitivity for the detection of Plasmodium spp was 93.2%. For P. falciparum, the sensitivity was 98.6%; for P. vivax, P. ovale and P. malariae, overall sensitivities were 90.9%, 60.0% and 85.7% respectively. For P. falciparum and for P. vivax, the sensitivities increased to 100% at parasite densities above 100/μl. The specificity was 100%. The test was easily to perform and the result was stable for at least 1 hour. Conclusion The Clearview® Malaria pLDH was efficient for the diagnosis of malaria. The test was very sensitive for P. falciparum and P. vivax detection. The sensitivities for P. ovale and P. malariae were better than other RDTs PMID:21951996

Admission EEG findings in diverse paediatric cerebral malaria populations predict outcomes.

PubMed

Postels, Douglas G; Wu, Xiaoting; Li, Chenxi; Kaplan, Peter W; Seydel, Karl B; Taylor, Terrie E; Kousa, Youssef A; Idro, Richard; Opoka, Robert; John, Chandy C; Birbeck, Gretchen L

2018-05-22

Electroencephalography at hospital presentation may offer important insights regarding prognosis that can inform understanding of cerebral malaria (CM) pathophysiology and potentially guide patient selection and risk stratification for future clinical trials. Electroencephalogram (EEG) findings in children with CM in Uganda and Malawi were compared and associations between admission EEG findings and outcome across this diverse population were assessed. Demographic, clinical and admission EEG data from Ugandan and Malawian children admitted from 2009 to 2012 with CM were gathered, and survivors assessed for neurological abnormalities at discharge. 281 children were enrolled (Uganda n = 122, Malawi n = 159). The Malawian population was comprised only of retinopathy positive children (versus 72.5% retinopathy positive in Uganda) and were older (4.2 versus 3.7 years; p = 0.046), had a higher HIV prevalence (9.0 versus 2.8%; p = 0.042), and worse hyperlactataemia (7.4 versus 5.2 mmol/L; p < 0.001) on admission compared to the Ugandan children. EEG findings differed between the two groups in terms of average voltage and frequencies, reactivity, asymmetry, and the presence/absence of sleep architecture. In univariate analyses pooling EEG and outcomes data for both sites, higher average and maximum voltages, faster dominant frequencies, and retained reactivity were associated with survival (all p < 0.05). Focal slowing was associated with death (OR 2.93; 95% CI 1.77-7.30) and a lower average voltage was associated with neurological morbidity in survivors (p = 0.0032). Despite substantial demographic and clinical heterogeneity between subjects in Malawi and Uganda as well as different EEG readers at each site, EEG findings on admission predicted mortality and morbidity. For CM clinical trials aimed at decreasing mortality or morbidity, EEG may be valuable for risk stratification and/or subject selection.

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria

PubMed Central

2010-01-01

Background The sun-dried rind of the immature fruit of pomegranate (Punica granatum) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by Plasmodium falciparum, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The in vitro anti-plasmodial activity of Punica granatum (Pg) was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response. Methods From the methanolic extract of the fruit rind, a fraction enriched in tannins (Pg-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the Pg-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated. Results Pg-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. Pg-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription. Conclusions The beneficial effect of the fruit rind of Punica granatum for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria. PMID:20642847

Identification of a Platelet Membrane Glycoprotein as a Falciparum Malaria Sequestration Receptor

NASA Astrophysics Data System (ADS)

Ockenhouse, Christian F.; Tandon, Narendra N.; Magowan, Cathleen; Jamieson, G. A.; Chulay, Jeffrey D.

1989-03-01

Infections with the human malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected with mature forms of the parasite. Sequestration of infected erythrocytes appears to be critical for survival of the parasite and to mediate immunopathological abnormalities in severe malaria. A leukocyte differentiation antigen (CD36) was previously suggested to have a role in sequestration of malaria-infected erythrocytes. CD36 was purified from platelets, where it is known as GPIV, and was shown to be a receptor for binding of infected erythrocytes. Infected erythrocytes adhered to CD36 immobilized on plastic; purified CD36 exhibited saturable, specific binding to infected erythrocytes; and purified CD36 or antibodies to CD36 inhibited and reversed binding of infected erythrocytes to cultured endothelial cells and melanoma cells in vitro. The portion of the CD36 molecule that reverses cytoadherence may be useful therapeutically for rapid reversal of sequestration in cerebral malaria.

Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach

PubMed Central

Wassmer, Samuel C.; Taylor, Terrie E.; Rathod, Pradipsinh K.; Mishra, Saroj K.; Mohanty, Sanjib; Arevalo-Herrera, Myriam; Duraisingh, Manoj T.; Smith, Joseph D.

2015-01-01

More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. The majority of malaria cases are caused by Plasmodium falciparum and Plasmodium vivax, which differ in virulence, red blood cell tropism, cytoadhesion of infected erythrocytes, and dormant liver hypnozoite stages. Cerebral malaria coma is one of the most severe manifestations of P. falciparum infection. Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. Nevertheless, important questions remain regarding why some patients develop life-threatening conditions while the majority of P. falciparum-infected individuals do not, and why clinical presentations differ between children and adults. For P. vivax, there is renewed recognition of severe malaria, but an understanding of the factors influencing disease severity is limited and remains an important research topic. Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program. PMID:26259939

Malaria in selected non-Amazonian countries of Latin America.

PubMed

Arevalo-Herrera, Myriam; Quiñones, Martha Lucia; Guerra, Carlos; Céspedes, Nora; Giron, Sandra; Ahumada, Martha; Piñeros, Juan Gabriel; Padilla, Norma; Terrientes, Zilka; Rosas, Angel; Padilla, Julio Cesar; Escalante, Ananias A; Beier, John C; Herrera, Socrates

2012-03-01

Approximately 170 million inhabitants of the American continent live at risk of malaria transmission. Although the continent's contribution to the global malaria burden is small, at least 1-1.2 million malaria cases are reported annually. Sixty percent of the malaria cases occur in Brazil and the other 40% are distributed in 20 other countries of Central and South America. Plasmodium vivax is the predominant species (74.2%) followed by P. falciparum (25.7%) and P. malariae (0.1%), and no less than 10 Anopheles species have been identified as primary or secondary malaria vectors. Rapid deforestation and agricultural practices are directly related to increases in Anopheles species diversity and abundance, as well as in the number of malaria cases. Additionally, climate changes profoundly affect malaria transmission and are responsible for malaria epidemics in some regions of South America. Parasite drug resistance is increasing, but due to bio-geographic barriers there is extraordinary genetic differentiation of parasites with limited dispersion. Although the clinical spectrum ranges from uncomplicated to severe malaria cases, due to the generally low to middle transmission intensity, features such as severe anemia, cerebral malaria and other complications appear to be less frequent than in other endemic regions and asymptomatic infections are a common feature. Although the National Malaria Control Programs (NMCP) of different countries differ in their control activities these are all directed to reduce morbidity and mortality by using strategies like health promotion, vector control and impregnate bed nets among others. Recently, international initiatives such as the Malaria Control Program in Andean-country Border Regions (PAMAFRO) (implemented by the Andean Organism for Health (ORAS) and sponsored by The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)) and The Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA) (sponsored by

Malaria in selected non-Amazonian countries of Latin America

PubMed Central

Arevalo-Herrera, Myriam; Quiñones, Martha Lucia; Guerra, Carlos; Céspedes, Nora; Giron, Sandra; Ahumada, Martha; Piñeros, Juan Gabriel; Padilla, Norma; Terrientes, Zilka; Rosas, Ángel; Padilla, Julio Cesar; Escalante, Ananias A.; Beier, John C.; Herrera, Socrates

2011-01-01

Approximately 170 million inhabitants of the American continent live at risk of malaria transmission. Although the continent’s contribution to the global malaria burden is small, at least 1 to 1.2 million malaria cases are reported annually. Sixty per cent of the malaria cases occur in Brazil and the other 40% are distributed in 20 other countries of Central and South America. Plasmodium vivax is the predominant species (74.2 %) followed by P. falciparum (25.7 %) and P. malariae (0.1%), and no less than 10 Anopheles species have been identified as primary or secondary malaria vectors. Rapid deforestation and agricultural practices are directly related to increases in Anopheles species diversity and abundance, as well as in the number of malaria cases. Additionally, climate changes profoundly affect malaria transmission and are responsible for malaria epidemics in some regions of South America. Parasite drug resistance is increasing, but due to bio-geographic barriers there is extraordinary genetic differentiation of parasites with limited dispersion. Although the clinical spectrum ranges from uncomplicated to severe malaria cases, due to the generally low to middle transmission intensity, features such as severe anemia, cerebral malaria and other complications appear to be less frequent than in other endemic regions and asymptomatic infections are a common feature. Although the National Malaria Control Programs (NMCP) of different countries differ in their control activities these are all directed to reduce morbidity and mortality by using strategies like health promotion, vector control and impregnate bed nets among others. Recently, international initiatives such as the Malaria Control Program in Andean-country Border Regions (PAMAFRO) (implemented by the Andean Organism for Health (ORAS) and sponsored by The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)) and The Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA

Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study

PubMed Central

Mallewa, Macpherson; Vallely, Pam; Faragher, Brian; Banda, Dan; Klapper, Paul; Mukaka, Mavuto; Khofi, Harriet; Pensulo, Paul; Taylor, Terrie; Molyneux, Malcolm; Solomon, Tom

2013-01-01

Summary Background Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. Methods We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. Findings Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and

Impact of Pregnancy-Associated Malaria on Infant Malaria Infection in Southern Benin

PubMed Central

Borgella, Sophie; Fievet, Nadine; Huynh, Bich-Tram; Ibitokou, Samad; Hounguevou, Gbetognon; Affedjou, Jacqueline; Sagbo, Jean-Claude; Houngbegnon, Parfait; Guezo-Mévo, Blaise; Massougbodji, Achille; Luty, Adrian J. F.

2013-01-01

Background Infants of mothers with placental Plasmodium falciparum infections at delivery are themselves more susceptible to malaria attacks or to infection in early life. Methodology/ Principal Findings To assess the impact of either the timing or the number of pregnancy-associated malaria (PAM) infections on the incidence of parasitemia or malaria attacks in infancy, we followed 218 mothers through pregnancy (monthly visits) up to delivery and their infants from birth to 12 months of age (fortnightly visits), collecting detailed clinical and parasitological data. After adjustment on location, mother’s age, birth season, bed net use, and placental malaria, infants born to a mother with PAM during the third trimester of pregnancy had a significantly increased risk of infection (OR [95% CI]: 4.2 [1.6; 10.5], p = 0.003) or of malaria attack (4.6 [1.7; 12.5], p = 0.003). PAM during the first and second trimesters had no such impact. Similarly significant results were found for the effect of the overall number of PAM episodes on the time to first parasitemia and first malaria attack (HR [95% CI]: 2.95 [1.58; 5.50], p = 0.001 and 3.19 [1.59; 6.38], p = 0.001) respectively. Conclusions/ Significance This study highlights the importance of protecting newborns by preventing repeated episodes of PAM in their mothers. PMID:24236190

Vaccines against malaria-still a long way to go.

PubMed

Matuschewski, Kai

2017-08-01

Several species of Plasmodium cause a broad spectrum of human disease that range from nausea and fever to severe anemia, cerebral malaria, and multiorgan failure. In malaria-endemic countries, continuous exposure to Plasmodium sporozoite inoculations and subsequent blood infections elicit only partial and short-lived immunity, which gradually develops over many years of parasite exposure and multiple clinical episodes. The ambitious goal of malaria vaccinology over the past 70 years has been to develop an immunization strategy that mounts protection superior to naturally acquired immunity. Herein, three principal concepts in evidence-based malaria vaccine development are compared. Feasible leads are typically stand-alone subunit vaccine approaches that block Plasmodium parasite life cycle progression or parasite/host interactions, and they constitute the majority of candidates in preclinical research and early clinical testing. Integrated approaches incorporate malaria antigen(s) into licensed or emerging pediatric vaccine formulations. This strategy can complement the malaria control portfolio even if the antimalarial component is only partially effective and has led to the development of the only candidate vaccine to date, namely RTS,S-AS01. Experimental whole parasite vaccine approaches have been repeatedly shown to elicit sterile and lasting protection against identical parasite strains, but mass production, proof of broad protection against different parasite strains, and routes of vaccine delivery remain significant translational road blocks. Global access to an effective and affordable malaria vaccine will critically depend on innovative translational research that builds on a better molecular understanding of Plasmodium biology and host immunity. © 2017 Federation of European Biochemical Societies.

High Levels of Plasmodium falciparum Rosetting in All Clinical Forms of Severe Malaria in African Children

PubMed Central

Doumbo, Ogobara K.; Thera, Mahamadou A.; Koné, Abdoulaye K.; Raza, Ahmed; Tempest, Louisa J.; Lyke, Kirsten E.; Plowe, Christopher V.; Rowe, J. Alexandra

2010-01-01

Plasmodium falciparum rosetting (the spontaneous binding of infected erythrocytes to uninfected erythrocytes) is a well-recognized parasite virulence factor. However, it is currently unclear whether rosetting is associated with all clinical forms of severe malaria, or only with specific syndromes such as cerebral malaria. We investigated the relationship between rosetting and clinical malaria in 209 Malian children enrolled in a case-control study of severe malaria. Rosetting was significantly higher in parasite isolates from severe malaria cases compared with non-severe hyperparasitemia and uncomplicated malaria controls (F2,117 = 8.15, P < 0.001). Analysis of sub-categories of severe malaria (unrousable coma, severe anemia, non-comatose neurological impairment, repeated seizures or a small heterogeneous group with signs of renal failure or jaundice) showed high levels of rosetting in all sub-categories, and no statistically significant differences in rosetting between sub-categories (F4,67 = 1.28, P = 0.28). Thus rosetting may contribute to the pathogenesis of all severe malaria syndromes in African children, and interventions to disrupt rosetting could be potential adjunctive therapies for all forms of severe malaria in Africa. PMID:19996426

Emerging roles for hemostatic dysfunction in malaria pathogenesis.

PubMed

O'Sullivan, Jamie M; Preston, Roger J S; O'Regan, Niamh; O'Donnell, James S

2016-05-12

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. © 2016 by The American Society of Hematology.

Glutathione peroxidase contributes with heme oxygenase-1 to redox balance in mouse brain during the course of cerebral malaria.

PubMed

Linares, María; Marín-García, Patricia; Martínez-Chacón, Gabriela; Pérez-Benavente, Susana; Puyet, Antonio; Diez, Amalia; Bautista, José M

2013-12-01

Oxidative stress has been attributed both a key pathogenic and rescuing role in cerebral malaria (CM). In a Plasmodium berghei ANKA murine model of CM, host redox signaling and functioning were examined during the course of neurological damage. Host antioxidant defenses were early altered at the transcriptional level indicated by the gradually diminished expression of superoxide dismutase-1 (sod-1), sod-2, sod-3 and catalase genes. During severe disease, this led to the dysfunctional activity of superoxide dismutase and catalase enzymes in damaged brain regions. Vitagene associated markers (heat shock protein 70 and thioredoxin-1) also showed a decaying expression pattern that paralleled reduced expression of the transcription factors Parkinson disease 7, Forkhead box O 3 and X-box binding protein 1 with a role in preserving brain redox status. However, the oxidative stress markers reactive oxygen/nitrogen species were not accumulated in the brains of CM mice and redox proteomics and immunohistochemistry failed to detect quantitative or qualitative differences in protein carbonylation. Thus, the loss of antioxidant capacity was compensated for in all cerebral regions by progressive upregulation of heme oxygenase-1, and in specific regions by early glutathione peroxidase-1 induction. This study shows for the first time a scenario of cooperative glutathione peroxidase and heme oxygenase-1 upregulation to suppress superoxide dismutase, catalase, heat shock protein-70 and thioredoxin-1 downregulation effects in experimental CM, counteracting oxidative damage and maintaining redox equilibrium. Our findings reconcile the apparent inconsistency between the lack of oxidative metabolite build up and reported protective effect of antioxidant therapy against CM. © 2013.

Accuracy of Rapid Tests for Malaria and Treatment Outcomes for Malaria and Non-Malaria Cases among Under-Five Children in Rural Ghana

PubMed Central

Baiden, Frank; Webster, Jayne; Tivura, Mathilda; Delimini, Rupert; Berko, Yvonne; Amenga-Etego, Seeba; Agyeman-Budu, Akua; Karikari, Akosua B.; Bruce, Jane; Owusu-Agyei, Seth; Chandramohan, Daniel

2012-01-01

Background WHO now recommends test-based management of malaria across all transmission settings. The accuracy of rapid diagnostic test (RDT) and the outcome of treatment based on the result of tests will influence acceptability of and adherence to the new guidelines. Method We conducted a study at the Kintampo hospital in rural Ghana to evaluate the performance of CareStart, a HRP-2 based RDT, using microscopy as reference. We applied IMCI treatment guidelines, restricted ACT to RDT-positive children and followed-up both RDT-positive (malaria) and RDT-negative (non-malaria) cases over 28 days. Results 436 children were enrolled in the RDT evaluation and 391 (children with haemoglobin >8.0 gm/dl) were followed-up to assess treatment outcomes. Mean age was 25.4 months (s.d. 14.6). Sensitivity and specificity of the RDT were 100.0% and 73.0% respectively. Over the follow-up period, 32 (18.5%) RDT-negative children converted to positive, with 7 (4.0%) of them presenting with fever. More children in the non-malaria group made unscheduled visits than children in the malaria group (13.3% versus 7.7%) On all scheduled follow-up visits, proportion of children having a temperature higher than that recorded on day 0 was higher in the non-malaria group compared to the malaria group. Reports of unfavourable treatment outcomes by caregivers were higher among the non-malaria group than the malaria group. Conclusions The RDT had good sensitivity and specificity. However a minority of children who will not receive ACT based on RDT results may develop clinical malaria within a short period in high transmission settings. This could undermine caregivers' and health workers' confidence in the new guidelines. Improving the quality of management of non-malarial febrile illnesses should be a priority in the era of test-based management of malaria. Trial Registration ClinicalTrials.gov NCT00832754 PMID:22514617

Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis

PubMed Central

Pai, Saparna; Qin, Jim; Cavanagh, Lois; Mitchell, Andrew; El-Assaad, Fatima; Jain, Rohit; Combes, Valery; Hunt, Nicholas H.; Grau, Georges E. R.; Weninger, Wolfgang

2014-01-01

During experimental cerebral malaria (ECM) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6Chi monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA)-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS). A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG)-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8+ T lymphocytes. A critical number of CD8+ T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8+ T lymphocytes in regulating vascular pathology in this disease. PMID:25033406

Specific Depletion of Ly6Chi Inflammatory Monocytes Prevents Immunopathology in Experimental Cerebral Malaria

PubMed Central

Kuepper, Janina M.; Biswas, Aindrila; Djie-Maletz, Andrea; Limmer, Andreas; van Rooijen, Nico; Mack, Matthias; Hoerauf, Achim; Dunay, Ildiko Rita

2015-01-01

Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6Chi inflammatory monocytes (by anti-CCR2), Ly6G+ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6Chi inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6Chi inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes. PMID:25884830

Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity

PubMed Central

Matar, Caline G.; Anthony, Neil R.; O’Flaherty, Brigid M.; Jacobs, Nathan T.; Priyamvada, Lalita; Engwerda, Christian R.; Speck, Samuel H.; Lamb, Tracey J.

2015-01-01

Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission. PMID:25996913

A chronic scheme of cranial window preparation to study pial vascular reactivity in murine cerebral malaria

PubMed Central

Ong, Peng Kai; Meays, Diana; Frangos, John A.; Carvalho, Leonardo J.M.

2013-01-01

Objective The acute implantation of a cranial window for studying cerebroarteriolar reactivity in living animals involves a highly surgically-invasive craniotomy procedure at the time of experimentation, which limits its application in severely ill animals such as in the experimental murine model of cerebral malaria (ECM). To overcome this problem, a chronic window implantation scheme was designed and implemented. Methods A partial craniotomy is first performed by creating a skull bone flap in the healthy mice, which are then left to recover for 1–2 weeks, followed by infection to induce ECM. Uninfected animals are utilized as control. When cranial superfusion is needed, the bone flap is retracted and window implantation completed by assembling a perfusion chamber for compound delivery to the exposed brain surface. The presurgical step is intended to minimize surgical trauma on the day of experimentation. Results Chronic preparations in uninfected mice exhibited remarkably improved stability over acute ones by significantly reducing periarteriolar tissue damage and enhancing cerebroarteriolar dilator responses. The chronic scheme was successfully implemented in ECM mice which unveiled novel preliminary insights on impaired cerebroarteriolar reactivity and eNOS dysfunction. Conclusion The chronic scheme presents an innovative approach for advancing our mechanistic understanding on cerebrovascular dysfunction in ECM. PMID:23279271

Urbanization and the global malaria recession

PubMed Central

2013-01-01

Background The past century has seen a significant contraction in the global extent of malaria transmission, resulting in over 50 countries being declared malaria free, and many regions of currently endemic countries eliminating the disease. Moreover, substantial reductions in transmission have been seen since 1900 in those areas that remain endemic today. Recent work showed that this malaria recession was unlikely to have been driven by climatic factors, and that control measures likely played a significant role. It has long been considered, however, that economic development, and particularly urbanization, has also been a causal factor. The urbanization process results in profound socio-economic and landscape changes that reduce malaria transmission, but the magnitude and extent of these effects on global endemicity reductions are poorly understood. Methods Global data at subnational spatial resolution on changes in malaria transmission intensity and urbanization trends over the past century were combined to examine the relationships seen over a range of spatial and temporal scales. Results/Conclusions A consistent pattern of increased urbanization coincident with decreasing malaria transmission and elimination over the past century was found. Whilst it remains challenging to untangle whether this increased urbanization resulted in decreased transmission, or that malaria reductions promoted development, the results point to a close relationship between the two, irrespective of national wealth. The continuing rapid urbanization in malaria-endemic regions suggests that such malaria declines are likely to continue, particularly catalyzed by increasing levels of direct malaria control. PMID:23594701

Plasma Uric Acid Levels Correlate with Inflammation and Disease Severity in Malian Children with Plasmodium falciparum Malaria

PubMed Central

Lopera-Mesa, Tatiana M.; Mita-Mendoza, Neida K.; van de Hoef, Diana L.; Doumbia, Saibou; Konaté, Drissa; Doumbouya, Mory; Gu, Wenjuan; Traoré, Karim; Diakité, Seidina A. S.; Remaley, Alan T.; Anderson, Jennifer M.; Rodriguez, Ana; Fay, Michael P.; Long, Carole A.; Diakité, Mahamadou; Fairhurst, Rick M.

2012-01-01

Background Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of ‘parasite-derived’ UA stimulate immune cells to produce inflammatory cytokines in vitro. Methods and Findings We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09–1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97–1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNFα (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34–1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl). Conclusions Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of

Maternal Malaria and Gravidity Interact to Modify Infant Susceptibility to Malaria

PubMed Central

Mutabingwa, Theonest K; Bolla, Melissa C; Li, Jin-Long; Domingo, Gonzalo J; Li, Xiaohong; Fried, Michal; Duffy, Patrick E

2005-01-01

Background In endemic areas, placental malaria due to Plasmodium falciparum is most frequent and severe in first-time mothers, and increases the risk of infant mortality in their offspring. Placental malaria may increase the susceptibility of infants to malaria parasitemia, but evidence for this effect is inconclusive. Methods and Findings During 2002–2004, we monitored parasitemia in 453 infants, including 69 who were born to mothers with placental malaria, in a region of northeastern Tanzania where malaria transmission is intense. We used a Cox proportional hazards model to evaluate the time from birth to first parasitemia, and a generalized estimating equations logistic regression model to evaluate risk of any parasitemia throughout the first year of life. Compared with infants whose mothers did not have placental malaria at delivery (“PM-negative”), offspring of mothers with placental malaria at delivery (“PM-positive”) were 41% more likely to experience their first parasitemia at a younger age (adjusted hazard ratio [AHR] = 1.41, 95% confidence interval [CI] 1.01–1.99). The odds of parasitemia throughout infancy were strongly modified by the interaction between placental malaria and gravidity (p for interaction = 0.008, Type 3 likelihood ratio test). Offspring of PM-negative primigravidae had lower odds of parasitemia during infancy (adjusted odds ratio [AOR] = 0.67, 95% CI 0.50–0.91) than offspring of PM-negative multigravidae, and offspring of PM-positive primigravidae had the lowest odds (AOR = 0.21, 95% CI 0.09–0.47). In contrast, offspring of PM-positive multigravidae had significantly higher odds of parasitemia (AOR = 1.59, 95% CI 1.16–2.17). Conclusion Although parasitemia is more frequent in primigravid than multigravid women, the converse is true in their offspring, especially in offspring of PM-positive women. While placental malaria is known to increase mortality risk for first-born infants, it surprisingly reduced their risk of

CD8+ T Cells and IFN-γ Mediate the Time-Dependent Accumulation of Infected Red Blood Cells in Deep Organs during Experimental Cerebral Malaria

PubMed Central

Claser, Carla; Malleret, Benoît; Gun, Sin Yee; Wong, Alicia Yoke Wei; Chang, Zi Wei; Teo, Pearline; See, Peter Chi Ee; Howland, Shanshan Wu; Ginhoux, Florent; Rénia, Laurent

2011-01-01

Background Infection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA–induced pathologies, which mechanisms are poorly understood. Methods and Findings Using transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC) accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8+ T cells and IFN-γ drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6–12 days post-infection, at a time when mice develop ECM. Other cells types like CD4+ T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-α did not influence the early increase of total parasite biomass and IRBC accumulation in different organs. Conclusions CD8+ T cells and IFN-γ are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues. PMID:21494565

Noninvasive measures of brain edema predict outcome in pediatric cerebral malaria.

PubMed

Kampondeni, Samuel D; Birbeck, Gretchen L; Seydel, Karl B; Beare, Nicholas A; Glover, Simon J; Hammond, Colleen A; Chilingulo, Cowles A; Taylor, Terrie E; Potchen, Michael J

2018-01-01

Increased brain volume (BV) and subsequent herniation are strongly associated with death in pediatric cerebral malaria (PCM), a leading killer of children in developing countries. Accurate noninvasive measures of BV are needed for optimal clinical trial design. Our objectives were to examine the performance of six different magnetic resonance imaging (MRI) BV quantification measures for predicting mortality in PCM and to review the advantages and disadvantages of each method. Receiver operator characteristics were generated from BV measures of MRIs of children admitted to an ongoing research project with PCM between 2009 and 2014. Fatal cases were matched to the next available survivor. A total of 78 MRIs of children aged 5 months to 13 years (mean 4.0 years), of which 45% were males, were included. Areas under the curve (AUC) with 95% confidence interval on measures from the initial MRIs were: Radiologist-derived score = 0.69 (0.58-0.79; P = 0.0037); prepontine cistern anteroposterior (AP) dimension = 0.70 (0.56-0.78; P = 0.0133); SamKam ratio [Rt. parietal lobe height/(prepontine AP dimension + fourth ventricle AP dimension)] = 0.74 (0.63-0.83; P = 0.0002); and global cerebrospinal fluid (CSF) space ascertained by ClearCanvas = 0.67 (0.55-0.77; P = 0.0137). For patients with serial MRIs ( n = 37), the day 2 global CSF space AUC was 0.87 (0.71-0.96; P < 0.001) and the recovery factor (CSF volume day 2/CSF volume day 1) was 0.91 (0.76-0.98; P < 0.0001). Poor prognosis is associated with radiologist score of ≥7; prepontine cistern dimension ≤3 mm; cisternal CSF volume ≤7.5 ml; SamKam ratio ≥6.5; and recovery factor ≤0.75. All noninvasive measures of BV performed well in predicting death and providing a proxy measure for brain volume. Initial MRI assessment may inform future clinical trials for subject selection, risk adjustment, or stratification. Measures of temporal change may be used to stage PCM.

Malaria in Brazilian military personnel deployed to Angola.

PubMed

Sanchez, J L; Bendet, I; Grogl, M; Lima, J B; Pang, L W; Guimaraes, M F; Guedes, C M; Milhous, W K; Green, M D; Todd, G D

2000-01-01

Malaria represents one of the most important infectious disease threats to deployed military forces; most personnel from developed countries are nonimmune personnel and are at high risk of infection and clinical malaria. This is especially true for forces deployed to highly-endemic areas in Africa and Southeast Asia where drug-resistant malaria is common. We conducted an outbreak investigation of malaria cases in Angola where a total of 439 nonimmune Brazilian troops were deployed for a 6-month period in 1995-1996. A post-travel medical evaluation was also performed on 338 (77%) of the 439 soldiers upon return to Brazil. Questionnaire, medical record, thick/thin smear, and serum anti-Plasmodium falciparum antibody titer (by IFA) data were obtained. Peak serum mefloquine (M) and methylmefloquine (MM) metabolite levels were measured in a subsample of 66 soldiers (42 cases, 24 nonmalaria controls) who were taking weekly mefloquine prophylaxis (250 mg). Seventy-eight cases of malaria occurred among the 439 personnel initially interviewed in Angola (attack rate = 18%). Four soldiers were hospitalized, and 3 subsequently died of cerebral malaria. Upon return to Brazil, 63 (19%) of 338 soldiers evaluated were documented to have had clinical symptoms and a diagnosis of malaria while in Angola. In addition, 37 (11%) asymptomatically infected individuals were detected upon return (< 1% parasitemia). Elevated, post-travel anti-P. falciparum IFA titers (> or = 1:64) were seen in 101 (35%) of 292 soldiers tested, and was associated with a prior history of malaria in-country (OR = 3.67, 95% CI 1.98-6.82, p <.001). Noncompliance with weekly mefloquine prophylaxis (250 mg) was associated with a malaria diagnosis in Angola (OR = 3.75, 95% CI 0.97-17.41, p =.03) but not with recent P. falciparum infection (by IFA titer). Mean peak levels (and ratios) of serum M and MM were also found to be lower in those who gave a history of malaria while in Angola. Malaria was a significant cause

Evaluation of the malaria rapid diagnostic test VIKIA malaria Ag Pf/Pan™ in endemic and non-endemic settings

PubMed Central

2013-01-01

Background Malaria rapid diagnostic tests (RDTs) are a useful tool in endemic malaria countries, where light microscopy is not feasible. In non-endemic countries they can be used as complementary tests to provide timely results in case of microscopy inexperience. This study aims to compare the new VIKIA Malaria Ag Pf/Pan™ RDT with PCR-corrected microscopy results and the commonly used CareStart™ RDT to diagnose falciparum and non-falciparum malaria in the endemic setting of Bamako, Mali and the non-endemic setting of Lyon, France. Methods Blood samples were collected during a 12-months and six-months period in 2011 from patients suspected to have malaria in Lyon and Bamako respectively. The samples were examined by light microscopy, the VIKIA Malaria Ag Pf/Pan™ test and in Bamako additionally with the CareStart™ RDT. Discordant results were corrected by real-time PCR. Sensitivity, specificity, positive predictive value and negative predictive value were used to evaluate test performance. Results Samples of 877 patients from both sites were included. The VIKIA Malaria Ag Pf/Pan™ had a sensitivity of 98% and 96% for Plasmodium falciparum in Lyon and Bamako, respectively, performing similar to PCR-corrected microscopy. Conclusions The VIKIA Malaria Ag Pf/Pan™ performs similar to PCR-corrected microscopy for the detection of P. falciparum, making it a valuable tool in malaria endemic and non-endemic regions. PMID:23742633

Performance of Paracheck™-Pf, SD Bioline malaria Ag-Pf and SD Bioline malaria Ag-Pf/pan for diagnosis of falciparum malaria in the Central African Republic

PubMed Central

2014-01-01

Background Rapid diagnostic tests (RDTs) are the current complement to microscopy for ensuring prompt malaria treatment. We determined the performance of three candidate RDTs (Paracheck™-Pf, SD Bioline malaria Ag-Pf and SD Bioline malaria Ag-Pf/pan) for rapid diagnosis of malaria in the Central African Republic. Methods Blood samples from consecutive febrile patients who attended for laboratory analysis of malaria at the three main health centres of Bangui were screened by microscopy and the RDTs. Two reference standards were used to assess the performance of the RDTs: microscopy and, a combination of microscopy plus nested PCR for slides reported as negative, on the assumption that negative results by microscopy were due to sub-patent parasitaemia. Results We analysed 436 samples. Using the combined reference standard of microscopy + PCR, the sensitivity of Paracheck™-Pf was 85.7% (95% CI, 80.8–89.8%), that of SD Bioline Ag-Pf was 85.4% (95% CI, 80.5–90.7%), and that of SD Bioline Ag-Pf/pan was 88.2% (95% CI, 83.2–92.0%). The tests performed less well in cases of low parasitaemia; however, the sensitivity was > 95% at > 500 parasites/μl. Conclusions Overall, SD Bioline malaria Ag-Pf and SD Bioline malaria Ag-Pf/pan performed slightly better than Paracheck™-Pf. Use of RDTs with reinforced microscopy practice and laboratory quality assurance should improve malaria treatment in the Central African Republic. PMID:24568311

Increasing Incidence of Plasmodium knowlesi Malaria following Control of P. falciparum and P. vivax Malaria in Sabah, Malaysia

PubMed Central

William, Timothy; Rahman, Hasan A.; Jelip, Jenarun; Ibrahim, Mohammad Y.; Menon, Jayaram; Grigg, Matthew J.; Yeo, Tsin W.; Anstey, Nicholas M.; Barber, Bridget E.

2013-01-01

Background The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo and threatens the prospect of malaria elimination. However, little is known about the emergence of P. knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each malaria species over time. Methods Reporting of microscopy-diagnosed malaria cases in Sabah is mandatory. We reviewed all available Department of Health malaria notification records from 1992–2011. Notifications of P. malariae and P. knowlesi were considered as a single group due to microscopic near-identity. Results From 1992–2011 total malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. malariae/P. knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ≈100/year in the late 1990s/early 2000s. However, P. malariae/P. knowlesi notifications increased >10-fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. malariae/P. knowlesi monoinfections accounted for 70%, 24% and 1% respectively of malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. malariae/P. knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly. Conclusions A significant recent increase has occurred in P. knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens malaria elimination. Determination of transmission dynamics and risk factors for knowlesi malaria is required to guide measures to control this rising incidence. PMID:23359830

Host immune response in returning travellers infected with malaria

PubMed Central

2012-01-01

Background Clinical observations suggest that Canadian-born (CB) travellers are prone to more severe malaria, characterized by higher parasite density in the blood, and severe symptoms, such as cerebral malaria and renal failure, than foreign-born travellers (FB) from areas of malaria endemicity. It was hypothesized that host cytokine and chemokine responses differ significantly in CB versus FB patients returning with malaria, contributing to the courses of severity. A more detailed understanding of the profiles of cytokines, chemokines, and endothelial activation may be useful in developing biomarkers and novel therapeutic approaches for malaria. Materials and methods The patient population for the study (n = 186) was comprised of travellers returning to Toronto, Canada between 2007 and 2011. The patient blood samples’ cytokine, chemokine and angiopoietin concentrations were determined using cytokine multiplex assays, and ELISA assays. Results Significantly higher plasma cytokine levels of IL-12 (p40) were observed in CB compared to FB travellers, while epidermal growth factor (EGF) was observed to be higher in FB than CB travellers. Older travellers (55 years old or greater) with Plasmodium vivax infections had significantly higher mean cytokine levels for IL-6 and macrophage colony-stimulating factor (M-CSF) than other adults with P. vivax (ages 18–55). Patients with P. vivax infections had significantly higher mean cytokine levels for monocyte chemotactic protein-1 (MCP-1), and M-CSF than patients with Plasmodium falciparum. Angiopoietin 2 (Ang-2) was higher for patients infected with P. falciparum than P. vivax, especially when comparing just the FB groups. IL-12 (p40) was higher in FB patients with P. vivax compared to P. falciparum. Il-12 (p40) was also higher in patients infected with P. vivax than those infected with Plasmodium ovale. For patients travelling to West Africa, IFN-γ and IL-6 was lower than for patients who were in other regions of Africa

Comparative evaluation of two rapid field tests for malaria diagnosis: Partec Rapid Malaria Test® and Binax Now® Malaria Rapid Diagnostic Test

PubMed Central

2011-01-01

Background About 90% of all malaria deaths in sub-Saharan Africa occur in children under five years. Fast and reliable diagnosis of malaria requires confirmation of the presence of malaria parasites in the blood of patients with fever or history suggestive of malaria; hence a prompt and accurate diagnosis of malaria is the key to effective disease management. Confirmation of malaria infection requires the availability of a rapid, sensitive, and specific testing at an affordable cost. We compared two recent methods (the novel Partec Rapid Malaria Test® (PT) and the Binax Now® Malaria Rapid Diagnostic Test (BN RDT) with the conventional Giemsa stain microscopy (GM) for the diagnosis of malaria among children in a clinical laboratory of a hospital in a rural endemic area of Ghana. Methods Blood samples were collected from 263 children admitted with fever or a history of fever to the pediatric clinic of the Agogo Presbyterian Hospital. The three different test methods PT, BN RDT and GM were performed independently by well trained and competent laboratory staff to assess the presence of malaria parasites. Results were analyzed and compared using GM as the reference standard. Results In 107 (40.7%) of 263 study participants, Plasmodium sp. was detected by GM. PT and BN RDT showed positive results in 111 (42.2%) and 114 (43.4%), respectively. Compared to GM reference standard, the sensitivities of the PT and BN RDT were 100% (95% CI: 96.6-100) and 97.2% (95% CI: 92.0-99.4), respectively, specificities were 97.4% (95% CI: 93.6-99.3) and 93.6% (95% CI: 88.5-96.9), respectively. There was a strong agreement (kappa) between the applied test methods (GM vs PT: 0.97; p < 0.001 and GM vs BN RDT: 0.90; p < 0.001). The average turnaround time per tests was 17 minutes. Conclusion In this study two rapid malaria tests, PT and BN RDT, demonstrated a good quality of their performance compared to conventional GM. Both methods require little training, have short turnaround times, are

Artemisinin derivatives for treating severe malaria.

PubMed

McIntosh, H M; Olliaro, P

2000-01-01

Artemisinin derivatives may have advantages over quinoline drugs for treating severe malaria since they are fast acting and effective against quinine resistant malaria parasites. The objective of this review was to assess the effects of artemisinin drugs for severe and complicated falciparum malaria in adults and children. We searched the Cochrane Infectious Diseases Group trials register, Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, Lilacs, African Index Medicus, conference abstracts and reference lists of articles. We contacted organisations, researchers in the field and drug companies. Randomised and pseudo-randomised trials comparing artemisinin drugs (rectal, intramuscular or intravenous) with standard treatment, or comparisons between artemisinin derivatives in adults or children with severe or complicated falciparum malaria. Eligibility, trial quality assessment and data extraction were done independently by two reviewers. Study authors were contacted for additional information. Twenty three trials are included, allocation concealment was adequate in nine. Sixteen trials compared artemisinin drugs with quinine in 2653 patients. Artemisinin drugs were associated with better survival (mortality odds ratio 0.61, 95% confidence interval 0.46 to 0.82, random effects model). In trials where concealment of allocation was adequate (2261 patients), this was barely statistically significant (odds ratio 0.72, 95% CI 0.54 to 0.96, random effects model). In 1939 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (odds ratio 0.63, 95% CI 0.44 to 0.88, random effects model). The difference was not significant however when only trials reporting adequate concealment of allocation were analysed (odds ratio 0.78, 95% CI 0.55 to 1.10, random effects model) based on 1607 patients. No difference in neurological sequelae was shown. Compared with quinine, artemisinin drugs showed faster parasite clearance from

A weather-driven model of malaria transmission

PubMed Central

Hoshen, Moshe B; Morse, Andrew P

2004-01-01

Background Climate is a major driving force behind malaria transmission and climate data are often used to account for the spatial, seasonal and interannual variation in malaria transmission. Methods This paper describes a mathematical-biological model of the parasite dynamics, comprising both the weather-dependent within-vector stages and the weather-independent within-host stages. Results Numerical evaluations of the model in both time and space show that it qualitatively reconstructs the prevalence of infection. Conclusion A process-based modelling structure has been developed that may be suitable for the simulation of malaria forecasts based on seasonal weather forecasts. PMID:15350206

Specific depletion of Ly6C(hi) inflammatory monocytes prevents immunopathology in experimental cerebral malaria.

PubMed

Schumak, Beatrix; Klocke, Katrin; Kuepper, Janina M; Biswas, Aindrila; Djie-Maletz, Andrea; Limmer, Andreas; van Rooijen, Nico; Mack, Matthias; Hoerauf, Achim; Dunay, Ildiko Rita

2015-01-01

Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6C(hi) inflammatory monocytes (by anti-CCR2), Ly6G+ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6C(hi) inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6C(hi) inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes.

Spatial analysis of malaria in Anhui province, China

PubMed Central

Zhang, Wenyi; Wang, Liping; Fang, Liqun; Ma, Jiaqi; Xu, Youfu; Jiang, Jiafu; Hui, Fengming; Wang, Jianjun; Liang, Song; Yang, Hong; Cao, Wuchun

2008-01-01

Background Malaria has re-emerged in Anhui Province, China, and this province was the most seriously affected by malaria during 2005–2006. It is necessary to understand the spatial distribution of malaria cases and to identify highly endemic areas for future public health planning and resource allocation in Anhui Province. Methods The annual average incidence at the county level was calculated using malaria cases reported between 2000 and 2006 in Anhui Province. GIS-based spatial analyses were conducted to detect spatial distribution and clustering of malaria incidence at the county level. Results The spatial distribution of malaria cases in Anhui Province from 2000 to 2006 was mapped at the county level to show crude incidence, excess hazard and spatial smoothed incidence. Spatial cluster analysis suggested 10 and 24 counties were at increased risk for malaria (P < 0.001) with the maximum spatial cluster sizes at < 50% and < 25% of the total population, respectively. Conclusion The application of GIS, together with spatial statistical techniques, provide a means to quantify explicit malaria risks and to further identify environmental factors responsible for the re-emerged malaria risks. Future public health planning and resource allocation in Anhui Province should be focused on the maximum spatial cluster region. PMID:18847489

MBL-2 polymorphisms (codon 54 and Y-221X) and low MBL levels are associated with susceptibility to multi organ dysfunction in P. falciparum malaria in Odisha, India.

PubMed

Das, Bidyut K; Panda, Aditya K

2015-01-01

Mannose binding lectin, a plasma protein protects host from virus, bacteria, and parasites. Deficiency in MBL levels has been associated with susceptibility to various infectious diseases including P. falciparum malaria. Common MBL polymorphisms in promoter and coding regions are associated with decrease in plasma MBL levels or production of deformed MBL, respectively. In the present study, we hypothesized that MBL2 variants and plasma MBL levels could be associated with different clinical phenotypes of severe P. falciparum malaria. A hospital based study was conducted in eastern Odisha, India which is endemic to P. falciparum malaria. Common MBL-2 polymorphisms (codon 54, H-550L, and Y-221X) were typed in 336 cases of severe malaria (SM) [94 cerebral malaria (CM), 120 multi-organ dysfunction (MOD), 122 non-cerebral severe malaria (NCSM)] and 131 un-complicated malaria patients (UM). Plasma MBL levels were quantified by ELISA. Severe malaria patients displayed lower plasma levels of MBL compared to uncomplicated falciparum malaria. Furthermore, on categorization of severe malaria patients into various subtypes, plasma MBL levels were very low in MOD patients compared to other categories. Higher frequency of AB genotype and allele B was observed in MOD compared to UM (AB genotype: P = 0.006; B allele: P = 0.008). In addition, prevalence of YX genotype of MBL Y-221X polymorphism was also statistically more frequent in MOD case than UM (P = 0.009). The observations of the present study reveal that MBL-2 polymorphisms (codon 54 and Y-221X) and lower plasma MBL levels are associated with increased susceptibility to multi organ dysfunctions in P. falciparum malaria.

Defibrotide interferes with several steps of the coagulation-inflammation cycle and exhibits therapeutic potential to treat severe malaria.

PubMed

Francischetti, Ivo M B; Oliveira, Carlo J; Ostera, Graciela R; Yager, Stephanie B; Debierre-Grockiego, Françoise; Carregaro, Vanessa; Jaramillo-Gutierrez, Giovanna; Hume, Jen C C; Jiang, Lubin; Moretz, Samuel E; Lin, Christina K; Ribeiro, José M C; Long, Carole A; Vickers, Brandi K; Schwarz, Ralph T; Seydel, Karl B; Iacobelli, Massimo; Ackerman, Hans C; Srinivasan, Prakash; Gomes, Regis B; Wang, Xunde; Monteiro, Robson Q; Kotsyfakis, Michail; Sá-Nunes, Anderson; Waisberg, Michael

2012-03-01

The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and abolishes oocysts development in Anopheles gambiae. In a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-γ levels, and ameliorated clinical score (day 5) with a trend for increased survival. Therapeutic use of DF in malaria is proposed.

Prevalence of human malaria infection in Pakistani areas bordering with Iran.

PubMed

Yasinzai, Mohammad Iqbal; Kakarsulemankhel, Juma Khan

2013-03-01

To study the prevalence of malarial infections in human population of district Panjgur in south-western Pakistan. The cross-sectional study identified malarial parasites in the blood slides of 6119 suspected malaria patients from July 2006 to June 2008 through passive and active case detection methods. SPSS 11 was used for statistical analysis. Out of 6119 suspected cases of malaria, 2346 (38.3%) were found to be positive for malarial parasite on blood smear slides. Of these, 1868 (79.6%) cases were due to Plasmodium vivax infection, and 478 (20.3%) had P. falciparum. However, seasonal variation was also noted: P. vivax infection was the highest (n = 131/144, 90.9%) in November and the lowest (n=83/176, 47.1%) in October. The prevalence was higher (n=1831, 78%) in males. Age-wise, the prevalence of the disease was 81.2% (n=334) and 80% (n=860) for age groups 1-10 years and 11-20 years. No case of P. malariae and P. ovale was detected in the study period. No association was found between types of infection and age groups. Human malaria infection was quite frequent in the study region, which is one of the hottest areas of Balochistan, Pakistan. In clinically-suspected cases of malaria, there was a high slide positivity rate. The high prevalence rate of P. vivax poses a significant health hazard but R falciparum also may lead to serious complications, including cerebral malaria.

Malaria

MedlinePlus

Quartan malaria; Falciparum malaria; Biduoterian fever; Blackwater fever; Tertian malaria; Plasmodium ... Malaria is caused by a parasite that is passed to humans by the bite of infected anopheles ...

In-depth comparative analysis of malaria parasite genomes reveals protein-coding genes linked to human disease in Plasmodium falciparum genome.

PubMed

Liu, Xuewu; Wang, Yuanyuan; Liang, Jiao; Wang, Luojun; Qin, Na; Zhao, Ya; Zhao, Gang

2018-05-02

Plasmodium falciparum is the most virulent malaria parasite capable of parasitizing human erythrocytes. The identification of genes related to this capability can enhance our understanding of the molecular mechanisms underlying human malaria and lead to the development of new therapeutic strategies for malaria control. With the availability of several malaria parasite genome sequences, performing computational analysis is now a practical strategy to identify genes contributing to this disease. Here, we developed and used a virtual genome method to assign 33,314 genes from three human malaria parasites, namely, P. falciparum, P. knowlesi and P. vivax, and three rodent malaria parasites, namely, P. berghei, P. chabaudi and P. yoelii, to 4605 clusters. Each cluster consisted of genes whose protein sequences were significantly similar and was considered as a virtual gene. Comparing the enriched values of all clusters in human malaria parasites with those in rodent malaria parasites revealed 115 P. falciparum genes putatively responsible for parasitizing human erythrocytes. These genes are mainly located in the chromosome internal regions and participate in many biological processes, including membrane protein trafficking and thiamine biosynthesis. Meanwhile, 289 P. berghei genes were included in the rodent parasite-enriched clusters. Most are located in subtelomeric regions and encode erythrocyte surface proteins. Comparing cluster values in P. falciparum with those in P. vivax and P. knowlesi revealed 493 candidate genes linked to virulence. Some of them encode proteins present on the erythrocyte surface and participate in cytoadhesion, virulence factor trafficking, or erythrocyte invasion, but many genes with unknown function were also identified. Cerebral malaria is characterized by accumulation of infected erythrocytes at trophozoite stage in brain microvascular. To discover cerebral malaria-related genes, fast Fourier transformation (FFT) was introduced to extract

Congenital malaria in Urabá, Colombia

PubMed Central

2011-01-01

Background Congenital malaria has been considered a rare event; however, recent reports have shown frequencies ranging from 3% to 54.2% among newborns of mothers who had suffered malaria during pregnancy. There are only a few references concerning the epidemiological impact of this entity in Latin-America and Colombia. Objective The aim of the study was to measure the prevalence of congenital malaria in an endemic Colombian region and to determine some of its characteristics. Methods A prospective, descriptive study was carried out in the mothers who suffered malaria during pregnancy and their newborns. Neonates were clinically evaluated at birth and screened for Plasmodium spp. infection by thick smear from the umbilical cord and peripheral blood, and followed-up weekly during the first 21 days of postnatal life through clinical examinations and thick smears. Results 116 newborns were included in the study and 80 umbilical cord samples were obtained. Five cases of congenital infection were identified (four caused by P. vivax and one by P. falciparum), two in umbilical cord blood and three in newborn peripheral blood. One case was diagnosed at birth and the others during follow-up. Prevalence of congenital infection was 4.3%. One of the infected newborns was severely ill, while the others were asymptomatic and apparently healthy. The mothers of the newborns with congenital malaria had been diagnosed with malaria in the last trimester of pregnancy or during delivery, and also presented placental infection. Conclusions Congenital malaria may be a frequent event in newborns of mothers who have suffered malaria during pregnancy in Colombia. An association was found between congenital malaria and the diagnosis of malaria in the mother during the last trimester of pregnancy or during delivery, and the presence of placental infection. PMID:21846373

Rapid Urban Malaria Appraisal (RUMA) III: epidemiology of urban malaria in the municipality of Yopougon (Abidjan)

PubMed Central

Wang, Shr-Jie; Lengeler, Christian; Smith, Thomas A; Vounatsou, Penelope; Cissé, Guéladio; Tanner, Marcel

2006-01-01

Background Currently, there is a significant lack of knowledge concerning urban malaria patterns in general and in Abidjan in particular. The prevalence of malaria, its distribution in the city and the fractions of fevers attributable to malaria in the health facilities have not been previously investigated. Methods A health facility-based survey and health care system evaluation was carried out in a peripheral municipality of Abidjan (Yopougon) during the rainy season of 2002, applying a standardized Rapid Urban Malaria Appraisal (RUMA) methodology. Results According to national statistics, approximately 240,000 malaria cases (both clinical cases and laboratory confirmed cases) were reported by health facilities in the whole of Abidjan in 2001. They accounted for 40% of all consultations. In the health facilities of the Yopougon municipality, the malaria infection rates in fever cases for different age groups were 22.1% (under one year-olds), 42.8% (one to five years-olds), 42.0% (> five to 15 years-olds) and 26.8% (over 15 years-olds), while those in the control group were 13.0%. 26.7%, 21.8% and 14.6%, respectively. The fractions of malaria-attributable fever were 0.12, 0.22, 0.27 and 0.13 in the same age groups. Parasitaemia was homogenously detected in different areas of Yopougon. Among all children, 10.1% used a mosquito net (treated or not) the night before the survey and this was protective (OR = 0.52, 95% CI 0.29–0.97). Travel to rural areas within the last three months was frequent (31% of all respondents) and associated with a malaria infection (OR = 1.75, 95% CI 1.25–2.45). Conclusion Rapid urbanization has changed malaria epidemiology in Abidjan and endemicity was found to be moderate in Yopougon. Routine health statistics are not fully reliable to assess the burden of disease, and the low level of the fractions of malaria-attributable fevers indicated substantial over-treatment of malaria. PMID:16584575

Vitamin D insufficiency is common in Ugandan children and is associated with severe malaria.

PubMed

Cusick, Sarah E; Opoka, Robert O; Lund, Troy C; John, Chandy C; Polgreen, Lynda E

2014-01-01

Vitamin D plays an increasingly recognized role in the innate and adaptive immune response to infection. Based on demonstrated roles in up-regulating innate immunity, decreasing inflammation, and reducing the severity of disease in illnesses such as tuberculosis and influenza, we hypothesized that poor vitamin D status would be associated with severe malaria. We measured 25-hydroxyvitamin D [25(OH)D] by immunoassay in a sample of Ugandan children aged 18 months-12 years with severe malaria (cerebral malaria or severe malarial anemia, n = 40) and in healthy community children (n = 20). Ninety-five percent of children with severe malaria (n = 38) and 80% of control children (n = 16) were vitamin D-insufficient [plasma 25(OH)D <30 ng/mL]. Mean plasma 25(OH)D levels were significantly lower in children with severe malaria than in community children (21.2 vs. 25.3 ng/mL, p = 0.03). Logistic regression revealed that for every 1 ng/mL increase in plasma 25(OH)D, the odds of having severe malaria declined by 9% [OR = 0.91 (95% CI: 0.84, 1.0)]. These preliminary results suggest that vitamin D insufficiency may play a role in the development of severe malaria. Further prospective studies in larger cohorts are indicated to confirm the relationship of vitamin D levels to severity of malaria infection and to investigate causality.

Vitamin D Insufficiency Is Common in Ugandan Children and Is Associated with Severe Malaria

PubMed Central

Cusick, Sarah E.; Opoka, Robert O.; Lund, Troy C.; John, Chandy C.; Polgreen, Lynda E.

2014-01-01

Vitamin D plays an increasingly recognized role in the innate and adaptive immune response to infection. Based on demonstrated roles in up-regulating innate immunity, decreasing inflammation, and reducing the severity of disease in illnesses such as tuberculosis and influenza, we hypothesized that poor vitamin D status would be associated with severe malaria. We measured 25-hydroxyvitamin D [25(OH)D] by immunoassay in a sample of Ugandan children aged 18 months –12 years with severe malaria (cerebral malaria or severe malarial anemia, n = 40) and in healthy community children (n = 20). Ninety-five percent of children with severe malaria (n = 38) and 80% of control children (n = 16) were vitamin D-insufficient [plasma 25(OH)D <30 ng/mL]. Mean plasma 25(OH)D levels were significantly lower in children with severe malaria than in community children (21.2 vs. 25.3 ng/mL, p = 0.03). Logistic regression revealed that for every 1 ng/mL increase in plasma 25(OH)D, the odds of having severe malaria declined by 9% [OR = 0.91 (95% CI: 0.84, 1.0)]. These preliminary results suggest that vitamin D insufficiency may play a role in the development of severe malaria. Further prospective studies in larger cohorts are indicated to confirm the relationship of vitamin D levels to severity of malaria infection and to investigate causality. PMID:25470777

The economic costs of malaria in children in three sub-Saharan countries: Ghana, Tanzania and Kenya

PubMed Central

2013-01-01

Background Malaria causes significant mortality and morbidity in sub-Saharan Africa (SSA), especially among children less than five years of age (U5 children). Although the economic burden of malaria in this region has been assessed previously, the extent and variation of this burden remains unclear. This study aimed to estimate the economic costs of malaria in U5 children in three countries (Ghana, Tanzania and Kenya). Methods Health system and household costs previously estimated were integrated with costs associated with co-morbidities, complications and productivity losses due to death. Several models were developed to estimate the expected treatment cost per episode per child, across different age groups, by level of severity and with or without controlling for treatment-seeking behaviour. Total annual costs (2009) were calculated by multiplying the treatment cost per episode according to severity by the number of episodes. Annual health system prevention costs were added to this estimate. Results Household and health system costs per malaria episode ranged from approximately US$ 5 for non-complicated malaria in Tanzania to US$ 288 for cerebral malaria with neurological sequelae in Kenya. On average, up to 55% of these costs in Ghana and Tanzania and 70% in Kenya were assumed by the household, and of these costs 46% in Ghana and 85% in Tanzania and Kenya were indirect costs. Expected values of potential future earnings (in thousands) lost due to premature death of children aged 0–1 and 1–4 years were US$ 11.8 and US$ 13.8 in Ghana, US$ 6.9 and US$ 8.1 in Tanzania, and US$ 7.6 and US$ 8.9 in Kenya, respectively. The expected treatment costs per episode per child ranged from a minimum of US$ 1.29 for children aged 2–11 months in Tanzania to a maximum of US$ 22.9 for children aged 0–24 months in Kenya. The total annual costs (in millions) were estimated at US$ 37.8, US$ 131.9 and US$ 109.0 nationwide in Ghana, Tanzania and Kenya and included average

Severe malaria in children: A descriptive report from Kinshasa, the Democratic Republic of Congo.

PubMed

Kunuanunua, Thomas S; Nsibu, Célestin N; Bodi, Joseph M; Tshibola, Thérèse K; Makusi Bura, Mimy; Magoga, Kumbundu; Ekila, Mathilde B; Situakibanza, Hypolite T; Aloni, Michel N

2015-08-01

The decline of susceptibility of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine resulted in the change of drug policy. This policy has probably changed the facies of the severe form of malaria. A prospective study was conducted in Kinshasa, the Democratic Republic of Congo. Data on children aged ≤13 years, diagnosed with severe malaria were analyzed. In total, 378 children were included with an overall median age of 8 years (age range: 1-13 years). Dark urine was seen in 25.1% of cases. Metabolic acidosis (85.2%), hypoglycemia (62.2%) and hemoglobin ≤5 g/dl (39.1%) were the common laboratories features. Severe malaria anemia, cerebral malaria and Blackwater fever (BWF) were found in 39.1, 30.1 and 25.4%, respectively. Mortality rate was 4%. BWF emerges as a frequent form of severe malaria in our midst. Availing artemisin-based combination treatments in the health care system is a priority to reduce the incidence of BWF in our environment. © The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Intramuscular arteether for treating severe malaria.

PubMed

Afolabi, B B; Okoromah, C N

2004-10-18

Quinine and artemisinin drugs are used in severe malaria, but quinine resistance is increasing. Arteether is a recently developed artemisinin derivative that is oil soluble, has a long elimination half life, and is more stable than other derivatives. To compare intramuscular arteether with other antimalarial drugs to treat severe malaria. We searched the Cochrane Infectious Diseases Group Specialized Register (August 2004), CENTRAL (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to August 2004), U.S. National Library of Medicine (NLM) Gateway (1953 to 1965), Web Science Citation (1981 to August 2004), LILACS (August 2004), Google search engine (August 2004), conference proceedings, and reference lists. We also contacted researchers, organizations, and pharmaceutical companies to help identify trials. Randomized and quasi-randomized controlled trials of intramuscular arteether in adults and children with severe malaria. We independently assessed the methodological quality of the trials and extracted data, and analysed data using Review Manager 4.2. Two small trials (n = 194) met the inclusion criteria. Both trials compared arteether with quinine in children with cerebral malaria and reported on similar outcomes. There was no statistically significant difference in the number of deaths (relative risk 0.75, 95% confidence interval 0.43 to 1.30; n = 194, 2 trials), neurological complications (relative risk 1.18, 95% confidence interval 0.31 to 4.46; n = 58, 1 trial), or other outcomes including time to regain consciousness, parasite clearance time, and fever clearance time. The meta-analyses lack statistical power to detect important differences. More trials with a larger number of participants are needed before a firm conclusion about the efficacy and safety of arteether can be reached.

Reappraisal of known malaria resistance loci in a large multi-centre study

PubMed Central

Rockett, Kirk A.; Clarke, Geraldine M.; Fitzpatrick, Kathryn; Hubbart, Christina; Jeffreys, Anna E.; Rowlands, Kate; Craik, Rachel; Jallow, Muminatou; Conway, David J.; Bojang, Kalifa A.; Pinder, Margaret; Usen, Stanley; Sisay-Joof, Fatoumatta; Sirugo, Giorgio; Toure, Ousmane; Thera, Mahamadou A.; Konate, Salimata; Sissoko, Sibiry; Niangaly, Amadou; Poudiougou, Belco; Mangano, Valentina D.; Bougouma, Edith C.; Sirima, Sodiomon B.; Modiano, David; Amenga-Etego, Lucas N.; Ghansah, Anita; Koram, Kwadwo A.; Wilson, Michael D.; Enimil, Anthony; Evans, Jennifer; Amodu, Olukemi; Olaniyan, Subulade; Apinjoh, Tobias; Mugri, Regina; Ndi, Andre; Ndila, Carolyne M.; Uyoga, Sophie; Macharia, Alexander; Peshu, Norbert; Williams, Thomas N.; Manjurano, Alphaxard; Riley, Eleanor; Drakeley, Chris; Reyburn, Hugh; Nyirongo, Vysaul; Kachala, David; Molyneux, Malcolm; Dunstan, Sarah J.; Phu, Nguyen Hoan; Ngoc Quyen, Nguyen Thi; Thai, Cao Quang; Hien, Tran Tinh; Manning, Laurens; Laman, Moses; Siba, Peter; Karunajeewa, Harin; Allen, Steve; Allen, Angela; Davis, Timothy M. E.; Michon, Pascal; Mueller, Ivo; Green, Angie; Molloy, Sile; Johnson, Kimberly J.; Kerasidou, Angeliki; Cornelius, Victoria; Hart, Lee; Vanderwal, Aaron; SanJoaquin, Miguel; Band, Gavin; Le, Si Quang; Pirinen, Matti; Sepúlveda, Nuno; Spencer, Chris C.A.; Clark, Taane G.; Agbenyega, Tsiri; Achidi, Eric; Doumbo, Ogobara; Farrar, Jeremy; Marsh, Kevin; Taylor, Terrie; Kwiatkowski, Dominic P.

2015-01-01

Many human genetic associations with resistance to malaria have been reported but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. There was strong evidence of association with the HBB, ABO, ATP2B4, G6PD and CD40LG loci but previously reported associations at 22 other loci did not replicate in the multi-centre analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anaemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed. PMID:25261933

Effect of mushroom Agaricus blazei on immune response and development of experimental cerebral malaria.

PubMed

Val, Cynthia H; Brant, Fátima; Miranda, Aline S; Rodrigues, Flávia G; Oliveira, Bruno C L; Santos, Elândia A; Assis, Diego R R; Esper, Lísia; Silva, Bruno C; Rachid, Milene A; Tanowitz, Herbert B; Teixeira, Antônio L; Teixeira, Mauro M; Régis, Wiliam C B; Machado, Fabiana S

2015-08-11

Cerebral malaria (CM) is debilitating and sometimes fatal. Disease severity has been associated with poor treatment access, therapeutic complexity and drug resistance and, thus, alternative therapies are increasingly necessary. In this study, the effect of the administration of Agaricus blazei, a mushroom of Brazilian origin in a model of CM caused by Plasmodium berghei, strain ANKA, was investigated in mice. C57BL/6 mice were pre-treated with aqueous extract or fractions of A. blazei, or chloroquine, infected with P. berghei ANKA and then followed by daily administration of A. blazei or chloroquine. Parasitaemia, body weight, survival and clinical signs of the disease were evaluated periodically. The concentration of pro-and anti-inflammatory cytokines, histopathology and in vitro analyses were performed. Mice treated with A. blazei aqueous extract or fraction C, that shows antioxidant activity, displayed lower parasitaemia, increased survival, reduced weight loss and protection against the development of CM. The administration of A. blazei resulted in reduced levels of TNF, IL-1β and IL-6 production when compared to untreated P. berghei-infected mice. Agaricus blazei (aqueous extract or fraction C) treated infected mice displayed reduction of brain lesions. Although chloroquine treatment reduced parasitaemia, there was increased production of proinflammatory cytokines and damage in the CNS not observed with A. blazei treatment. Moreover, the in vitro pretreatment of infected erythrocytes followed by in vivo infection resulted in lower parasitaemia, increased survival, and little evidence of clinical signs of disease. This study strongly suggests that the administration of A. blazei (aqueous extract or fraction C) was effective in improving the consequences of CM in mice and may provide novel therapeutic strategies.

Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate

PubMed Central

2012-01-01

Background The simian parasite Plasmodium knowlesi is recognized as a common cause of severe and fatal human malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe malaria cases of any species. This paper reviews all malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of malaria deaths in Malaysia is mandatory. Methods Details of reported malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe malaria caused by each species were compared. Results Fourteen malaria deaths were reported, comprising seven Plasmodium falciparum, six P. knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. knowlesi deaths, five were attributable to knowlesi malaria and one was attributable to P. knowlesi-associated enterobacter sepsis. Patients with directly attributable P. knowlesi deaths (N = 5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p = 0.06). Complications in fatal P. knowlesi included respiratory distress (N = 5, 100%), hypotension (N = 4, 80%), and renal failure (N = 4, 80%). All patients with P. knowlesi were reported as P. malariae by microscopy. Only two of five patients with severe knowlesi malaria on presentation received immediate parenteral anti-malarial treatment. The patient with P. vivax-associated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum malaria received immediate parenteral treatment. Conclusion Plasmodium knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of malaria deaths in Sabah

Plasmodium vivax associated severe malaria complications among children in some malaria endemic areas of Ethiopia

PubMed Central

2013-01-01

Background Although, Plasmodium vivax is a rare parasite in most parts of Africa, it has significant public health importance in Ethiopia. In some parts of the country, it is responsible for majority of malaria associated morbidity. Recently severe life threatening malaria syndromes, frequently associated to P. falciparum, has been reported from P. vivax mono-infections. This prompted designing of the current study to assess prevalence of severe malaria complications related to P. vivax malaria in Ethiopia. Methods The study was conducted in two study sites, namely Kersa and Halaba Kulito districts, located in southwest and southern parts of Ethiopia, respectively. Children, aged ≤ 10 years, who visited the two health centers during the study period, were recruited to the study. Clinical and demographic characteristics such as age, sex, temperature, diarrhea, persistent vomiting, confusion, respiratory distress, hepatomegaly, splenomegaly, hemoglobinuria, and epitaxis were assessed for a total of 139 children diagnosed to have P. vivax mono-infection. Parasitological data were collected following standard procedures. Hemoglobin and glucose level were measured using portable hemocue instrument. Results Median age of children was 4.25 ± 2.95 years. Geometric mean parasite count and mean hemoglobin level were 4254.89 parasite/μl and 11.55 g/dl, respectively. Higher prevalence rate of malaria and severe malaria complications were observed among children enrolled in Halaba district (P < 0.001). However, severe parasitemia was higher (72.4%) among children who visited Serbo health center (Kersa district). Male children had significantly higher risk of malaria infection (OR = 1.9, 95% CI, 1.08 to 3.34), while female had higher risk to anemia (OR = 1.91, 95% CI, 1.08 - 3.34). The observed number of anemic children was 43%, of which most of them were found in age range from 0–3 years. Furthermore, P. vivax malaria was a risk factor for incidence of anemia (P < 0

Opportunities and obstacles to the elimination of malaria from Peninsular Malaysia: knowledge, attitudes and practices on malaria among aboriginal and rural communities

PubMed Central

2010-01-01

Background Despite continuous efforts by the government and private sectors, malaria is still a public health problem in rural Peninsular Malaysia. This study investigated household knowledge, attitude and practices (KAP) regarding malaria in two malaria endemic communities, forest-aboriginal and rural communities, in the Lipis district of Pahang state, Malaysia. Methods A descriptive cross-sectional study with a semi-structured questionnaire was carried out among 100 and 123 households from forest-aboriginal and rural areas, respectively. Results Knowledge about malaria and its transmission is significantly higher among the rural participants than the aborigines (86.2% vs 76%, p < 0.01). However, use of medicinal plants and beliefs in witchcraft and sorcery in treating febrile diseases were significantly higher among the aboriginal population (p < 0.01). There were no significant differences between the two communities in terms of the knowledge about malaria symptoms, attitudes towards its severity and practices in preventive measures against malaria by using mosquito bed nets. However, the knowledge and practice of different preventive measures to combat malaria, such as insecticide and the elimination of breeding areas, was significantly higher among the rural population than the aborigines (p < 0.001). Conclusions Both communities were aware of malaria as a disease, but knowledge, attitudes and practices were inadequate. Providing efficient health education to people residing in malaria endemic areas would improve their understanding about malaria prevention in order to bring about the elimination of malaria from the country. PMID:20497543

Sociodemographic Determinants of Malaria among Under-Five Children in Ghana.

PubMed

Nyarko, Samuel Harrenson; Cobblah, Anastasia

2014-01-01

Background. Malaria is an entrenched global health challenge particularly in the sub-Saharan African countries. However, in Ghana, little is known about the determinants of malaria prevalence among under-five children. As such, this study sought to examine the sociodemographic factors that determine malaria among under-five children in Ghana. Methods. This paper used secondary data drawn from the 2008 Ghana Demographic and Health Survey. Bivariate analysis and complementary log-log regression models were used to examine the determinants of malaria prevalence among under-five children in Ghana for the study period. Results. The results therefore revealed that region of residence, age of child, and ownership of mosquito net were the key predictors of malaria cases among under-five children in Ghana for the five-year period preceding the survey. Conclusion. It is therefore imperative that special education on prevention of malaria should be intensified by the National Malaria Control Programme in all the regions in order to reduce malaria prevalence particularly among under-five children in Ghana.

Plants used traditionally to treat malaria in Brazil: the archives of Flora Medicinal

PubMed Central

Botsaris, Alexandros S

2007-01-01

The archives of Flora Medicinal, an ancient pharmaceutical laboratory that supported ethnomedical research in Brazil for more than 30 years, were searched for plants with antimalarial use. Forty plant species indicated to treat malaria were described by Dr. J. Monteiro da Silva (Flora Medicinal leader) and his co-workers. Eight species, Bathysa cuspidata, Cosmos sulphureus, Cecropia hololeuca, Erisma calcaratum, Gomphrena arborescens, Musa paradisiaca, Ocotea odorifera, and Pradosia lactescens, are related as antimalarial for the first time in ethnobotanical studies. Some species, including Mikania glomerata, Melampodium divaricatum, Galipea multiflora, Aspidosperma polyneuron, and Coutarea hexandra, were reported to have activity in malaria patients under clinical observation. In the information obtained, also, there were many details about the appropriate indication of each plant. For example, some plants are indicated to increase others' potency. There are also plants that are traditionally employed for specific symptoms or conditions that often accompany malaria, such as weakness, renal failure or cerebral malaria. Many plants that have been considered to lack activity against malaria due to absence of in vitro activity against Plasmodium can have other mechanisms of action. Thus researchers should observe ethnomedical information before deciding which kind of screening should be used in the search of antimalarial drugs. PMID:17472740

Using Structured Additive Regression Models to Estimate Risk Factors of Malaria: Analysis of 2010 Malawi Malaria Indicator Survey Data

PubMed Central

Chirombo, James; Lowe, Rachel; Kazembe, Lawrence

2014-01-01

Background After years of implementing Roll Back Malaria (RBM) interventions, the changing landscape of malaria in terms of risk factors and spatial pattern has not been fully investigated. This paper uses the 2010 malaria indicator survey data to investigate if known malaria risk factors remain relevant after many years of interventions. Methods We adopted a structured additive logistic regression model that allowed for spatial correlation, to more realistically estimate malaria risk factors. Our model included child and household level covariates, as well as climatic and environmental factors. Continuous variables were modelled by assuming second order random walk priors, while spatial correlation was specified as a Markov random field prior, with fixed effects assigned diffuse priors. Inference was fully Bayesian resulting in an under five malaria risk map for Malawi. Results Malaria risk increased with increasing age of the child. With respect to socio-economic factors, the greater the household wealth, the lower the malaria prevalence. A general decline in malaria risk was observed as altitude increased. Minimum temperatures and average total rainfall in the three months preceding the survey did not show a strong association with disease risk. Conclusions The structured additive regression model offered a flexible extension to standard regression models by enabling simultaneous modelling of possible nonlinear effects of continuous covariates, spatial correlation and heterogeneity, while estimating usual fixed effects of categorical and continuous observed variables. Our results confirmed that malaria epidemiology is a complex interaction of biotic and abiotic factors, both at the individual, household and community level and that risk factors are still relevant many years after extensive implementation of RBM activities. PMID:24991915

The Utility of Malaria Rapid Diagnostic Tests as a Tool in Enhanced Surveillance for Malaria Elimination in Vanuatu

PubMed Central

Guintran, Jean-Olivier; Iata, Harry; Anderson, Karen; Nausien, Johnny; Gresty, Karryn J; Waters, Norman C.; Vestergaard, Lasse S.; Taleo, George; Cheng, Qin

2016-01-01

Background As part of efforts to eliminate malaria, Vanuatu has piloted the implementation of enhanced malaria surveillance and response strategies since 2011. This involves passive case detection (PCD) in health facilities, proactive case detection (Pro-ACD) and reactive case detection (Re-ACD) in communities using malaria rapid diagnostic tests (RDTs). While RDTs improve case management, their utility for detection of malaria infections in ACDs in this setting is unclear. Methods The utility of malaria RDTs as diagnostic tools was evaluated in PCD, in five rounds of Pro-ACDs and five rounds of Re-ACDs conducted in Tafea and Torba Provinces between 2011 and 2014. The number of malaria infections detected by RDTs was compared to that detected by PCR from collected used-RDTs. Results PCD in Tafea Province (2013) showed a RDT-positive rate of 0.21% (2/939) and a PCR-positive rate of 0.44% (2/453), indicating less than 1% of suspected malaria cases in Tafea Province were due to malaria. In Pro-ACDs conducted in Tafea and Torba Provinces, RDT-positive rates in 2013 and 2014 were 0.14% (3/2145) and 0% (0/2823), respectively, while the corresponding PCR-positive rates were 0.72% (9/1242) and 0.79% (9/1141). PCR identified villages in both provinces appearing to be transmission foci with a small number of low-density infections, mainly P. falciparum infections. In five rounds of Re-ACD, RDTs did not identify any additional infections while PCR detected only one among 173 subjects screened. Conclusions PCD and Pro-ACDs demonstrate that both Tafea and Torba Provinces in Vanuatu has achieved very low malaria prevalence. In these low-transmission areas, conducting Pro-ACD and Re-ACDs using RDTs appears not cost-effective and may have limited impact on interrupting malaria transmission due to the small number of infections identified by RDTs and considerable operational resources invested. More sensitive, field deployable and affordable diagnostic tools will improve malaria

Malaria vaccines: looking back and lessons learnt

PubMed Central

Lorenz, Veronique; Karanis, Panagiotis

2011-01-01

The current status of malaria vaccine approaches has the background of a long and arduous path of malaria disease control and vaccine development. Here, we critically review with regard to unilateral interventional approaches and highlight the impact of socioeconomic elements of malaria endemicity. The necessity of re-energizing basic research of malaria life-cycle and Plasmodium developmental biology to provide the basis for promising and cost-effective vaccine approaches and to reach eradication goals is more urgent than previously believed. We closely analyse the flaws of various vaccine approaches, outline future directions and challenges that still face us and conclude that the focus of the field must be shifted to the basic research efforts including findings on the skin stage of infection. We also reflect on economic factors of vaccine development and the impact of public perception when it comes to vaccine uptake. PMID:23569729

Strengthening the policy setting process for global malaria control and elimination.

PubMed

D'Souza, Bianca J; Newman, Robert D

2012-01-27

The scale-up of malaria control efforts in recent years, coupled with major investments in malaria research, has produced impressive public health impact in a number of countries and has led to the development of new tools and strategies aimed at further consolidating malaria control goals. As a result, there is a growing need for the malaria policy setting process to rapidly review increasing amounts of evidence. The World Health Organization Global Malaria Programme, in keeping with its mandate to set evidence-informed policies for malaria control, has convened the Malaria Policy Advisory Committee as a mechanism to increase the timeliness, transparency, independence and relevance of its recommendations to World Health Organization member states in relation to malaria control and elimination. The Malaria Policy Advisory Committee, composed of 15 world-renowned malaria experts, will meet in full twice a year, with the inaugural meeting scheduled for 31 January to 2 February 2012 in Geneva. Policy recommendations, and the evidence to support them, will be published within two months of every meeting as part of an open access Malaria Journal thematic series. This article is a prelude to that series and provides the global malaria community with the background and overview of the Committee and its terms of reference.

The economic benefits of malaria elimination: do they include increases in tourism?

PubMed Central

2012-01-01

Background Policy makers have speculated that one of the economic benefits of malaria elimination includes increases in foreign direct investment, particularly tourism. Methods This study examines the empirical relationship between the demand for travel and malaria cases in two countries with large tourism industries around the time in which they carried out malaria-elimination campaigns. In Mauritius, this analysis examines historical, yearly tourist arrivals and malaria cases from 1978–1999, accounting for the background secular trend of increasing international travel. In Dominican Republic, a country embarking upon malaria elimination, it employs a time-series analysis of the monthly, international tourist arrivals from 1998–2010 to determine whether the timing of significant deviations in tourist arrivals coincides with malaria outbreaks. Results While naïve relationships exist in both cases, the results show that the relationships between tourist arrivals and malaria cases are relatively weak and statistically insignificant once secular confounders are accounted for. Conclusions This suggests that any economic benefits from tourism that may be derived from actively pursuing elimination in countries that have high tourism potential are likely to be small when measured at a national level. Rather, tourism benefits are likely to be experienced with greater impact in more concentrated tourist areas within countries, and future studies should seek to assess these relationships at a regional or local level. PMID:22839351

Does treatment of intestinal helminth infections influence malaria? Background and methodology of a longitudinal study of clinical, parasitological and immunological parameters in Nangapanda, Flores, Indonesia (ImmunoSPIN Study)

PubMed Central

2010-01-01

Background Given that helminth infections are thought to have strong immunomodulatory activity, the question whether helminth infections might affect responses to malaria antigens needs to be addressed. Different cross-sectional studies using diverse methodologies have reported that helminth infections might either exacerbate or reduce the severity of malaria attacks. The same discrepancies have been reported for parasitemia. Methods/Design To determine the effect of geohelminth infections and their treatment on malaria infection and disease outcome, as well as on immunological parameters, the area of Nangapanda on Flores Island, Indonesia, where malaria and helminth parasites are co-endemic was selected for a longitudinal study. Here a Double-blind randomized trial will be performed, incorporating repeated treatment with albendazole (400 mg) or placebo at three monthly intervals. Household characteristic data, anthropometry, the presence of intestinal helminth and Plasmodium spp infections, and the incidence of malaria episodes are recorded. In vitro cultures of whole blood, stimulated with a number of antigens, mitogens and toll like receptor ligands provide relevant immunological parameters at baseline and following 1 and 2 years of treatment rounds. The primary outcome of the study is the prevalence of Plasmodium falciparum and P. vivax infection. The secondary outcome will be incidence and severity of malaria episodes detected via both passive and active follow-up. The tertiary outcome is the inflammatory cytokine profile in response to parasite antigens. The project also facilitates the transfer of state of the art methodologies and technologies, molecular diagnosis of parasitic diseases, immunology and epidemiology from Europe to Indonesia. Discussion The study will provide data on the effect of helminth infections on malaria. It will also give information on anthelminthic treatment efficacy and effectiveness and could help develop evidence

Origin of malaria cases: a 7-year audit of global trends in indigenous and imported cases in relation to malaria elimination

PubMed Central

Velarde-Rodríguez, Mar; Van den Bergh, Rafael; Fergus, Cristin; Casellas, Aina; Sanz, Sergi; Cibulskis, Richard; Ramsay, Andrew R.; Bissell, Karen; Zachariah, Rony

2015-01-01

Background Countries in the different stages of pre-elimination, elimination, and prevention of reintroduction are required to report the number of indigenous and imported malaria cases to the World Health Organization (WHO). However, these data have not been systematically analysed at the global level. Objective For the period 2007 to 2013, we aimed to report on 1) the proportion of countries providing data on the origin of malaria cases and 2) the origin of malaria cases in countries classified as being in the stages of pre-elimination, elimination and prevention of reintroduction. Design An observational study using annual data reported through routine health information systems to the WHO Global Malaria Programme between 2007 and 2013. Results For all countries classified as being in pre-elimination, elimination, and prevention of reintroduction in the year 2013, there has been a substantial decrease in the total number of indigenous malaria cases, from more than 15,000 cases reported in 2007 to less than 4,000 cases reported in 2013. However, the total number of imported malaria cases has increased over that time period, from 5,600 imported cases in 2007 to approximately 6,800 in 2013. Conclusions Vigilant monitoring of the numbers of imported and indigenous malaria cases at national and global levels as well as appropriate strategies to target these cases will be critical to achieve malaria eradication. PMID:26449205

Asymptomatic Malaria and its Challenges in the Malaria Elimination Program in Iran: a Systematic Review

PubMed Central

Hassanpour, Gholmreza; Mohebali, Mehdi; Zeraati, Hojjat; Raeisi, Ahmad; Keshavarz, Hossein

2017-01-01

Background: The objective of this study was to find an appropriate approach to asymptomatic malaria in elimination setting through a systematic review. Methods: A broad search was conducted to find articles with the words ‘malaria’ in their titles and ‘asymptomatic’ or ‘submicroscopic’ in their texts, irrespective of the type of study conducted. The Cochrane, Medline/Pub Med, and Scopus databases, as well as Google Scholar were systematically searched for English articles and reports and Iran’s databases-Iran Medex, SID and Magiran were searched for Persian reports and articles, with no time limitation. The study was qualitatively summarized if it contained precise information on the role of asymptomatic malaria in the elimination phase. Results: Six articles were selected from the initial 2645 articles. The results all re-emphasize the significance of asymptomatic malaria in the elimination phase, and emphasize the significance of diagnostic tests of higher sensitivity to locate these patients and perform interventions to reduce the asymptomatic parasitic reservoirs particularly in regions of low transmission. However, we may infer from the results that the current evidence cannot yet specify an accurate strategy on the role of asymptomatic malaria in the elimination phase. Conclusion: To eliminate malaria, alongside vector control, and treatment of symptomatic and asymptomatic patients, active and inactive methods of case detection need to be employed. The precise monitoring of asymptomatic individuals and submicroscopic cases of malaria through molecular assays and valid serological methods, especially in regions where seasonal and low transmission exists can be very helpful at this phase. PMID:29062842

Amodiaquine analogues containing NO-donor substructures: synthesis and their preliminary evaluation as potential tools in the treatment of cerebral malaria.

PubMed

Bertinaria, Massimo; Guglielmo, Stefano; Rolando, Barbara; Giorgis, Marta; Aragno, Cristina; Fruttero, Roberta; Gasco, Alberto; Parapini, Silvia; Taramelli, Donatella; Martins, Yuri C; Carvalho, Leonardo J M

2011-05-01

The synthesis and physico-chemical properties of novel compounds obtained by conjugation of amodiaquine with moieties containing either furoxan or nitrooxy NO-donor substructures are described. The synthesised compounds were tested in vitro against both the chloroquine sensitive, D10 and the chloroquine resistant, W-2 strains of Plasmodium falciparum (P. falciparum). Most of the compounds showed an antiplasmodial activity comparable to that of the parent drug. By comparing the activities of simple related structures devoid of the ability to release NO, it appears that the contribution of NO to the antiplasmodial action in vitro is marginal. All the compounds were able to relax rat aorta strips with a NO-dependent mechanism, thus showing their capacity to release NO in the vessels. A preliminary in vivo study using Plasmodium berghei ANKA-infected mice showed a trend for prolonged survival of mice with cerebral malaria treated with compound 40, which is potent and fast amodiaquine-derived NO-donor, when compared with amodiaquine alone or with compound 31, a milder NO-donor. The two compounds showed in vivo antiplasmodial activity similar to that of amodiaquine. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Intravenous Artesunate for the Treatment of Severe and Complicated Malaria in the United States: Clinical Use Under an Investigational New Drug Protocol.

PubMed

Twomey, Patrick S; Smith, Bryan L; McDermott, Cathy; Novitt-Moreno, Anne; McCarthy, William; Kachur, S Patrick; Arguin, Paul M

2015-10-06

Quinidine gluconate, the only U.S. Food and Drug Administration-approved treatment for life-threatening malaria in the United States, has a problematic safety profile and is often unavailable in hospitals. To assess the safety and clinical benefit of intravenous artesunate as an alternative to quinidine. Retrospective case series. U.S. hospitals. 102 patients aged 1 to 72 years (90% adults; 61% men) with severe and complicated malaria. Patients received 4 weight-based doses of intravenous artesunate (2.4 mg/kg) under a treatment protocol implemented by the Centers for Disease Control and Prevention between January 2007 and December 2010. At baseline, 35% had evidence of cerebral malaria, and 17% had severe hepatic impairment. Eligibility required the presence of microscopically confirmed malaria, need for intravenous treatment, and an impediment to quinidine. Clinical and laboratory data from each patient's hospital records were abstracted retrospectively, including information from baseline through a maximum 7-day follow-up, and presented before a physician committee to evaluate safety and clinical benefit outcomes. 7 patients died (mortality rate, 6.9%). The most frequent adverse events were anemia (65%) and elevated hepatic enzyme levels (49%). All deaths and most adverse events were attributed to the severity of malaria. Patients' symptoms generally improved or resolved within 3 days, and the median time to discharge from the intensive care unit was 4 days, even for patients with severe liver disease or cerebral malaria. More than 100 concomitant medications were used, with no documented drug-drug interactions. Potential late-presenting safety issues might occur outside the 7-day follow-up. Artesunate was a safe and clinically beneficial alternative to quinidine.

T cell-derived IL-10 and its impact on the regulation of host responses during malaria.

PubMed

Freitas do Rosario, Ana Paula; Langhorne, Jean

2012-05-15

Despite intense research, malaria still is the one of the most devastating diseases killing more people than any other parasitic infection. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response. However, this response is also associated with complications, such as severe anaemia, hypoglycaemia and cerebral malaria. This pronounced production of pro-inflammatory cytokines response is a common feature of malaria caused by parasites infecting humans as well as rodents and primates. A balance between pro- and anti-inflammatory responses may be fundamental to the elimination of the parasite without inducing excessive host pathology. IL-10 is a key cytokine that has been shown to have an important regulatory function in establishing this balance in malaria. Here we discuss which cells can produce IL-10 during infection, and present an overview of the evidence showing that T-cell derived IL-10 plays an important role in regulating malaria pathology. Many different subsets of T cells can produce IL-10, however, evidence is accumulating that it is effector Th1 CD4(+) T cells which provide the crucial source that down-regulates inflammatory pathology during blood-stage malaria infections. Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers.

PubMed

Toovey, Stephen; Nieforth, Keith; Smith, Patrick; Schlagenhauf, Patricia; Adamcova, Miriam; Tatt, Iain; Tomianovic, Danitza; Schnetzler, Gabriel

2014-01-01

Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases--model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2

Global malaria connectivity through air travel

PubMed Central

2013-01-01

Background Air travel has expanded at an unprecedented rate and continues to do so. Its effects have been seen on malaria in rates of imported cases, local outbreaks in non-endemic areas and the global spread of drug resistance. With elimination and global eradication back on the agenda, changing levels and compositions of imported malaria in malaria-free countries, and the threat of artemisinin resistance spreading from Southeast Asia, there is a need to better understand how the modern flow of air passengers connects each Plasmodium falciparum- and Plasmodium vivax-endemic region to the rest of the world. Methods Recently constructed global P. falciparum and P.vivax malaria risk maps, along with data on flight schedules and modelled passenger flows across the air network, were combined to describe and quantify global malaria connectivity through air travel. Network analysis approaches were then utilized to describe and quantify the patterns that exist in passenger flows weighted by malaria prevalence. Finally, the connectivity within and to the Southeast Asia region where the threat of imported artemisinin resistance arising is highest, was examined to highlight risk routes for its spread. Results The analyses demonstrate the substantial connectivity that now exists between and from malaria-endemic regions through air travel. While the air network provides connections to previously isolated malarious regions, it is clear that great variations exist, with significant regional communities of airports connected by higher rates of flow standing out. The structures of these communities are often not geographically coherent, with historical, economic and cultural ties evident, and variations between P. falciparum and P. vivax clear. Moreover, results highlight how well connected the malaria-endemic areas of Africa are now to Southeast Asia, illustrating the many possible routes that artemisinin-resistant strains could take. Discussion The continuing growth in air

A cross-sectional analysis of traditional medicine use for malaria alongside free antimalarial drugs treatment amongst adults in high-risk malaria endemic provinces of Indonesia

PubMed Central

Suswardany, Dwi Linna; Sibbritt, David W.; Supardi, Sudibyo; Pardosi, Jerico F.; Chang, Sungwon; Adams, Jon

2017-01-01

Background The level of traditional medicine use, particularly Jamu use, in Indonesia is substantial. Indonesians do not always seek timely treatment for malaria and may seek self-medication via traditional medicine. This paper reports findings from the first focused analyses of traditional medicine use for malaria in Indonesia and the first such analyses worldwide to draw upon a large sample of respondents across high-risk malaria endemic areas. Methods A sub-study of the Indonesia Basic Health Research/Riskesdas Study 2010 focused on 12,226 adults aged 15 years and above residing in high-risk malaria-endemic provinces. Logistic regression was undertaken to determine the significant associations for traditional medicine use for malaria symptoms. Findings Approximately one in five respondents use traditional medicine for malaria symptoms and the vast majority experiencing multiple episodes of malaria use traditional medicine alongside free antimalarial drug treatments. Respondents consuming traditional medicine for general health/common illness purposes every day (odds ratio: 3.75, 95% Confidence Interval: 2.93 4.79), those without a hospital in local vicinity (odds ratio: 1.31, 95% Confidence Interval: 1.10 1.57), and those living in poorer quality housing, were more likely to use traditional medicine for malaria symptoms. Conclusion A substantial percentage of those with malaria symptoms utilize traditional medicine for treating their malaria symptoms. In order to promote safe and effective malaria treatment, all providing malaria care in Indonesia need to enquire with their patients about possible traditional medicine use. PMID:28329019

Prevalence of gestational, placental and congenital malaria in north-west Colombia

PubMed Central

2013-01-01

Background The frequency of pregnancy-associated malaria is increasingly being documented in American countries. In Colombia, with higher frequency of Plasmodium vivax over Plasmodium falciparum infection, recent reports confirmed gestational malaria as a serious public health problem. Thick smear examination is the gold standard to diagnose malaria in endemic settings, but in recent years, molecular diagnostic methods have contributed to elucidate the dimension of the problem of gestational malaria. The study was aimed at exploring the prevalence of gestational, placental and congenital malaria in women who delivered at the local hospitals of north-west Colombia, between June 2008 and April 2011. Methods A group of 129 parturient women was selected to explore the prevalence of gestational, placental and congenital malaria in a descriptive, prospective and transversal (prevalence) design. Diagnosis was based on the simultaneous application of two independent diagnostic tests: microscopy of thick blood smears and a polymerase chain reaction assay (PCR). Results The prevalence of gestational malaria (thick smear /PCR) was 9.1%/14.0%; placental malaria was 3.3%/16.5% and congenital malaria was absent. A history of gestational malaria during the current pregnancy was significantly associated with gestational malaria at delivery. Plasmodium vivax caused 65% of cases of gestational malaria, whereas P. falciparum caused most cases of placental malaria. Conclusions Gestational and placental malaria are a serious problem in the region, but the risk of congenital malaria is low. A history of malaria during pregnancy may be a practical indicator of infection at delivery. PMID:24053184

Declining incidence of imported malaria in the Netherlands, 2000-2007

PubMed Central

2010-01-01

Background To describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007. Methods Based on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers. Results Importation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007. Conclusion The annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome. PMID:21029424

The incidence of malaria in travellers to South-East Asia: is local malaria transmission a useful risk indicator?

PubMed Central

2010-01-01

Background The presence of ongoing local malaria transmission, identified though local surveillance and reported to regional WHO offices, by S-E Asian countries, forms the basis of national and international chemoprophylaxis recommendations in western countries. The study was designed to examine whether the strategy of using malaria transmission in a local population was an accurate estimate of the malaria threat faced by travellers and a correlate of malaria in returning travellers. Methods Malaria endemicity was described from distribution and intensity in the local populations of ten S-E Asian destination countries over the period 2003-2008 from regionally reported cases to WHO offices. Travel acquired malaria was collated from malaria surveillance reports from the USA and 12 European countries over the same period. The numbers of travellers visiting the destination countries was based on immigration and tourism statistics collected on entry of tourists to the destination countries. Results In the destination countries, mean malaria rates in endemic countries ranged between 0.01 in Korea to 4:1000 population per year in Lao PDR, with higher regional rates in a number of countries. Malaria cases imported into the 13 countries declined by 47% from 140 cases in 2003 to 66 in 2008. A total of 608 cases (27.3% Plasmodium falciparum (Pf)) were reported over the six years, the largest number acquired in Indonesia, Thailand and Korea. Four countries had an incidence > 1 case per 100,000 traveller visits; Burma (Myanmar), Indonesia, Cambodia and Laos (range 1 to 11.8-case per 100,000 visits). The remaining six countries rates were < 1 case per 100,000 visits. The number of visitors arriving from source countries increased by 60% from 8.5 Million to 13.6 million over the 6 years. Conclusion The intensity of malaria transmission particularly sub-national activity did not correlate with the risk of travellers acquiring malaria in the large numbers of arriving visitors. It

Mobile phones improve case detection and management of malaria in rural Bangladesh

PubMed Central

2013-01-01

Background The recent introduction of mobile phones into the rural Bandarban district of Bangladesh provided a resource to improve case detection and treatment of patients with malaria. Methods During studies to define the epidemiology of malaria in villages in south-eastern Bangladesh, an area with hypoendemic malaria, the project recorded 986 mobile phone calls from families because of illness suspected to be malaria between June 2010 and June 2012. Results Based on phone calls, field workers visited the homes with ill persons, and collected blood samples for malaria on 1,046 people. 265 (25%) of the patients tested were positive for malaria. Of the 509 symptomatic malaria cases diagnosed during this study period, 265 (52%) were detected because of an initial mobile phone call. Conclusion Mobile phone technology was found to be an efficient and effective method for rapidly detecting and treating patients with malaria in this remote area. This technology, when combined with local knowledge and field support, may be applicable to other hard-to-reach areas to improve malaria control. PMID:23374585

The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology

PubMed Central

Safeukui, Innocent; Deplaine, Guillaume; Brousse, Valentine; Prendki, Virginie; Thellier, Marc; Turner, Gareth D.; Mercereau-Puijalon, Odile

2011-01-01

Clinical manifestations of Plasmodium falciparum infection are induced by the asexual stages of the parasite that develop inside red blood cells (RBCs). Because splenic microcirculatory beds filter out altered RBCs, the spleen can innately clear subpopulations of infected or uninfected RBC modified during falciparum malaria. The spleen appears more protective against severe manifestations of malaria in naïve than in immune subjects. The spleen-specific pitting function accounts for a large fraction of parasite clearance in artemisinin-treated patients. RBC loss contributes to malarial anemia, a clinical form associated with subacute progression, frequent splenomegaly, and relatively low parasitemia. Stringent splenic clearance of ring-infected RBCs and uninfected, but parasite-altered, RBCs, may altogether exacerbate anemia and reduce the risks of severe complications associated with high parasite loads, such as cerebral malaria. The age of the patient directly influences the risk of severe manifestations. We hypothesize that coevolution resulting in increased splenic clearance of P. falciparum–altered RBCs in children favors the survival of the host and, ultimately, sustained parasite transmission. This analysis of the RBC–spleen dynamic interactions during P falciparum infection reflects both data and hypotheses, and provides a framework on which a more complete immunologic understanding of malaria pathogenesis may be elaborated. PMID:20852127

Evaluation of a rapid diagnostic test (CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test) for the diagnosis of malaria in a reference setting

PubMed Central

2010-01-01

Background Malaria Rapid Diagnostic Tests (RDTs) are widely used for diagnosing malaria. The present retrospective study evaluated the CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test targeting the Plasmodium falciparum specific antigen histidine-rich protein (HRP-2) and the pan-Plasmodium antigen lactate dehydrogenase (pLDH) in a reference setting. Methods The CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test was evaluated on a collection of samples obtained in returned international travellers using microscopy corrected by PCR as the reference method. Included were P. falciparum (n = 320), Plasmodium vivax (n = 76), Plasmodium ovale (n = 76), Plasmodium malariae (n = 23) and Plasmodium negative samples (n = 95). Results Overall sensitivity for the detection of P. falciparum was 88.8%, increasing to 94.3% and 99.3% at parasite densities above 100 and 1,000/μl respectively. For P. vivax, P. ovale and P. malariae, overall sensitivities were 77.6%, 18.4% and 30.4% respectively. For P. vivax sensitivity reached 90.2% for parasite densities above 500/μl. Incorrect species identification occurred in 11/495 samples (2.2%), including 8/320 (2.5%) P. falciparum samples which generated only the pan-pLDH line. For P. falciparum samples, 205/284 (72.2%) HRP-2 test lines had strong or medium line intensities, while for all species the pan-pLDH lines were less intense, especially in the case of P. ovale. Agreement between observers was excellent (kappa values > 0.81 for positive and negative readings) and test results were reproducible. The test was easy to perform with good clearing of the background. Conclusion The CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test performed well for the detection of P. falciparum and P. vivax, but sensitivities for P. ovale and P. malariae were poor. PMID:20565816

The Malaria System MicroApp: A New, Mobile Device-Based Tool for Malaria Diagnosis.

PubMed

Oliveira, Allisson Dantas; Prats, Clara; Espasa, Mateu; Zarzuela Serrat, Francesc; Montañola Sales, Cristina; Silgado, Aroa; Codina, Daniel Lopez; Arruda, Mercia Eliane; I Prat, Jordi Gomez; Albuquerque, Jones

2017-04-25

Malaria is a public health problem that affects remote areas worldwide. Climate change has contributed to the problem by allowing for the survival of Anopheles in previously uninhabited areas. As such, several groups have made developing news systems for the automated diagnosis of malaria a priority. The objective of this study was to develop a new, automated, mobile device-based diagnostic system for malaria. The system uses Giemsa-stained peripheral blood samples combined with light microscopy to identify the Plasmodium falciparum species in the ring stage of development. The system uses image processing and artificial intelligence techniques as well as a known face detection algorithm to identify Plasmodium parasites. The algorithm is based on integral image and haar-like features concepts, and makes use of weak classifiers with adaptive boosting learning. The search scope of the learning algorithm is reduced in the preprocessing step by removing the background around blood cells. As a proof of concept experiment, the tool was used on 555 malaria-positive and 777 malaria-negative previously-made slides. The accuracy of the system was, on average, 91%, meaning that for every 100 parasite-infected samples, 91 were identified correctly. Accessibility barriers of low-resource countries can be addressed with low-cost diagnostic tools. Our system, developed for mobile devices (mobile phones and tablets), addresses this by enabling access to health centers in remote communities, and importantly, not depending on extensive malaria expertise or expensive diagnostic detection equipment. ©Allisson Dantas Oliveira, Clara Prats, Mateu Espasa, Francesc Zarzuela Serrat, Cristina Montañola Sales, Aroa Silgado, Daniel Lopez Codina, Mercia Eliane Arruda, Jordi Gomez i Prat, Jones Albuquerque. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 25.04.2017.

Low perception of malaria risk among the Ra-glai ethnic minority in south-central Vietnam: implications for forest malaria control

PubMed Central

2010-01-01

Background Despite Vietnam's success in reducing malaria mortality and morbidity over the last decade, malaria persists in the forested and mountainous areas of the central and southern provinces, where more than 50% of the clinical cases and 90% of severe cases and malaria deaths occur. Methods Between July 2005 and September 2006, a multi-method study, triangulating a malariometric cross-sectional survey and qualitative data from focused ethnography, was carried out among the Ra-glai ethnic minority in the hilly forested areas of south-central Vietnam. Results Despite the relatively high malaria burden among the Ra-glai and their general awareness that mosquitoes can transmit an unspecific kind of fever (84.2%), the use of bed nets, distributed free of charge by the national malaria control programme, remains low at the farmers' forest fields where the malaria risk is the highest. However, to meet work requirements during the labour intensive malaria transmission and rainy season, Ra-glai farmers combine living in government supported villages along the road with a second home or shelter at their slash and burn fields located in the forest. Bed net use was 84.6% in the villages but only 52.9% at the forest fields; 20.6% of the respondents slept unprotected in both places. Such low use may be explained by the low perception of the risk for malaria, decreasing the perceived need to sleep protected. Several reasons may account for this: (1) only 15.6% acknowledged the higher risk of contracting malaria in the forest than in the village; (2) perceived mosquito biting times only partially coincided with Anopheles dirus ss and Anopheles minimus A true biting times; (3) the disease locally identified as 'malaria' was hardly perceived as having an impact on forest farmers' daily lives as they were unaware of the specific kind of fevers from which they had suffered even after being diagnosed with malaria at the health centre (20.9%). Conclusions The progressive

Spatial and temporal distribution of falciparum malaria in China

PubMed Central

Lin, Hualiang; Lu, Liang; Tian, Linwei; Zhou, Shuisen; Wu, Haixia; Bi, Yan; Ho, Suzanne C; Liu, Qiyong

2009-01-01

Background Falciparum malaria is the most deadly among the four main types of human malaria. Although great success has been achieved since the launch of the National Malaria Control Programme in 1955, malaria remains a serious public health problem in China. This paper aimed to analyse the geographic distribution, demographic patterns and time trends of falciparum malaria in China. Methods The annual numbers of falciparum malaria cases during 1992–2003 and the individual case reports of each clinical falciparum malaria during 2004–2005 were extracted from communicable disease information systems in China Center for Diseases Control and Prevention. The annual number of cases and the annual incidence were mapped by matching them to corresponding province- and county-level administrative units in a geographic information system. The distribution of falciparum malaria by age, gender and origin of infection was analysed. Time-series analysis was conducted to investigate the relationship between the falciparum malaria in the endemic provinces and the imported falciparum malaria in non-endemic provinces. Results Falciparum malaria was endemic in two provinces of China during 2004–05. Imported malaria was reported in 26 non-endemic provinces. Annual incidence of falciparum malaria was mapped at county level in the two endemic provinces of China: Yunnan and Hainan. The sex ratio (male vs. female) for the number of cases in Yunnan was 1.6 in the children of 0–15 years and it reached 5.7 in the adults over 15 years of age. The number of malaria cases in Yunnan was positively correlated with the imported malaria of concurrent months in the non-endemic provinces. Conclusion The endemic area of falciparum malaria in China has remained restricted to two provinces, Yunnan and Hainan. Stable transmission occurs in the bordering region of Yunnan and the hilly-forested south of Hainan. The age and gender distribution in the endemic area is characterized by the predominance

Performance of Rapid Diagnostic Tests for Plasmodium ovale Malaria in Japanese Travellers

PubMed Central

Tanizaki, Ryutaro; Kato, Yasuyuki; Iwagami, Moritoshi; Kutsuna, Satoshi; Ujiie, Mugen; Takeshita, Nozomi; Hayakawa, Kayoko; Kanagawa, Shuzo; Kano, Shigeyuki; Ohmagari, Norio

2014-01-01

Background: Rapid diagnostic tests (RDTs) are used widely in the diagnosis of malaria. Although the effectiveness of RDTs for malaria has been described in many previous studies, the low performance of RDT particularly for Plasmodium ovale malaria in traveller has rarely been reported. Methods: This was a retrospective cohort study conducted on Japanese travellers diagnosed with malaria at the National Center for Global Health and Medicine between January 2004 and June 2013. The diagnosis of malaria was confirmed by microscopic examination, RDT, and polymerase chain reaction in all patients. The RDTs used in our study were Binax NOW Malaria (Binax Inc., Scarborough, Maine, USA) (BN) and SD Malaria Antigen Pf/Pan (Standard Diagnostics Inc., Korea) (SDMA). We compared the sensitivity of the RDTs to P. ovale malaria and Plasmodium vivax malaria. Results: A total of 153 cases of malaria were observed, 113 of which were found among Japanese travellers. Nine patients with P. ovale malaria and 17 patients with P. vivax malaria undergoing RDTs were evaluated. The overall sensitivity of RDTs for P. ovale malaria and P. vivax malaria was 22.2% and 94.1%, respectively (P < 0.001). The sensitivity of SDMA for P. ovale malaria and P. vivax malaria was 50% and 100%, respectively. The sensitivity of BN for P. vivax malaria was 90.0%, but it was ineffective in detecting the cases of P. ovale malaria. Conclusions: The sensitivity of RDTs was not high enough to diagnose P. ovale malaria in our study. In order not to overlook P. ovale malaria, therefore, microscopic examination is indispensable. PMID:25473374

Malaria

MedlinePlus

Malaria is a serious disease caused by a parasite. You get it when an infected mosquito bites you. Malaria is a major cause of death worldwide, but ... at risk. There are four different types of malaria caused by four related parasites. The most deadly ...

Biodiversity Can Help Prevent Malaria Outbreaks in Tropical Forests

PubMed Central

Laporta, Gabriel Zorello; de Prado, Paulo Inácio Knegt Lopez; Kraenkel, Roberto André; Coutinho, Renato Mendes; Sallum, Maria Anice Mureb

2013-01-01

Background Plasmodium vivax is a widely distributed, neglected parasite that can cause malaria and death in tropical areas. It is associated with an estimated 80–300 million cases of malaria worldwide. Brazilian tropical rain forests encompass host- and vector-rich communities, in which two hypothetical mechanisms could play a role in the dynamics of malaria transmission. The first mechanism is the dilution effect caused by presence of wild warm-blooded animals, which can act as dead-end hosts to Plasmodium parasites. The second is diffuse mosquito vector competition, in which vector and non-vector mosquito species compete for blood feeding upon a defensive host. Considering that the World Health Organization Malaria Eradication Research Agenda calls for novel strategies to eliminate malaria transmission locally, we used mathematical modeling to assess those two mechanisms in a pristine tropical rain forest, where the primary vector is present but malaria is absent. Methodology/Principal Findings The Ross–Macdonald model and a biodiversity-oriented model were parameterized using newly collected data and data from the literature. The basic reproduction number () estimated employing Ross–Macdonald model indicated that malaria cases occur in the study location. However, no malaria cases have been reported since 1980. In contrast, the biodiversity-oriented model corroborated the absence of malaria transmission. In addition, the diffuse competition mechanism was negatively correlated with the risk of malaria transmission, which suggests a protective effect provided by the forest ecosystem. There is a non-linear, unimodal correlation between the mechanism of dead-end transmission of parasites and the risk of malaria transmission, suggesting a protective effect only under certain circumstances (e.g., a high abundance of wild warm-blooded animals). Conclusions/Significance To achieve biological conservation and to eliminate Plasmodium parasites in human populations

Effectiveness of Implementation of Electronic Malaria Information System as the National Malaria Surveillance System in Thailand

PubMed Central

2016-01-01

Background In moving toward malaria elimination, one strategy is to implement an active surveillance system for effective case management. Thailand has developed and implemented the electronic Malaria Information System (eMIS) capturing individualized electronic records of suspected or confirmed malaria cases. Objective The main purpose of this study was to determine how well the eMIS improves the quality of Thailand’s malaria surveillance system. In particular, the focus of the study was to evaluate the effectiveness of the eMIS in terms of the system users’ perception and the system outcomes (ie, quality of data) regarding the management of malaria patients. Methods A mixed-methods technique was used with the framework based on system effectiveness attributes: data quality, timeliness, simplicity, acceptability, flexibility, stability, and usefulness. Three methods were utilized: data records review, survey of system users, and in-depth interviews with key stakeholders. From the two highest endemic provinces, paper forms matching electronic records of 4455 noninfected and 784 malaria-infected cases were reviewed. Web-based anonymous questionnaires were distributed to all 129 eMIS data entry staff throughout Thailand, and semistructured interviews were conducted with 12 management-level officers. Results The eMIS is well accepted by system users at both management and operational levels. The data quality has enabled malaria personnel to perform more effective prevention and control activities. There is evidence of practices resulting in inconsistencies and logical errors in data reporting. Critical data elements were mostly completed, except for a few related to certain dates and area classifications. Timeliness in reporting a case to the system was acceptable with a delay of 3-4 days. The evaluation of quantitative and qualitative data confirmed that the eMIS has high levels of simplicity, acceptability, stability, and flexibility. Conclusions Overall, the

Could the RTS,S/AS01 meningitis safety signal really be a protective effect of rabies vaccine?

PubMed

Gessner, Bradford D; Knobel, Darryn L; Conan, Anne; Finn, Adam

2017-02-01

The RTS,S/AS01 malaria vaccine has been associated with meningitis and cerebral malaria safety signals. Key characteristics of the meningitis signal include presence, in the 5-17month but not the 6-12week age group, of delayed and variable meningitis onset after vaccination, and multiple etiologies. For both meningitis and cerebral malaria, the 5-17month old age group control arm had abnormally low incidences while other arms in both age groups had meningitis and cerebral malaria incidences similar to background rates. No single hypothesis postulating an adverse effect from RTS,S/AS01 unites these observations. Unlike the 6-12week group, the control population in the 5-17month old age group received rabies vaccine. This raises the possibility that non-specific rabies vaccine effects had a protective effect against central nervous system infection, a hypothesis consistent with the epidemiologic data. The lack of a confirmed biologic mechanism for such an effect emphasizes the need for additional studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Progress towards malaria elimination in Sabang Municipality, Aceh, Indonesia

PubMed Central

2013-01-01

Background Indonesia has set 2030 as its deadline for elimination of malaria transmission in the archipelago, with regional deadlines established according to present levels of malaria endemicity and strength of health infrastructure. The Municipality of Sabang which historically had one of the highest levels of malaria in Aceh province aims to achieve elimination by the end of 2013. Method From 2008 to 2010, baseline surveys of malaria interventions, mapping of all confirmed malaria cases, categorization of residual foci of malaria transmission and vector surveys were conducted in Sabang, Aceh, a pilot district for malaria elimination in Indonesia. To inform future elimination efforts, mass screening from the focal areas to measure prevalence of malaria with both microscopy and PCR was conducted. G6PD deficiency prevalence was also measured. Result Despite its small size, a diverse mixture of potential malaria vectors were documented in Sabang, including Anopheles sundaicus, Anopheles minimus, Anopheles aconitus and Anopheles dirus. Over a two-year span, the number of sub-villages with ongoing malaria transmission reduced from 61 to 43. Coverage of malaria diagnosis and treatment, IRS, and LLINs was over 80%. Screening of 16,229 residents detected 19 positive people, for a point prevalence of 0.12%. Of the 19 positive cases, three symptomatic infections and five asymptomatic infections were detected with microscopy and 11 asymptomatic infections were detected with PCR. Of the 19 cases, seven were infected with Plasmodium falciparum, 11 were infected with Plasmodium vivax, and one subject was infected with both species. Analysis of the 937 blood samples for G6PD deficiency revealed two subjects (0.2%) with deficient G6PD. Discussion The interventions carried out by the government of Sabang have dramatically reduced the burden of malaria over the past seven years. The first phase, carried out between 2005 and 2007, included improved malaria diagnosis, introduction

Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure.

PubMed

Kessler, Anne; Campo, Joseph J; Harawa, Visopo; Mandala, Wilson L; Rogerson, Stephen J; Mowrey, Wenzhu B; Seydel, Karl B; Kim, Kami

2018-04-25

Antibody immunity is thought to be essential to prevent severe Plasmodium falciparum infection, but the exact correlates of protection are unknown. Over time, children in endemic areas acquire non-sterile immunity to malaria that correlates with development of antibodies to merozoite invasion proteins and parasite proteins expressed on the surface of infected erythrocytes. A 1000 feature P. falciparum 3D7 protein microarray was used to compare P. falciparum-specific seroreactivity during acute infection and 30 days after infection in 23 children with uncomplicated malaria (UM) and 25 children with retinopathy-positive cerebral malaria (CM). All children had broad P. falciparum antibody reactivity during acute disease. IgM reactivity decreased and IgG reactivity increased in convalescence. Antibody reactivity to CIDR domains of "virulent" PfEMP1 proteins was low with robust reactivity to the highly conserved, intracellular ATS domain of PfEMP1 in both groups. Although children with UM and CM differed markedly in parasite burden and PfEMP1 exposure during acute disease, neither acute nor convalescent PfEMP1 seroreactivity differed between groups. Greater seroprevalence to a conserved Group A-associated ICAM binding extracellular domain was observed relative to linked extracellular CIDRα1 domains in both case groups. Pooled immune IgG from Malawian adults revealed greater reactivity to PfEMP1 than observed in children. Children with uncomplicated and cerebral malaria have similar breadth and magnitude of P. falciparum antibody reactivity. The utility of protein microarrays to measure serological recognition of polymorphic PfEMP1 antigens needs to be studied further, but the study findings support the hypothesis that conserved domains of PfEMP1 are more prominent targets of cross reactive antibodies than variable domains in children with symptomatic malaria. Protein microarrays represent an additional tool to identify cross-reactive Plasmodium antigens including Pf

Role of Serum Lactate and Malarial Retinopathy in Prognosis and Outcome of Falciparum and Vivax Cerebral Malaria: A Prospective Cohort Study in Adult Assamese Tribes

PubMed Central

Chaudhari, Kaustubh Suresh; Uttarwar, Sahil Prashant; Tambe, Nikhil Narayan; Sharma, Rohan S; Takalkar, Anant Arunrao

2016-01-01

Introduction: There is no comprehensive data or studies relating to clinical presentation and prognosis of cerebral malaria (CM) in the tribal settlements of Assam. High rates of transmission and deaths from complicated malaria guided us to conduct a prospective observational cohort study to evaluate the factors associated with poor outcome and prognosis in patients of CM. Materials and Methods: We admitted 112 patients to the Bandarpara and Damodarpur Tribal Health Centers (THCs) between 2011 and 2013 with a strict diagnosis of CM. We assessed the role of clinical, fundoscopy and laboratory findings (mainly lactic acid) in the immediate outcome in terms of death and recovery, duration of hospitalization, neurocognitive impairment, cranial nerve palsies and focal neurological deficit. Results: The case fatality rate of CM was 33.03% and the prevalence of residual neurological sequelae at discharge was 16.07%. These are significantly higher than the previous studies. The mortality rate and neurological complications rate in patients with retinal whitening was 38.46% and 23.07%, with vessel changes was 25% and 18.75%, with retinal hemorrhage was 55.55% and 11.11% and with hyperlactatemia was 53.85% and 18.46%, respectively. Three patients of papilledema alone died. Conclusion: Our study suggests a strong correlation between hyperlactatemia, retinal changes (whitening, vessel changes and hemorrhage) and depth and duration of coma with longer duration of hospitalization, increased mortality, neurological sequelae and death. Plasmodium vivax mono-infection as a cause of CM has been confirmed. Prognostic evaluation of CM is useful for judicious allocation of resources in the THC. PMID:27293360

Role of Serum Lactate and Malarial Retinopathy in Prognosis and Outcome of Falciparum and Vivax Cerebral Malaria: A Prospective Cohort Study in Adult Assamese Tribes.

PubMed

Chaudhari, Kaustubh Suresh; Uttarwar, Sahil Prashant; Tambe, Nikhil Narayan; Sharma, Rohan S; Takalkar, Anant Arunrao

2016-01-01

There is no comprehensive data or studies relating to clinical presentation and prognosis of cerebral malaria (CM) in the tribal settlements of Assam. High rates of transmission and deaths from complicated malaria guided us to conduct a prospective observational cohort study to evaluate the factors associated with poor outcome and prognosis in patients of CM. We admitted 112 patients to the Bandarpara and Damodarpur Tribal Health Centers (THCs) between 2011 and 2013 with a strict diagnosis of CM. We assessed the role of clinical, fundoscopy and laboratory findings (mainly lactic acid) in the immediate outcome in terms of death and recovery, duration of hospitalization, neurocognitive impairment, cranial nerve palsies and focal neurological deficit. The case fatality rate of CM was 33.03% and the prevalence of residual neurological sequelae at discharge was 16.07%. These are significantly higher than the previous studies. The mortality rate and neurological complications rate in patients with retinal whitening was 38.46% and 23.07%, with vessel changes was 25% and 18.75%, with retinal hemorrhage was 55.55% and 11.11% and with hyperlactatemia was 53.85% and 18.46%, respectively. Three patients of papilledema alone died. Our study suggests a strong correlation between hyperlactatemia, retinal changes (whitening, vessel changes and hemorrhage) and depth and duration of coma with longer duration of hospitalization, increased mortality, neurological sequelae and death. Plasmodium vivax mono-infection as a cause of CM has been confirmed. Prognostic evaluation of CM is useful for judicious allocation of resources in the THC.

Seasonal prevalence of malaria in West Sumba district, Indonesia

PubMed Central

Syafruddin, Din; Krisin; Asih, Puji; Sekartuti; Dewi, Rita M; Coutrier, Farah; Rozy, Ismail E; Susanti, Augustina I; Elyazar, Iqbal RF; Sutamihardja, Awalludin; Rahmat, Agus; Kinzer, Michael; Rogers, William O

2009-01-01

Background Accurate information about the burden of malaria infection at the district or provincial level is required both to plan and assess local malaria control efforts. Although many studies of malaria epidemiology, immunology, and drug resistance have been conducted at many sites in Indonesia, there is little published literature describing malaria prevalence at the district, provincial, or national level. Methods Two stage cluster sampling malaria prevalence surveys were conducted in the wet season and dry season across West Sumba, Nusa Tenggara Province, Indonesia. Results Eight thousand eight hundred seventy samples were collected from 45 sub-villages in the surveys. The overall prevalence of malaria infection in the West Sumba District was 6.83% (95% CI, 4.40, 9.26) in the wet season and 4.95% (95% CI, 3.01, 6.90) in the dry. In the wet season Plasmodium falciparum accounted for 70% of infections; in the dry season P. falciparum and Plasmodium vivax were present in equal proportion. Malaria prevalence varied substantially across the district; prevalences in individual sub-villages ranged from 0–34%. The greatest malaria prevalence was in children and teenagers; the geometric mean parasitaemia in infected individuals decreased with age. Malaria infection was clearly associated with decreased haemoglobin concentration in children under 10 years of age, but it is not clear whether this association is causal. Conclusion Malaria is hypoendemic to mesoendemic in West Sumba, Indonesia. The age distribution of parasitaemia suggests that transmission has been stable enough to induce some clinical immunity. These prevalence data will aid the design of future malaria control efforts and will serve as a baseline against which the results of current and future control efforts can be assessed. PMID:19134197

A rapid malaria appraisal in the Venezuelan Amazon

PubMed Central

2009-01-01

Background While the federal state of Amazonas bears the highest risk for malaria in Venezuela (2007: 68.4 cases/1000 inhabitants), little comprehensive information about the malaria situation is available from this area. The purpose of this rapid malaria appraisal (RMA) was to provide baseline data about malaria and malaria control in Amazonas. Methods The RMA methodology corresponds to a rapid health impact assessment (HIA) as described in the 1999 Gothenburg consensus. In conjunction with the actors of the malaria surveillance system, all useful data and information, which were accessible within a limited time-frame of five visits to Amazonas, were collected, analysed and interpreted. Results Mortality from malaria is low (< 1 in 105) and slide positivity rates have stayed at the same level for the last two decades (15% ± 6% (SD)). Active case detection accounts for ca. 40% of slides taken. The coverage of the censured population with malaria notification points (NPs) has been achieved in recent years. The main parasite is Plasmodium vivax (84% of cases). The proportion of Plasmodium falciparum is on the decline, possibly driven by the introduction of cost-free artemisinin-based combination therapy (ACT) (1988: 33.4%; 2007: 15.4%). Monitoring and documentation is complete, systematic and consistent, but poorly digitalized. Malaria transmission displayed a visible lag behind rainfall in the capital municipality of Atures, but not in the other municipalities. In comparison to reference microscopy, quality of field microscopy and rapid diagnostic tests (RDTs) is suboptimal (kappa < 0.75). Hot spots of malaria risk were seen in some indigenous ethnic groups. Conflicting strategies in respect of training of community health workers (CHW) and the introduction of new diagnostic tools (RDTs) were observed. Conclusion Malaria control is possible, even in tropical rain forest areas, if the health system is working adequately. Interventions have to be carefully designed

School-based surveys of malaria in Oromia Regional State, Ethiopia: a rapid survey method for malaria in low transmission settings

PubMed Central

2011-01-01

Background In Ethiopia, malaria transmission is seasonal and unstable, with both Plasmodium falciparum and Plasmodium vivax endemic. Such spatial and temporal clustering of malaria only serves to underscore the importance of regularly collecting up-to-date malaria surveillance data to inform decision-making in malaria control. Cross-sectional school-based malaria surveys were conducted across Oromia Regional State to generate up-to-date data for planning malaria control interventions, as well as monitoring and evaluation of operational programme implementation. Methods Two hundred primary schools were randomly selected using a stratified and weighted sampling frame; 100 children aged five to 18 years were then randomly chosen within each school. Surveys were carried out in May 2009 and from October to December 2009, to coincide with the peak of malaria transmission in different parts of Oromia. Each child was tested for malaria by expert microscopy, their haemoglobin measured and a simple questionnaire completed. Satellite-derived environmental data were used to assess ecological correlates of Plasmodium infection; Bayesian geostatistical methods and Kulldorff's spatial scan statistic were employed to investigate spatial heterogeneity. Results A total 20,899 children from 197 schools provided blood samples, two selected schools were inaccessible and one school refused to participate. The overall prevalence of Plasmodium infection was found to be 0.56% (95% CI: 0.46-0.67%), with 53% of infections due to P. falciparum and 47% due to P. vivax. Of children surveyed, 17.6% (95% CI: 17.0-18.1%) were anaemic, while 46% reported sleeping under a mosquito net the previous night. Malaria was found at 30 (15%) schools to a maximum elevation of 2,187 metres, with school-level Plasmodium prevalence ranging between 0% and 14.5%. Although environmental variables were only weakly associated with P. falciparum and P. vivax infection, clusters of infection were identified within

GCRBS score: a new scoring system for predicting outcome in severe falciparum malaria.

PubMed

Mohapatra, Biranchi Narayan; Jangid, Sanjay Kumar; Mohanty, Rina

2014-01-01

Severe falciparum malaria is a critical illness resulting in multi-organ dysfunction and death. Severe malaria is defined by the World Health Organisation as a qualitative variable. The purpose of this study is to devise a scoring system for predicting outcome in severe falciparum malaria. 112 cases of severe falciparum malaria diagnosed as per the WHO criteria, were evaluated to determine the parameters which were significantly associated with mortality. Of all the parameters studied, five variables namely cerebral malaria (GCS < 11), Renal failure (Creatinine > 3 mg/dl), Respiratory distress (Respiratory rate > 24/min), Jaundice (Bilirubin >10 mg/dl) and Shock (Systolic BP < 90 mm of Hg) were all found to be associated with a poor prognosis. The five selected parameters were analysed using the Odds ratio and a new scoring system named as GCRBS score was designed with a possible score from 0-10. With a cut-off score of 5, the GCRBS score predicted mortality with a sensitivity of 85.3% and a specificity of 95.6%. The GCRBS score is easy to calculate and apply. Of the 5 parameters, 3 are clinical which can be determined at bedside and only 2 are biochemical which can be done in any laboratory.The most important advantage of this scoring system is that all the 5 parameters are to be assessed quantitatively for allotting a score, which would eliminate the possibility of observer bias.

Malaria Rapid Diagnostic Tests and Malaria Microscopy for Guiding Malaria Treatment of Uncomplicated Fevers in Nigeria and Prereferral Cases in 3 African Countries

PubMed Central

Falade, Catherine O.; Ajayi, IkeOluwapo O.; Nsungwa-Sabiiti, Jesca; Siribié, Mohamadou; Diarra, Amidou; Sermé, Luc; Afonne, Chinenye; Yusuf, Oyindamola B.; Gansane, Zakaria; Jegede, Ayodele S.; Singlovic, Jan; Gomes, Melba

2016-01-01

Background. The World Health Organization recommends that malaria treatment be based on demonstration of the infecting Plasmodium parasite specie. Malaria rapid diagnostic tests (RDTs) are recommended at community points of care because they are accurate and rapid. We report on parasitological results in a malaria study in selected rural communities in 3 African countries. Methods. In Nigeria, community health workers (CHWs) performed RDTs (SD-Bioline) and thick blood smears on all children suspected to have malaria. Malaria RDT-positive children able to swallow received artemisinin-based combination therapy (Coartem). In all countries, children unable to take oral drugs received prereferral rectal artesunate irrespective of RDT result and were referred to the nearest health facility. Thick blood smears and RDTs were usually taken at hospital admission. In Nigeria and Burkina Faso, RDT cassettes and blood smears were re-read by an experienced investigator at study end. Results. Trained CHWs enrolled 2148 children in Nigeria. Complete parasitological data of 1860 (86.6%) enrollees were analyzed. The mean age of enrollees was 30.4 ± 15.7 months. The prevalence of malaria parasitemia in the study population was 77.8% (1447/1860), 77.6% (1439/1855), and 54.1% (862/1593) by RDT performed by CHWs vs an expert clinical research assistant vs microscopy (gold standard), respectively. Geometric mean parasite density was 6946/µL (range, 40–436 450/µL). There were 49 cases of RDT false-negative results with a parasite density range of 40–54 059/µL. False-negative RDT results with high parasitemia could be due to non-falciparum infection or result from a prozone effect. Sensitivity and specificity of SD-Bioline RDT results as read by CHWs were 94.3% and 41.6%, respectively, while the negative and positive predictive values were 86.1% and 65.6%, respectively. The level of agreement in RDT reading by the CHWs and experienced research staff was 86.04% and κ

Knowledge, attitudes and practices of malaria in Colombia

PubMed Central

2014-01-01

Background Although Colombia has witnessed an important decrease in malaria transmission, the disease remains a public health problem with an estimated ~10 million people currently living in areas with malaria risk and ~61,000 cases reported in 2012. This study aimed to determine and compare the level of knowledge, attitudes and practices (KAP) about malaria in three endemic communities of Colombia to provide the knowledge framework for development of new intervention strategies for malaria elimination. Methods A cross-sectional KAP survey was conducted in the municipalities of Tierralta, Buenaventura and Tumaco, categorized according to high risk (HR) and moderate risk (MR) based on the annual parasite index (API). Surveys were managed using REDCap and analysed using MATLAB and GraphPad Prism. Results A total of 267 residents, mostly women (74%) were surveyed. Although no differences were observed on the knowledge of classical malaria symptoms between HR and MR regions, significant differences were found in knowledge and attitudes about transmission mechanisms, anti-malarial use and malaria diagnosis. Most responders in both regions (93.5% in MR, and 94.3% in HR areas) indicated use of insecticide-treated nets (ITNs) to protect themselves from malaria, and 75.5% of responders in HR indicated they did nothing to prevent malaria transmission outdoors. Despite a high level of knowledge in the study regions, significant gaps persisted relating to practices. Self-medication and poor adherence to treatment, as well as lack of both indoor and outdoor vector control measures, were significantly associated with higher malaria risk. Conclusions Although significant efforts are currently being made by the Ministry of Health to use community education as one of the main components of the control strategy, these generic education programmes may not be applicable to all endemic regions of Colombia given the substantial geographic, ethnic and cultural diversity. PMID:24885909

Discourse on malaria elimination: where do forcibly displaced persons fit in these discussions?

PubMed Central

2013-01-01

Background Individuals forcibly displaced are some of the poorest people in the world, living in areas where infrastructure and services are at a bare minimum. Out of a total of 10,549,686 refugees protected and assisted by the United Nations High Commissioner for Refugees globally, 6,917,496 (65.6%) live in areas where malaria is transmitted. Historically, national malaria control programmes have excluded displaced populations. Results The current discourse on malaria elimination rarely includes discussion of forcibly displaced persons who reside within malaria-eliminating countries. Of the 100 malaria-endemic countries, 64 are controlling malaria and 36 are in some stage of elimination. Of these, 30 malaria-controlling countries and 13 countries in some phase of elimination host displaced populations of ≥50,000, even though 13 of the 36 (36.1%) malaria-elimination countries host displaced populations of ≥50,000 people. Discussion Now is the time for the malaria community to incorporate forcibly displaced populations residing within malarious areas into malaria control activities. Beneficiaries, whether they are internally displaced persons or refugees, should be viewed as partners in the delivery of malaria interventions and not simply as recipients. Conclusion Until equitable and sustainable malaria control includes everyone residing in an endemic area, the goal of malaria elimination will not be met. PMID:23575209

Malaria in rural Mozambique. Part II: children admitted to hospital

PubMed Central

Bassat, Quique; Guinovart, Caterina; Sigaúque, Betuel; Aide, Pedro; Sacarlal, Jahit; Nhampossa, Tacilta; Bardají, Azucena; Nhacolo, Ariel; Macete, Eusébio; Mandomando, Inácio; Aponte, John J; Menéndez, Clara; Alonso, Pedro L

2008-01-01

Background Characterization of severe malaria cases on arrival to hospital may lead to early recognition and improved management. Minimum community based-incidence rates (MCBIRs) complement hospital data, describing the malaria burden in the community. Methods A retrospective analysis of all admitted malaria cases to a Mozambican rural hospital between June 2003 and May 2005 was conducted. Prevalence and case fatality rates (CFR) for each sign and symptom were calculated. Logistic regression was used to identify variables which were independent risk factors for death. MCBIRs for malaria and severe malaria were calculated using data from the Demographic Surveillance System. Results Almost half of the 8,311 patients admitted during the study period had malaria and 13,2% had severe malaria. Children under two years accounted for almost 60% of all malaria cases. CFR for malaria was 1.6% and for severe malaria 4.4%. Almost 19% of all paediatric hospital deaths were due to malaria. Prostration (55.0%), respiratory distress (41.1%) and severe anaemia (17.3%) were the most prevalent signs among severe malaria cases. Severe anaemia and inability to look for mother's breast were independent risk factors for death in infants younger than eight months. For children aged eight months to four years, the risk factors were malnutrition, hypoglycaemia, chest indrawing, inability to sit and a history of vomiting. MCBIRs for severe malaria cases were highest in children aged six months to two years of age. MCBIRs for severe malaria per 1,000 child years at risk for the whole study period were 27 in infants, 23 in children aged 1 to <5 years and two in children aged ≥5 years. Conclusion Malaria remains the number one cause of admission in this area of rural Mozambique, predominantly affecting young children, which are also at higher risk of dying. Measures envisaged to protect children during their first two years of life are likely to have a greater impact than at any other age

Malaria resurgence: a systematic review and assessment of its causes

PubMed Central

2012-01-01

Background Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes. Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics. Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past. Methods A systematic review of the literature was conducted to identify historical malaria resurgence events. All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance. Results The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%). Over half of the events (44/75 = 59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance. Conclusions Given that most malaria resurgences have been linked to weakening of control programmes, there is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining today’s successful malaria control programmes. PMID:22531245

Malaria.

ERIC Educational Resources Information Center

Dupasquier, Isabelle

1989-01-01

Malaria, the greatest pandemia in the world, claims an estimated one million lives each year in Africa alone. While it may still be said that for the most part malaria is found in what is known as the world's poverty belt, cases are now frequently diagnosed in western countries. Due to resistant strains of malaria which have developed because of…

A Field Trial to Assess a Blood-Stage Malaria Vaccine

PubMed Central

Thera, Mahamadou A.; Doumbo, Ogobara K.; Coulibaly, Drissa; Laurens, Matthew B.; Ouattara, Amed; Kone, Abdoulaye K.; Guindo, Ando B.; Traore, Karim; Traore, Idrissa; Kouriba, Bourema; Diallo, Dapa A.; Diarra, Issa; Daou, Modibo; Dolo, Amagana; Tolo, Youssouf; Sissoko, Mahamadou S.; Niangaly, Amadou; Sissoko, Mady; Takala-Harrison, Shannon; Lyke, Kirsten E.; Wu, Yukun; Blackwelder, William C.; Godeaux, Olivier; Vekemans, Johan; Dubois, Marie-Claude; Ballou, W. Ripley; Cohen, Joe; Thompson, Darby; Dube, Tina; Soisson, Lorraine; Diggs, Carter L.; House, Brent; Lanar, David E.; Dutta, Sheetij; Heppner, D. Gray; Plowe, Christopher V.

2011-01-01

BACKGROUND Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02A, a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. METHODS In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. RESULTS The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P = 0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P = 0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. CONCLUSIONS On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. PMID:21916638

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65.

PubMed

Martins, Yuri C; Freeman, Brandi D; Akide Ndunge, Oscar B; Weiss, Louis M; Tanowitz, Herbert B; Desruisseaux, Mahalia S

2016-11-01

Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10 6 PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Early Childhood Malaria Prevention and Children's Patterns of School Leaving in the Gambia

ERIC Educational Resources Information Center

Zuilkowski, Stephanie S.; Jukes, Matthew C. H.

2014-01-01

Background: Early childhood malaria is often fatal, but its impact on the development and education of survivors has not received much attention. Malaria impacts cognitive development in a number of ways that may impact later educational participation. Aims: In this study, we examine the long-term educational effects of preventing early childhood…

Placental Plasmodium falciparum malaria infection: Operational accuracy of HRP2 rapid diagnostic tests in a malaria endemic setting

PubMed Central

2011-01-01

Background Malaria has a negative effect on the outcome of pregnancy. Pregnant women are at high risk of severe malaria and severe haemolytic anaemia, which contribute 60-70% of foetal and perinatal losses. Peripheral blood smear microscopy under-estimates sequestered placental infections, therefore malaria rapid diagnostic tests (RDTs) detecting histidine rich protein-2 antigen (HRP-2) in peripheral blood are a potential alternative. Methods HRP-2 RDTs accuracy in detecting malaria in pregnancy (MIP >28 weeks gestation) and placental Plasmodium falciparum malaria (after childbirth) were conducted using Giemsa microscopy and placental histopathology respectively as the reference standard. The study was conducted in Mbale Hospital, using the midwives to perform and interpret the RDT results. Discordant results samples were spot checked using PCR techniques. Results Among 433 febrile women tested, RDTs had a sensitivity of 96.8% (95% CI 92-98.8), specificity of 73.5% (95% CI 67.8-78.6), a positive predictive value (PPV) of 68.0% (95% CI 61.4-73.9), and negative predictive value (NPV) of 97.5% (95% CI 94.0-99.0) in detecting peripheral P. falciparum malaria during pregnancy. At delivery, in non-symptomatic women, RDTs had a 80.9% sensitivity (95% CI 57.4-93.7) and a 87.5% specificity (95%CI 80.9-92.1), PPV of 47.2% (95% CI 30.7-64.2) and NPV of 97.1% (95% CI 92.2-99.1) in detecting placental P. falciparum infections among 173 samples. At delivery, 41% of peripheral infections were detected by microscopy without concurrent placental infection. The combination of RDTs and microscopy improved the sensitivity to 90.5% and the specificity to 98.4% for detecting placental malaria infection (McNemar's X 2> 3.84). RDTs were not superior to microscopy in detecting placental infection (McNemar's X 2< 3.84). Presence of malaria in pregnancy and active placental malaria infection were 38% and 12% respectively. Placental infections were associated with poor pregnancy outcome [pre

A preliminary study of placental umbilical cord whole blood transfusion in under resourced patients with malaria in the background of anaemia.

PubMed

Bhattacharya, Niranjan

2006-03-23

Malaria is an annual killer of over one million people globally and its essential co-morbidity is anaemia. Cord blood, because of its rich mix of foetal and adult haemoglobin, high platelet and WBC counts, hypo-antigenic nature, altered metabolic profile and high affinity for oxygen as well as its anti-malarial effect, is an ideal choice in malaria with anaemia, necessitating blood transfusion. This paper presents an alternative protocol for fresh whole blood/packed cell transfusion from the hospital's biological waste resources, i.e., the placenta, after the birth of a healthy baby from a healthy mother. This collected blood was routinely transfused to patients admitted in our hospital with severe anaemia in the background of confirmed malaria. 94 units of placental umbilical cord whole blood were collected after lower uterine caesarean section (LUCS) from consenting mothers (from 1st April 1999 to April 2005), and safely transfused to 39 informed, consenting patients (age varying from 8 to 72 years). The collected volume of cord blood from each placenta (Unit) varied from 52 ml to 143 ml, with a mean packed cell volume of 48.9 +/- 4.1 SD and a mean haemoglobin concentration of 16.4 Gm percent +/- 1.6 Gm percent SD. The blood was immediately transfused after following the standard adult blood transfusion protocol of screening and cross-matching between the donor and the recipient. On occasion, the collected cord blood was preserved in the refrigerator, if no volunteer was readily available, and transfused within 72 hours of collection. Cord blood transfusion was tested on twenty two patients infected with Plasmodium falciparum and 17 patients with Plasmodium vivax. For inclusion in this study, the patient's plasma haemoglobin had to be 8 gm percent or less (the pre-transfusion haemoglobin in the malaria-infected patients in this series varied from 5.4 gm/dl to 7.9 gm/dl). The rise of haemoglobin within 72 hours of two units of freshly collected cord blood

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria

PubMed Central

Dobbs, Katherine R.; Embury, Paula; Odada, Peter S.; Rosa, Bruce A.; Mitreva, Makedonka; Kazura, James W.; Dent, Arlene E.

2017-01-01

BACKGROUND. Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood. METHODS. We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community. RESULTS. Acute malaria was marked by elevated levels of proinflammatory and regulatory cytokines and expansion of the inflammatory “intermediate” monocyte subset that returned to levels of healthy asymptomatic children 6 weeks later. Monocytes displayed activated phenotypes during acute malaria, with changes in surface expression of markers important to innate and adaptive immunity. Functionally, acute malaria monocytes and monocytes from asymptomatic infected children had impaired phagocytosis of P. falciparum–infected erythrocytes relative to asymptomatic children with no blood-stage infection. Monocytes from both acute malaria and recovery time points displayed strong and equivalent cytokine responsiveness to innate immune agonists that were independent of infection status. Monocyte transcriptional profiles revealed regulated and balanced proinflammatory and antiinflammatory and altered phagocytosis gene expression patterns distinct from malaria-naive monocytes. CONCLUSION. These observations provide insights into monocyte functions and the innate immune response during uncomplicated malaria and suggest that asymptomatic parasitemia in children is not clinically benign. FUNDING. Support for this work was provided by NIH/National Institute of Allergy and Infectious Diseases (R01AI095192

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

PubMed

Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

2017-01-01

Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

Cost-effectiveness analysis of malaria chemoprophylaxis for travellers to West-Africa

PubMed Central

2010-01-01

Background The importation of malaria to non-endemic countries remains a major cause of travel-related morbidity and a leading cause of travel-related hospitalizations. Currently they are three priority medications for malaria prophylaxis to West Africa: mefloquine, atovaquone/proguanil and doxycycline. We investigate the cost effectiveness of a partial reimbursement of the cheapest effective malaria chemoprophylaxis (mefloquine) for travellers to high risk areas of malaria transmission compared with the current situation of no reimbursement. Methods This study is a cost-effectiveness analysis based on malaria cases imported from West Africa to Switzerland from the perspective of the Swiss health system. We used a decision tree model and made a literature research on the components of travel related malaria. The main outcome measure was the cost effectiveness of malaria chemoprophylaxis reimbursement based on malaria and deaths averted. Results Using a program where travellers would be reimbursed for 80% of the cost of the cheapest malaria chemoprophylaxis is dominant (i.e. cost saving and more effective than the current situation) using the assumption that currently 68.7% of travellers to West Africa use malaria chemoprophylaxis. If the current usage of malaria chemoprophylaxis would be higher, 82.4%, the incremental cost per malaria case averted is € 2'302. The incremental cost of malaria death averted is € 191'833. The most important factors influencing the model were: the proportion of travellers using malaria chemoprophylaxis, the probability of contracting malaria without malaria chemoprophylaxis, the cost of the mefloquine regimen, the decrease in the number of travellers without malaria chemoprophylaxis in the reimbursement strategy. Conclusions This study suggests that a reimbursement of 80% of the cost of the cheapest effective malaria chemoprophylaxis (mefloquine) for travellers from Switzerland to West Africa is highly effective in terms of malaria

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes.

PubMed

Hernandez-Valladares, Maria; Rihet, Pascal; Iraqi, Fuad A

2014-01-01

There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific host-pathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development.

Impact of malaria during pregnancy on pregnancy outcomes in a Ugandan prospective cohort with intensive malaria screening and prompt treatment

PubMed Central

2013-01-01

Background Malaria in pregnancy (MiP) is a major public health problem in endemic areas of sub-Saharan Africa and has important consequences on birth outcome. Because MiP is a complex phenomenon and malaria epidemiology is rapidly changing, additional evidence is still required to understand how best to control malaria. This study followed a prospective cohort of pregnant women who had access to intensive malaria screening and prompt treatment to identify factors associated with increased risk of MiP and to analyse how various characteristics of MiP affect delivery outcomes. Methods Between October 2006 and May 2009, 1,218 pregnant women were enrolled in a prospective cohort. After an initial assessment, they were screened weekly for malaria. At delivery, blood smears were obtained from the mother, placenta, cord and newborn. Multivariate analyses were performed to analyse the association between mothers’ characteristics and malaria risk, as well as between MiP and birth outcome, length and weight at birth. This study is a secondary analysis of a trial registered with ClinicalTrials.gov, number NCT00495508. Results Overall, 288/1,069 (27%) mothers had 345 peripheral malaria infections. The risk of peripheral malaria was higher in mothers who were younger, infected with HIV, had less education, lived in rural areas or reported no bed net use, whereas the risk of placental infection was associated with more frequent malaria infections and with infection during late pregnancy. The risk of pre-term delivery and of miscarriage was increased in mothers infected with HIV, living in rural areas and with MiP occurring within two weeks of delivery. In adjusted analysis, birth weight but not length was reduced in babies of mothers exposed to MiP (−60g, 95%CI: -120 to 0 for at least one infection and -150 g, 95%CI: -280 to −20 for >1 infections). Conclusions In this study, the timing, parasitaemia level and number of peripherally-detected malaria infections, but not the

Is Plasmodium vivax Malaria a Severe Malaria?: A Systematic Review and Meta-Analysis

PubMed Central

Naing, Cho; Whittaker, Maxine A.; Nyunt Wai, Victor; Mak, Joon Wah

2014-01-01

Background Plasmodium vivax is one of the major species of malaria infecting humans. Although emphasis on P. falciparum is appropriate, the burden of vivax malaria should be given due attention. This study aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection. Methods/Principal Findings We searched relevant studies in electronic databases. The main outcomes required for inclusion in the review were mortality, severe malaria (SM) and severe anaemia (SA). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Overall, 26 studies were included. The main meta-analysis was restricted to the high quality studies. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04–5.68, I 2:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83–5.1, I 2:83%), the 5–15 year-age group (OR: 0.6, 95% CI: 0.31–1.16, I 2:81%) and adults (OR: 0.83, 95% CI: 0.67–1.03, I 2:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64–18.94, I 2: 92%), the 5–15 year-age group (OR:0.71, 95% CI: 0.06–8.57, I 2:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62–0.92, I 2:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5–0.76, I 2:0%), while this was comparable in the 5–15 year- age group (OR: 0.43, 95% CI:0.06–2.91, I 2:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59–1.01, I 2:0%). Conclusion Overall, the present analysis identified that the incidence of SM in patients infected with P. vivax was considerable, indicating that P. vivax is a major

Analysing the quality of routine malaria data in Mozambique

PubMed Central

Chilundo, Baltazar; Sundby, Johanne; Aanestad, Margunn

2004-01-01

Background In Mozambique, malaria is the principal cause of morbidity and mortality. Efforts are being made to increase control activities within communities. These activities require management decisions based on evidence of malaria incidence. Although some data generated are of poor quality, there is little research towards improving the reporting systems. Methods An analysis of the quality of routine malaria data was performed in selected districts in Southern Mozambique from August to September 2003. The aim was to assess the quality of the source data in terms of completeness, correctness and consistency across management levels. Results Analysis revealed primary data to be of poor quality. The diversity of reporting systems with limited coordination give rise to redundancies and wastage of resources. There was evidence of "invention" of data in health facilities contributing to an incorrect representation of malaria incidence. Large, "non-clinical", time-based variations of malaria cases due to reporting delays were also noted, contributing to false alerts of outbreaks. Furthermore, targets established in the national strategic plan for malaria cannot be calculated through the existing systems; this is the case, for example, for data related to pregnant women and children under-five years. Discussion and recommendations The existing reporting system for malaria is currently not satisfying the information needs of managers. It is suggested that one standardized system, including the creation of one form to include the essential variables required for the calculation of key indicators by age, gender and pregnancy status, and to establish a national database that maps malaria by location. PMID:14998435

Vaccines Against Malaria

PubMed Central

Ouattara, Amed; Laurens, Matthew B.

2015-01-01

Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. PMID:25452593

Heterogeneous alleles comprising G6PD deficiency trait in West Africa exert contrasting effects on two major clinical presentations of severe malaria.

PubMed

Shah, Shivang S; Rockett, Kirk A; Jallow, Muminatou; Sisay-Joof, Fatou; Bojang, Kalifa A; Pinder, Margaret; Jeffreys, Anna; Craik, Rachel; Hubbart, Christina; Wellems, Thomas E; Kwiatkowski, Dominic P

2016-01-07

Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance. It has long been thought that G6PD deficiency confers partial protection against severe malaria, however prior genetic association studies have disagreed with regard to the strength and specificity of a protective effect, which might reflect differences in the host genetic background, environmental influences, or in the specific clinical phenotypes considered. A case-control association study of severe malaria was conducted in The Gambia, a region in West Africa where there is considerable allelic heterogeneity underlying expression of G6PD deficiency trait, evaluating the three major nonsynonymous polymorphisms known to be associated with enzyme deficiency (A968G, T542A, and C202T) in a cohort of 3836 controls and 2379 severe malaria cases. Each deficiency allele exhibited a similar trend toward protection against severe malaria overall (15-26% reduced risk); however, in stratifying severe malaria to two of its constituent clinical subphenotypes, severe malarial anaemia (SMA) and cerebral malaria (CM), the three deficiency alleles exhibited trends of opposing effect, with risk conferred to SMA and protection with respect to CM. To assess the overall effect of G6PD deficiency trait, deficiency alleles found across all three loci were pooled. G6PD deficiency trait was found to be significantly associated with protection from severe malaria overall (OR 0.83 [0.75-0.92], P = 0.0006), but this was limited to CM (OR 0.73 [0.61-0.87], P = 0.0005), with a trend toward increased risk for SMA, especially in fully-deficient individuals (OR 1.43 [0.99-2.08], P = 0.056). Sex-stratified testing largely comported with these results, with evidence suggesting that protection by G6PD deficiency trait is conferred to both males and females, though susceptibility to SMA may be restricted to fully-deficient male hemizygotes

Placental malaria and the risk of malaria in infants in a high malaria transmission area in ghana: a prospective cohort study.

PubMed

Asante, Kwaku Poku; Owusu-Agyei, Seth; Cairns, Matthew; Dodoo, Daniel; Boamah, Ellen Abrafi; Gyasi, Richard; Adjei, George; Gyan, Ben; Agyeman-Budu, Akua; Dodoo, Theophilus; Mahama, Emmanuel; Amoako, Nicholas; Dosoo, David Kwame; Koram, Kwadwo; Greenwood, Brian; Chandramohan, Daniel

2013-11-01

Whether the risk of malaria is increased in infants born to mothers who experience malaria during pregnancy is uncertain.  We investigated malaria incidence among an infant cohort born to 355 primigravidae and 1500 multigravidae with or without placental malaria (PM) in a high malaria transmission area of Ghana. PM was assessed using placental histology. The incidence of all episodes of malaria parasitemia or clinical malaria was very similar among 3 groups of infants: those born to multigravidae without PM, multigravidae with PM, and primigravidae with PM. Infants born to primigravidae without PM experienced a lower incidence of malaria parasitemia or clinical malaria than the other 3 groups: adjusted hazard ratio, 0.64 (95% confidence interval [CI], .48-.86, P < .01) and 0.60 (95% CI, .43-.84, P < .01), respectively. The incidence of malaria parasitemia or clinical malaria was about 2 times higher in most poor infants compared to least poor infants. There was no suggestion that exposure to PM directly increased incidence of malaria among infants of multigravidae. In our study area, absence of placental malaria in primigravidae is a marker of low exposure, and this probably explains the lower incidence of malaria-related outcomes among infants of PM-negative primigravidae.

Malaria diagnostic capacity in health facilities in Ethiopia

PubMed Central

2014-01-01

Background Accurate early diagnosis and prompt treatment is one of the key strategies to control and prevent malaria in Ethiopia where both Plasmodium falciparum and Plasmodium vivax are sympatric and require different treatment regimens. Microscopy is the standard for malaria diagnosis at the health centres and hospitals whereas rapid diagnostic tests are used at community-level health posts. The current study was designed to assess malaria microscopy capacity of health facilities in Oromia Regional State and Dire Dawa Administrative City, Ethiopia. Methods A descriptive cross-sectional study was conducted from February to April 2011 in 122 health facilities, where health professionals were interviewed using a pre-tested, standardized assessment tool and facilities’ laboratory practices were assessed by direct observation. Results Of the 122 assessed facilities, 104 (85%) were health centres and 18 (15%) were hospitals. Out of 94 health facilities reportedly performing blood films, only 34 (36%) used both thin and thick smears for malaria diagnosis. The quality of stained slides was graded in 66 health facilities as excellent, good and poor quality in 11(17%), 31 (47%) and 24 (36%) respectively. Quality assurance guidelines and malaria microscopy standard operating procedures were found in only 13 (11%) facilities and 12 (10%) had involved in external quality assessment activities, and 32 (26%) had supportive supervision within six months of the survey. Only seven (6%) facilities reported at least one staff’s participation in malaria microscopy refresher training during the previous 12 months. Although most facilities, 96 (79%), had binocular microscopes, only eight (7%) had the necessary reagents and supplies to perform malaria microscopy. Treatment guidelines for malaria were available in only 38 (31%) of the surveyed facilities. Febrile patients with negative malaria laboratory test results were managed with artemether-lumefantrine or chloroquine in 51% (53

Mortality and pathology in birds due to Plasmodium (Giovannolaia) homocircumflexum infection, with emphasis on the exoerythrocytic development of avian malaria parasites.

PubMed

Ilgūnas, Mikas; Bukauskaitė, Dovilė; Palinauskas, Vaidas; Iezhova, Tatjana A; Dinhopl, Nora; Nedorost, Nora; Weissenbacher-Lang, Christiane; Weissenböck, Herbert; Valkiūnas, Gediminas

2016-05-04

Species of avian malaria parasites (Plasmodium) are widespread, but their virulence has been insufficiently investigated, particularly in wild birds. During avian malaria, several cycles of tissue merogony occur, and many Plasmodium spp. produce secondary exoerythrocytic meronts (phanerozoites), which are induced by merozoites developing in erythrocytic meronts. Phanerozoites markedly damage organs, but remain insufficiently investigated in the majority of described Plasmodium spp. Avian malaria parasite Plasmodium (Giovannolaia) homocircumflexum (lineage pCOLL4) is virulent and produces phanerozoites in domestic canaries Serinus canaria, but its pathogenicity in wild birds remains unknown. The aim of this study was to investigate the pathology caused by this infection in species of common European birds. One individual of Eurasian siskin Carduelis spinus, common crossbill Loxia curvirostra and common starling Sturnus vulgaris were exposed to P. homocircumflexum infection by intramuscular sub-inoculation of infected blood. The birds were maintained in captivity and parasitaemia was monitored until their death due to malaria. Brain, heart, lungs, liver, spleen, kidney, and a piece of breast muscle were examined using histology and chromogenic in situ hybridization (ISH) methods. All exposed birds developed malaria infection, survived the peak of parasitaemia, but suddenly died between 30 and 38 days post exposure when parasitaemia markedly decreased. Numerous phanerozoites were visible in histological sections of all organs and were particularly easily visualized after ISH processing. Blockage of brain capillaries with phanerozoites may have led to cerebral ischaemia, causing cerebral paralysis and is most likely the main reason of sudden death of all infected individuals. Inflammatory response was not visible around the brain, heart and muscle phanerozoites, and it was mild in parenchymal organs. The endothelial damage likely causes dysfunction and failure of

Beer Consumption Increases Human Attractiveness to Malaria Mosquitoes

PubMed Central

Lefèvre, Thierry; Gouagna, Louis-Clément; Dabiré, Kounbobr Roch; Elguero, Eric; Fontenille, Didier; Renaud, François; Costantini, Carlo; Thomas, Frédéric

2010-01-01

Background Malaria and alcohol consumption both represent major public health problems. Alcohol consumption is rising in developing countries and, as efforts to manage malaria are expanded, understanding the links between malaria and alcohol consumption becomes crucial. Our aim was to ascertain the effect of beer consumption on human attractiveness to malaria mosquitoes in semi field conditions in Burkina Faso. Methodology/Principal Findings We used a Y tube-olfactometer designed to take advantage of the whole body odour (breath and skin emanations) as a stimulus to gauge human attractiveness to Anopheles gambiae (the primary African malaria vector) before and after volunteers consumed either beer (n = 25 volunteers and a total of 2500 mosquitoes tested) or water (n = 18 volunteers and a total of 1800 mosquitoes). Water consumption had no effect on human attractiveness to An. gambiae mosquitoes, but beer consumption increased volunteer attractiveness. Body odours of volunteers who consumed beer increased mosquito activation (proportion of mosquitoes engaging in take-off and up-wind flight) and orientation (proportion of mosquitoes flying towards volunteers' odours). The level of exhaled carbon dioxide and body temperature had no effect on human attractiveness to mosquitoes. Despite individual volunteer variation, beer consumption consistently increased attractiveness to mosquitoes. Conclusions/Significance These results suggest that beer consumption is a risk factor for malaria and needs to be integrated into public health policies for the design of control measures. PMID:20209056

Prevalence of malaria infection in pregnant women compared with children for tracking malaria transmission in sub-Saharan Africa: a systematic review and meta-analysis

PubMed Central

van Eijk, Anna M; Hill, Jenny; Noor, Abdisalan M; Snow, Robert W; ter Kuile, Feiko O

2015-01-01

Summary Background In malarious areas, pregnant women are more likely to have detectable malaria than are their non-pregnant peers, and the excess risk of infection varies with gravidity. Pregnant women attending antenatal clinic for their first visit are a potential pragmatic sentinel group to track the intensity of malaria transmission; however, the relation between malaria prevalence in children, a standard measure to estimate malaria endemicity, and pregnant women has never been compared. Methods We obtained data on malaria prevalence in pregnancy from the Malaria in Pregnancy Library (January, 2015) and data for children (0–59 months) were obtained from recently published work on parasite prevalence in Africa and the Malaria in Pregnancy Library. We used random effects meta-analysis to obtain a pooled prevalence ratio (PPR) of malaria in children versus pregnant women (during pregnancy, not at delivery) and by gravidity, and we used meta-regression to assess factors affecting the prevalence ratio. Findings We used data from 18 sources that included 57 data points. There was a strong linear relation between the prevalence of malaria infection in pregnant women and children (r=0·87, p<0·0001). Prevalence was higher in children when compared with all gravidae (PPR=1·44, 95% CI 1·29–1·62; I2=80%, 57 studies), and against multigravidae (1·94, 1·68–2·24; I2=80%, 7 studies), and marginally higher against primigravidae (1·16, 1·05–1·29; I2=48%, 8 studies). PPR was higher in areas of higher transmission. Interpretation Malaria prevalence in pregnant women is strongly correlated with prevalence data in children obtained from household surveys, and could provide a pragmatic adjunct to survey strategies to track trends in malaria transmission in Africa. Funding The Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine, UK; US Centers for Disease Control and

Malaria and World War II: German malaria experiments 1939-45.

PubMed

Eckart, W U; Vondra, H

2000-06-01

The epidemiological and pharmacological fight against malaria and German malaria research during the Nazi dictatorship were completely under the spell of war. The Oberkommando des Heeres (German supreme command of the army) suffered the bitter experience of unexpected high losses caused by malaria especially at the Greek front (Metaxes line) but also in southern Russia and in the Ukraine. Hastily raised anti-malaria units tried to teach soldiers how to use the synthetic malaria drugs (Plasmochine, Atebrine) properly. Overdoses of these drugs were numerous during the first half of the war whereas in the second half it soon became clear that it would not be possible to support the army due to insufficient quantities of plasmochine and atebrine. During both running fights and troop withdrawals at all southern and southeastern fronts there was hardly any malaria prophylaxis or treatment. After war and captivity many soldiers returned home to endure heavy malaria attacks. In German industrial (Bayer, IG-Farben) and military malaria laboratories of the Heeres-Sanitäts-Akademie (Army Medical Academy) the situation was characterised by a hasty search for proper dosages of anti-malaria drugs, adequate mechanical and chemical prophylaxis (Petroleum, DDT, and other insecticides) as well as an anti-malaria vaccine. Most importantly, large scale research for proper atebrine and plasmochine dosages was conducted in German concentration camps and mental homes. In Dachau Professor Claus Schilling tested synthetic malaria drugs and injected helpless prisoners with high and sometimes lethal doses. Since the 1920s he had been furiously looking for an anti-malaria vaccine in Italian mental homes and from 1939 he continued his experiments in Dachau. Similar experiments were also performed in Buchenwald and in a psychiatric clinic in Thuringia, where Professor Gerhard Rose tested malaria drugs with mentally ill Russian prisoners of war. Schilling was put to death for his criminal

Imported malaria in pregnant women: a retrospective pooled analysis

PubMed Central

Käser, Annina K.; Arguin, Paul M.; Chiodini, Peter L.; Smith, Valerie; Delmont, Jean; Jiménez, Beatriz C.; Färnert, Anna; Kimura, Mikio; Ramharter, Michael; Grobusch, Martin P.; Schlagenhauf, Patricia

2015-01-01

Summary Background Data on imported malaria in pregnant women are scarce. Method A retrospective, descriptive study of pooled data on imported malaria in pregnancy was done, using data from 1977 to 2014 from 8 different collaborators in Europe, the United States and Japan. Most cases were from the period 1991–2014. National malaria reference centresas well as specialists on this topic were asked to search their archives for cases of imported malaria in pregnancy. A total of 632 cases were collated, providing information on Plasmodium species, region of acquisition, nationality, country of residence, reason for travel, age, gestational age, prophylactic measures and treatment used, as well as on complications and outcomes in mother and child. Results Datasets from some sources were incomplete. The predominant Plasmodium species was P. falciparum in 72% of cases. Among the 543 cases where information on the use of chemoprophylaxis was known, 471 (74.5%) did not use chemoprophylaxis or used incorrect or incomplete chemoprophylaxis. The main reason for travelling was “visiting friends and relatives” VFR (48.6%) and overall, most cases of malaria were imported from West Africa (85.9%). Severe anaemia was the most frequent complication in the mother. Data on offspring outcome was limited, but spontaneous abortion was a frequently reported foetal outcome (n = 14). A total of 50 different variants of malaria treatment regimens were reported. Conclusion Imported cases of malaria in pregnancy are mainly P. falciparum acquired in sub-Saharan Africa. Malaria prevention and treatment in pregnant travellers is a challenge for travel medicine due to few data on medication safety and maternal and foetal outcomes. International, collaborative efforts are needed to capture standardized data on imported malaria cases in pregnant women. PMID:26227740

Summary of recommendations on malaria issues in special hosts

PubMed Central

Boggild, A; Brophy, J; Charlebois, P; Crockett, M; Geduld, J; Ghesquiere, W; McDonald, P; Plourde, P; Teitelbaum, P; Tepper, M; Schofield, S; McCarthy, A

2014-01-01

Background On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. Objective To provide guidelines on malaria issues related to special hosts. Methods CATMAT reviewed all major sources of information on malaria prevention, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. Recommendations All people visiting malaria endemic regions should use effective personal protective measures (PPM; topical repellants, bed nets, behavioural choices) and the prescribed chemoprophylaxis. Chemoprophylaxis for pregnant and breastfeeding women and for children requires careful consideration in the context of the pregnancy trimester, the age or size of the infant/child as well as their glucose-6-phosphate dehydrogenase (G6PD) status. Recommendations for long-term travellers, expatriates and people visiting friends and relatives (VFRs) do not differ markedly from those for short-term travellers. Some underlying medical conditions may make individuals more vulnerable to malaria. In addition, some conditions or their treatment may preclude the use of one or more antimalarial medications. PMID:29769841

Toll-like receptor polymorphisms in malaria-endemic populations

PubMed Central

Greene, Jennifer A; Moormann, Ann M; Vulule, John; Bockarie, Moses J; Zimmerman, Peter A; Kazura, James W

2009-01-01

Background Toll-like receptors (TLR) and related downstream signaling pathways of innate immunity have been implicated in the pathogenesis of Plasmodium falciparum malaria. Because of their potential role in malaria pathogenesis, polymorphisms in these genes may be under selective pressure in populations where this infectious disease is endemic. Methods A post-PCR Ligation Detection Reaction-Fluorescent Microsphere Assay (LDR-FMA) was developed to determine the frequencies of TLR2, TLR4, TLR9, MyD88-Adaptor Like Protein (MAL) single nucleotide polymorphisms (SNPs), and TLR2 length polymorphisms in 170 residents of two regions of Kenya where malaria transmission is stable and high (holoendemic) or episodic and low, 346 residents of a malaria holoendemic region of Papua New Guinea, and 261 residents of North America of self-identified ethnicity. Results The difference in historical malaria exposure between the two Kenyan sites has significantly increased the frequency of malaria protective alleles glucose-6-phoshpate dehydrogenase (G6PD) and Hemoglobin S (HbS) in the holoendemic site compared to the episodic transmission site. However, this study detected no such difference in the TLR2, TLR4, TLR9, and MAL allele frequencies between the two study sites. All polymorphisms were in Hardy Weinberg Equilibrium in the Kenyan and Papua New Guinean populations. TLR9 SNPs and length polymorphisms within the TLR2 5' untranslated region were the only mutant alleles present at a frequency greater than 10% in all populations. Conclusion Similar frequencies of TLR2, TLR4, TLR9, and MAL genetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. Genotype frequencies are consistent with Hardy-Weinberg Equilibrium and the Neutral Theory, suggesting that genetic drift has influenced allele frequencies to a greater extent than selective pressure from malaria or any

Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.

PubMed

Campos, A C; Brant, F; Miranda, A S; Machado, F S; Teixeira, A L

2015-03-19

Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits. Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties. In the present work, we evaluated the effects of CBD in a murine model of CM. Female mice were infected with Plasmodium berghei ANKA (PbA) and treated with CBD (30mg/kg/day - 3 or 7days i.p.) or vehicle. On 5th day-post-infection (dpi), at the peak of the disease), animals were treated with single or repeated doses of Artesunate, an antimalarial drug. All groups were tested for memory impairment (Novel Object Recognition or Morris Water Maze) and anxiety-like behaviors (Open field or elevated plus maze test) in different stages of the disease (at the peak or after the complete clearance of the disease). Th1/Th2 cytokines and neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) were measured in the prefrontal cortex and hippocampus of experimental groups. PbA-infected mice displayed memory deficits and exhibited increase in anxiety-like behaviors on the 5dpi or after the clearance of the parasitemia, effects prevented by CBD treatment. On 5dpi, TNF-α and IL-6 increased in the hippocampus, while only IL-6 increased in the prefrontal cortex. CBD treatment resulted in an increase in BDNF expression in the hippocampus and decreased levels of proinflammatory cytokines in the hippocampus (TNF-α) and prefrontal cortex (IL-6). Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Rapid urban malaria appraisal (RUMA) in sub-Saharan Africa

PubMed Central

Wang, Shr-Jie; Lengeler, Christian; Smith, Thomas A; Vounatsou, Penelope; Cissé, Guéladio; Diallo, Diadie A; Akogbeto, Martin; Mtasiwa, Deo; Teklehaimanot, Awash; Tanner, Marcel

2005-01-01

Background The rapid urban malaria appraisal (RUMA) methodology aims to provide a cost-effective tool to conduct rapid assessments of the malaria situation in urban sub-Saharan Africa and to improve the understanding of urban malaria epidemiology. Methods This work was done in Yopougon municipality (Abidjan), Cotonou, Dar es Salaam and Ouagadougou. The study design consists of six components: 1) a literature review, 2) the collection of available health statistics, 3) a risk mapping, 4) school parasitaemia surveys, 5) health facility-based surveys and 6) a brief description of the health care system. These formed the basis of a multi-country evaluation of RUMA's feasibility, consistency and usefulness. Results A substantial amount of literature (including unpublished theses and statistics) was found at each site, providing a good overview of the malaria situation. School and health facility-based surveys provided an overview of local endemicity and the overall malaria burden in different city areas. This helped to identify important problems for in-depth assessment, especially the extent to which malaria is over-diagnosed in health facilities. Mapping health facilities and breeding sites allowed the visualization of the complex interplay between population characteristics, health services and malaria risk. However, the latter task was very time-consuming and required special expertise. RUMA is inexpensive, costing around 8,500–13,000 USD for a six to ten-week period. Conclusion RUMA was successfully implemented in four urban areas with different endemicity and proved to be a cost-effective first approach to study the features of urban malaria and provide an evidence basis for planning control measures. PMID:16153298

Reduced risk for placental malaria in iron deficient women

PubMed Central

2011-01-01

Background Nutritional iron deficiency may limit iron availability to the malaria parasite reducing infection risk, and/or impair host immunity thereby increasing this risk. In pregnant women, there is evidence of an adverse effect with iron supplementation, but the few reported studies are strongly confounded. Methods A case control study in pregnant Malawian women was undertaken in Chikhwawa southern Malawi in order to describe iron status in relation to placental malaria controlling for several confounding factors. Pregnancy characteristics were obtained and a blood sample at delivery. A full blood count was performed and serum ferritin and transferrin receptor quantified by enzyme-linked immunoassay. DNA analysis was used to identify genetic polymorphisms for ABO phenotype, hemoglobin HbS, and glucose -6 phosphate dehydrogenase deficiency. Placental tissue was obtained and malaria histology classified as active, past or no malaria infection. Results 112 cases with placental malaria were identified and 110 women with no evidence of placental infection. Iron deficiency was less frequent in women with placental Plasmodium falciparum infection. In those with acute, chronic or past placental infections the odds ratio for iron deficiency was 0.4, 95% CI 0.2-0.8, p = 0.01; for acute and chronic infections 0.4, 0.2-0.8, p = 0.006; for acute infection 0.3, 0.1-0.7, p = 0.001. The association was greater in multigravidae. Conclusion Women with either acute, or acute and chronic placental malaria were less likely to have iron deficiency than women without placental malaria infection There is a priority to establish if reversing iron deficiency through iron supplementation programs either prior to or during pregnancy enhances malaria risk. PMID:21345193

A Literature Review of the Effect of Malaria on Stunting.

PubMed

Jackson, Bianca D; Black, Robert E

2017-11-01

Background: The current version of the Lives Saved Tool (LiST) maternal and child health impact modeling software does not include an effect of malaria on stunting. Objective: This literature review was undertaken to determine whether such a causal link should be included in the LiST model. Methods: The PubMed, Embase, and Scopus databases were searched by using broad search terms. The searches returned a total of 4281 documents. Twelve studies from among the retrieved documents were included in the review according to the inclusion and exclusion criteria. Results: There was mixed evidence for an effect of malaria on stunting among longitudinal observational studies, and none of the randomized controlled trials of malaria interventions found an effect of the interventions on stunting. Conclusions: There is insufficient evidence to include malaria as a determinant of stunting or an effect of malaria interventions on stunting in the LiST model. The paucity and heterogeneity of the available literature were a major limitation. In addition, the studies included in the review consistently fulfilled their ethical responsibility to treat children under observation for malaria, which may have interfered with the natural history of the disease and prevented any observable effect on stunting or linear growth. © 2017 American Society for Nutrition.

Vaccines against malaria.

PubMed

Ouattara, Amed; Laurens, Matthew B

2015-03-15

Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Application of loop analysis for evaluation of malaria control interventions

PubMed Central

2014-01-01

Background Despite continuous efforts and recent rapid expansion in the financing and implementation of malaria control interventions, malaria still remains one of the most devastating global health issues. Even in countries that have been successful in reducing the incidence of malaria, malaria control is becoming more challenging because of the changing epidemiology of malaria and waning community participation in control interventions. In order to improve the effectiveness of interventions and to promote community understanding of the necessity of continued control efforts, there is an urgent need to develop new methodologies that examine the mechanisms by which community-based malaria interventions could reduce local malaria incidence. Methods This study demonstrated how the impact of community-based malaria control interventions on malaria incidence can be examined in complex systems by qualitative analysis combined with an extensive review of literature. First, sign digraphs were developed through loop analysis to analyse seven interventions: source reduction, insecticide/larvicide use, biological control, treatment with anti-malarials, insecticide-treated mosquito net/long-lasting insecticidal net, non-chemical personal protection measures, and educational intervention. Then, for each intervention, the sign digraphs and literature review were combined to analyse a variety of pathways through which the intervention can influence local malaria incidence as well as interactions between variables involved in the system. Through loop analysis it is possible to see whether increases in one variable qualitatively increases or decreases other variables or leaves them unchanged and the net effect of multiple, interacting variables. Results Qualitative analysis, specifically loop analysis, can be a useful tool to examine the impact of community-based malaria control interventions. Without relying on numerical data, the analysis was able to describe pathways through

Dynamics of positional warfare malaria: Finland and Korea compared

PubMed Central

Huldén, Lena; Huldén, Larry

2008-01-01

Background A sudden outbreak of vivax malaria among Finnish troops in SE-Finland and along the front line in Hanko peninsula in the southwest occurred in 1941 during World War II. The common explanation has been an invasion of infective Anopheles mosquitoes from the Russian troops crossing the front line between Finland and Soviet Union. A revised explanation is presented based on recent studies of Finnish malaria. Methods The exact start of the epidemic and the phenology of malaria cases among the Finnish soldiers were reanalyzed. The results were compared with the declining malaria in Finland. A comparison with a corresponding situation starting in the 1990's in Korea was performed. Results and discussion The malaria cases occurred in July in 1941 when it was by far too early for infective mosquitoes to be present. The first Anopheles mosquitoes hatched at about the same time as the first malaria cases were observed among the Finnish soldiers. It takes about 3 – 6 weeks for the completion of the sporogony in Finland. The new explanation is that soldiers in war conditions were suddenly exposed to uninfected mosquitoes and those who still were carriers of hypnozoites developed relapses triggered by these mosquitoes. It is estimated that about 0.5% of the Finnish population still were carriers of hypnozoites in the 1940's. A corresponding outbreak of vivax malaria in Korea in the 1990's is similarly interpreted as relapses from activated hypnozoites among Korean soldiers. The significance of the mosquito induced relapses is emphasized by two benefits for the Plasmodium. There is a synchronous increase of gametocytes when new mosquitoes emerge. It also enables meiotic recombination between different strains of the Plasmodium. Conclusion The malaria peak during the positional warfare in the 1940's was a short outbreak during the last phase of declining indigenous malaria in Finland. The activation of hypnozoites among a large number of soldiers and subsequent

Socio-demographic factors influencing knowledge, attitude and practice (KAP) regarding malaria in Bangladesh

PubMed Central

2012-01-01

Background A clear understanding of the social and behavioral risk factors, and knowledge gaps, related to exposure to malaria are essential when developing guidelines and recommendations for more effective disease prevention in many malaria endemic areas of the world including Bangladesh and elsewhere in the South East Asia. To-date, the level of knowledge that human populations, residing in moderate to high malaria risk zones, have with respect to the basic pathogen transmission dynamics, risk factors for malaria or disease preventative strategies, has not been assessed in Bangladesh. The purpose of this study was to address this gap by conducting surveys of the knowledge, attitudes and practices (KAP) of people, from variable socio-demographic backgrounds, residing in selected rural malaria endemic areas in Bangladesh. Methods The KAP survey was conducted in portions of six different malaria endemic districts in Bangladesh from July to October 2011. The survey consisted of interviewing residence of these malaria endemic districts using a structured questionnaire and interviewers also completed observational checklists at each household where people were interviewed. The study area was further divided into two zones (1 and 2) based on differences in the physical geography and level of malaria endemicity in the two zones. Data from the questionnaires and observational checklists were analysised using Statistical Package for Social Sciences 16.0 (SPSS, Inc., Chicago, IL, USA). Results A total of 468 individuals from individual households were interviewed, and most respondents were female. Monthly incomes varied within and among the zones. It was found that 46.4% and 41% of respondents’ family had malaria within the past one year in zones 1 and 2, respectively. Nearly 86% of the respondents did not know the exact cause of malaria or the role of Anopheles mosquitoes in the pathogen’s transmission. Knowledge on malaria transmission and symptoms of the respondents

Malaria transmission in two localities in north-western Argentina

PubMed Central

Dantur Juri, María J; Zaidenberg, Mario; Claps, Guillermo L; Santana, Mirta; Almirón, Walter R

2009-01-01

Background Malaria is one of the most important tropical diseases that affects people globally. The influence of environmental conditions in the patterns of temporal distribution of malaria vectors and the disease has been studied in different countries. In the present study, ecological aspects of the malaria vector Anopheles (Anopheles) pseudopunctipennis and their relationship with climatic variables, as well as the seasonality of malaria cases, were studied in two localities, El Oculto and Aguas Blancas, in north-western Argentina. Methods The fluctuation of An. pseudopunctipennis and the malaria cases distribution was analysed with Random Effect Poisson Regression. This analysis takes into account the effect of each climatic variable on the abundance of both vector and malaria cases, giving as results predicted values named Incidence Rate Radio. Results The number of specimens collected in El Oculto and Aguas Blancas was 4224 (88.07%) and 572 (11.93%), respectively. In El Oculto no marked seasonality was found, different from Aguas Blancas, where high abundance was detected at the end of spring and the beginning of summer. The maximum mean temperature affected the An. pseudopunctipennis fluctuation in El Oculto and Aguas Blancas. When considering the relationship between the number of malaria cases and the climatic variables in El Oculto, maximum mean temperature and accumulated rainfall were significant, in contrast with Aguas Blancas, where mean temperature and humidity showed a closer relationship to the fluctuation in the disease. Conclusion The temporal distribution patterns of An. pseudopunctipennis vary in both localities, but spring appears as the season with better conditions for mosquito development. Maximum mean temperature was the most important variable in both localities. Malaria cases were influenced by the maximum mean temperature in El Oculto, while the mean temperature and humidity were significant in Aguas Blancas. In Aguas Blancas peaks of

Malaria transmission and vector behaviour in a forested malaria focus in central Vietnam and the implications for vector control

PubMed Central

2010-01-01

Background In Vietnam, malaria is becoming progressively restricted to specific foci where human and vector characteristics alter the known malaria epidemiology, urging for alternative or adapted control strategies. Long-lasting insecticidal hammocks (LLIH) were designed and introduced in Ninh Thuan province, south-central Vietnam, to control malaria in the specific context of forest malaria. An entomological study in this specific forested environment was conducted to assess the behavioural patterns of forest and village vectors and to assess the spatio-temporal risk factors of malaria transmission in the province. Methods Five entomological surveys were conducted in three villages in Ma Noi commune and in five villages in Phuoc Binh commune in Ninh Thuan Province, south-central Vietnam. Collections were made inside the village, at the plot near the slash-and-burn fields in the forest and on the way to the forest. All collected mosquito species were subjected to enzyme-linked immunosorbent assay (ELISA) to detect Plasmodium in the head-thoracic portion of individual mosquitoes after morphological identification. Collection data were analysed by use of correspondence and multivariate analyses. Results The mosquito density in the study area was low with on average 3.7 anopheline bites per man-night and 17.4 culicine bites per man-night. Plasmodium-infected mosquitoes were only found in the forest and on the way to the forest. Malaria transmission in the forested malaria foci was spread over the entire night, from dusk to dawn, but was most intense in the early evening as nine of the 13 Plasmodium positive bites occurred before 21H. The annual entomological inoculation rate of Plasmodium falciparum was 2.2 infective bites per person-year to which Anopheles dirus s.s. and Anopheles minimus s.s. contributed. The Plasmodium vivax annual entomological inoculation rate was 2.5 infective bites per person-year with Anopheles sawadwongporni, Anopheles dirus s.s. and

The complexities of malaria disease manifestations with a focus on asymptomatic malaria

PubMed Central

2012-01-01

Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted. PMID:22289302

Malaria in rural Burkina Faso: local illness concepts, patterns of traditional treatment and influence on health-seeking behaviour.

PubMed

Beiersmann, Claudia; Sanou, Aboubakary; Wladarsch, Evelyn; De Allegri, Manuela; Kouyaté, Bocar; Müller, Olaf

2007-08-08

The literature on health care seeking behaviour in sub-Saharan Africa for children suffering from malaria is quite extensive. This literature, however, is predominantly quantitative and, inevitably, fails to explore how the local concepts of illness may affect people's choices. Understanding local concepts of illness and their influence on health care-seeking behaviour can complement existing knowledge and lead to the development of more effective malaria control interventions. In a rural area of Burkina Faso, four local concepts of illness resembling the biomedical picture of malaria were described according to symptoms, aetiology, and treatment. Data were collected through eight focus group discussions, 17 semi-structured interviews with key informants, and through the analysis of 100 verbal autopsy questionnaires of children under-five diagnosed with malaria. Sumaya, dusukun yelema, kono, and djoliban were identified as the four main local illness concepts resembling respectively uncomplicated malaria, respiratory distress syndrome, cerebral malaria, and severe anaemia. The local disease categorization was found to affect both treatment and provider choice. While sumaya is usually treated by a mix of traditional and modern methods, dusukun yelema and kono are preferably treated by traditional healers, and djoliban is preferably treated in modern health facilities. Besides the conceptualization of illness, poverty was found to be another important influencing factor of health care-seeking behaviour. The findings complement previous evidence on health care-seeking behaviour, by showing how local concepts of illness strongly influence treatment and choice of provider. Local concepts of illness need to be considered when developing specific malaria control programmes.

Plasma uric acid levels correlate with inflammation and disease severity in Malian children with Plasmodium falciparum malaria.

PubMed

Lopera-Mesa, Tatiana M; Mita-Mendoza, Neida K; van de Hoef, Diana L; Doumbia, Saibou; Konaté, Drissa; Doumbouya, Mory; Gu, Wenjuan; Traoré, Karim; Diakité, Seidina A S; Remaley, Alan T; Anderson, Jennifer M; Rodriguez, Ana; Fay, Michael P; Long, Carole A; Diakité, Mahamadou; Fairhurst, Rick M

2012-01-01

Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of 'parasite-derived' UA stimulate immune cells to produce inflammatory cytokines in vitro. We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNFα (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl). Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA

Coexistence of Malaria and Thalassemia in Malaria Endemic Areas of Thailand

PubMed Central

Kuesap, Jiraporn; Chaijaroenkul, W.; Rungsihirunrat, K.; Pongjantharasatien, K.; Na-Bangchang, Kesara

2015-01-01

Hemoglobinopathy and malaria are commonly found worldwide particularly in malaria endemic areas. Thalassemia, the alteration of globin chain synthesis, has been reported to confer resistance against malaria. The prevalence of thalassemia was investigated in 101 malaria patients with Plasmodium falciparum and Plasmodium vivax along the Thai-Myanmar border to examine protective effect of thalassemia against severe malaria. Hemoglobin typing was performed using low pressure liquid chromatography (LPLC) and α-thalassemia was confirmed by multiplex PCR. Five types of thalassemia were observed in malaria patients. The 2 major types of thalassemia were Hb E (18.8%) and α-thalassemia-2 (11.9%). There was no association between thalassemia hemoglobinopathy and malaria parasitemia, an indicator of malaria disease severity. Thalassemia had no significant association with P. vivax infection, but the parasitemia in patients with coexistence of P. vivax and thalassemia was about 2-3 times lower than those with coexistence of P. falciparum and thalassemia and malaria without thalassemia. Furthermore, the parasitemia of P. vivax in patients with coexistence of Hb E showed lower value than coexistence with other types of thalassemia and malaria without coexistence. Parasitemia, hemoglobin, and hematocrit values in patients with coexistence of thalassemia other than Hb E were significantly lower than those without coexistence of thalassemia. Furthermore, parasitemia with coexistence of Hb E were 2 times lower than those with coexistence of thalassemia other than Hb E. In conclusion, the results may, at least in part, support the protective effect of thalassemia on the development of hyperparasitemia and severe anemia in malaria patients. PMID:26174819

Modelling entomological-climatic interactions of Plasmodium falciparum malaria transmission in two Colombian endemic-regions: contributions to a National Malaria Early Warning System

PubMed Central

Ruiz, Daniel; Poveda, Germán; Vélez, Iván D; Quiñones, Martha L; Rúa, Guillermo L; Velásquez, Luz E; Zuluaga, Juan S

2006-01-01

Background Malaria has recently re-emerged as a public health burden in Colombia. Although the problem seems to be climate-driven, there remain significant gaps of knowledge in the understanding of the complexity of malaria transmission, which have motivated attempts to develop a comprehensive model. Methods The mathematical tool was applied to represent Plasmodium falciparum malaria transmission in two endemic-areas. Entomological exogenous variables were estimated through field campaigns and laboratory experiments. Availability of breeding places was included towards representing fluctuations in vector densities. Diverse scenarios, sensitivity analyses and instabilities cases were considered during experimentation-validation process. Results Correlation coefficients and mean square errors between observed and modelled incidences reached 0.897–0.668 (P > 0.95) and 0.0002–0.0005, respectively. Temperature became the most relevant climatic parameter driving the final incidence. Accordingly, malaria outbreaks are possible during the favourable epochs following the onset of El Niño warm events. Sporogonic and gonotrophic cycles showed to be the entomological key-variables controlling the transmission potential of mosquitoes' population. Simulation results also showed that seasonality of vector density becomes an important factor towards understanding disease transmission. Conclusion The model constitutes a promising tool to deepen the understanding of the multiple interactions related to malaria transmission conducive to outbreaks. In the foreseeable future it could be implemented as a tool to diagnose possible dynamical patterns of malaria incidence under several scenarios, as well as a decision-making tool for the early detection and control of outbreaks. The model will be also able to be merged with forecasts of El Niño events to provide a National Malaria Early Warning System. PMID:16882349

X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria.

PubMed

Guindo, Aldiouma; Fairhurst, Rick M; Doumbo, Ogobara K; Wellems, Thomas E; Diallo, Dapa A

2007-03-01

Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. We conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. The A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these

Helminth Infection and Eosinophilia and the Risk of Plasmodium falciparum Malaria in 1- to 6-Year-Old Children in a Malaria Endemic Area

PubMed Central

Bejon, Philip; Mwangi, Tabitha W.; Lowe, Brett; Peshu, Norbert; Hill, Adrian V. S.; Marsh, Kevin

2008-01-01

Background Helminth infection is common in malaria endemic areas, and an interaction between the two would be of considerable public health importance. Animal models suggest that helminth infections may increase susceptibility to malaria, but epidemiological data has been limited and contradictory. Methodology/Principal Findings In a vaccine trial, we studied 387 one- to six-year-old children for the effect of helminth infections on febrile Plasmodium falciparum malaria episodes. Gastrointestinal helminth infection and eosinophilia were prevalent (25% and 50% respectively), but did not influence susceptibility to malaria. Hazard ratios were 1 for gastrointestinal helminth infection (95% CI 0.6–1.6) and 0.85 and 0.85 for mild and marked eosinophilia, respectively (95% CI 0.56–1.76 and 0.69–1.96). Incident rate ratios for multiple episodes were 0.83 for gastro-intestinal helminth infection (95% CI 0.5–1.33) and 0.86 and 0.98 for mild and marked eosinophilia (95% CI 0.5–1.4 and 0.6–1.5). Conclusions/Significance There was no evidence that infection with gastrointestinal helminths or urinary schistosomiasis increased susceptibility to Plasmodium falciparum malaria in this study. Larger studies including populations with a greater prevalence of helminth infection should be undertaken. PMID:18265875

Malaria in Brazil, Colombia, Peru and Venezuela: current challenges in malaria control and elimination.

PubMed

Recht, Judith; Siqueira, André M; Monteiro, Wuelton M; Herrera, Sonia M; Herrera, Sócrates; Lacerda, Marcus V G

2017-07-04

In spite of significant progress towards malaria control and elimination achieved in South America in the 2000s, this mosquito-transmitted tropical disease remains an important public health concern in the region. Most malaria cases in South America come from Amazon rain forest areas in northern countries, where more than half of malaria is caused by Plasmodium vivax, while Plasmodium falciparum malaria incidence has decreased in recent years. This review discusses current malaria data, policies and challenges in four South American Amazon countries: Brazil, Colombia, Peru and the Bolivarian Republic of Venezuela. Challenges to continuing efforts to further decrease malaria incidence in this region include: a significant increase in malaria cases in recent years in Venezuela, evidence of submicroscopic and asymptomatic infections, peri-urban malaria, gold mining-related malaria, malaria in pregnancy, glucose-6-phosphate dehydrogenase (G6PD) deficiency and primaquine use, and possible under-detection of Plasmodium malariae. Some of these challenges underscore the need to implement appropriate tools and procedures in specific regions, such as a field-compatible molecular malaria test, a P. malariae-specific test, malaria diagnosis and appropriate treatment as part of regular antenatal care visits, G6PD test before primaquine administration for P. vivax cases (with weekly primaquine regimen for G6PD deficient individuals), single low dose of primaquine for P. falciparum malaria in Colombia, and national and regional efforts to contain malaria spread in Venezuela urgently needed especially in mining areas. Joint efforts and commitment towards malaria control and elimination should be strategized based on examples of successful regional malaria fighting initiatives, such as PAMAFRO and RAVREDA/AMI.

Toluidine blue: rapid and simple malaria parasite screening and species identification.

PubMed

Awale, Rupali; Maji, Ratnaprabha; Patil, Parag; Lingiah, Raghavendra; Mukhopadhyay, Ashok Kumar; Sharma, Subhadra

2017-01-01

Malaria, a febrile illness mostly confined to the tropical countries is transmitted by bite of infected female Anopheles mosquito. In 2015 alone, 88% of the malaria burden and 90% deaths due to malaria were confined to the African and Asian countries. Although number of tests are available for rapid diagnosis and screening for malaria, peripheral blood smear examination remains the gold standard. Leishman stain is recommended by WHO however herein we evaluate one of the alternative methods of staining which is simple and rapid. Fifty patients attending the various outpatient departments of the tertiary care hospital with fever and suspected to have malaria were selected. Two thin-air dried smears prepared from the peripheral venous blood from these subjects were stained by Leishman and Toluidine blue method. The findings of the slides by two independent qualified professionals were noted and the results were analyzed. A total of 14% (7/50) cases were diagnosed to have malaria. All the malaria cases which were positive in Leishman stain were also detected in Toluidine blue stain. Malarial parasites were clearly visible against the homogenously light green background in Toluidine blue. The detection of malarial parasite by Toluidine blue was quick, easy and confirmative. Toluidine blue stained peripheral blood smear allows for easy identification and speciation of malarial parasite at low magnification and in shorter period of time.

Forecasting malaria cases using climatic factors in delhi, India: a time series analysis.

PubMed

Kumar, Varun; Mangal, Abha; Panesar, Sanjeet; Yadav, Geeta; Talwar, Richa; Raut, Deepak; Singh, Saudan

2014-01-01

Background. Malaria still remains a public health problem in developing countries and changing environmental and climatic factors pose the biggest challenge in fighting against the scourge of malaria. Therefore, the study was designed to forecast malaria cases using climatic factors as predictors in Delhi, India. Methods. The total number of monthly cases of malaria slide positives occurring from January 2006 to December 2013 was taken from the register maintained at the malaria clinic at Rural Health Training Centre (RHTC), Najafgarh, Delhi. Climatic data of monthly mean rainfall, relative humidity, and mean maximum temperature were taken from Regional Meteorological Centre, Delhi. Expert modeler of SPSS ver. 21 was used for analyzing the time series data. Results. Autoregressive integrated moving average, ARIMA (0,1,1) (0,1,0)(12), was the best fit model and it could explain 72.5% variability in the time series data. Rainfall (P value = 0.004) and relative humidity (P value = 0.001) were found to be significant predictors for malaria transmission in the study area. Seasonal adjusted factor (SAF) for malaria cases shows peak during the months of August and September. Conclusion. ARIMA models of time series analysis is a simple and reliable tool for producing reliable forecasts for malaria in Delhi, India.

Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines

PubMed Central

2013-01-01

Background Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination. Discussion The Malaria Vaccine Technology Roadmap’s goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%’. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine. Conclusions Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine. PMID:24228861

Pathogenesis of cerebral malaria—inflammation and cytoadherence

PubMed Central

Storm, Janet; Craig, Alister G.

2014-01-01

Despite decades of research on cerebral malaria (CM) there is still a paucity of knowledge about what actual causes CM and why certain people develop it. Although sequestration of P. falciparum infected red blood cells has been linked to pathology, it is still not clear if this is directly or solely responsible for this clinical syndrome. Recent data have suggested that a combination of parasite variant types, mainly defined by the variant surface antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1), its receptors, coagulation and host endothelial cell activation (or inflammation) are equally important. This makes CM a multi-factorial disease and a challenge to unravel its causes to decrease its detrimental impact. PMID:25120958

Advances in malaria elimination in Botswana: a dramatic shift to parasitological diagnosis, 2008-2014.

PubMed

Moakofhi, K; Edwards, J K; Motlaleng, M; Namboze, J; Butt, W; Obopile, M; Mosweunyane, T; Manzi, M; Takarinda, K C; Owiti, P

2018-04-25

Background: Malaria elimination requires infection detection using quality assured diagnostics and appropriate treatment regimens. Although Botswana is moving towards malaria elimination, reports of unconfirmed cases may jeopardise this effort. This study aimed to determine the proportion of cases treated for malaria that were confirmed by rapid diagnostic testing (RDT) and/or microscopy. Methods: This was a retrospective descriptive study using routine national data from the integrated disease surveillance and case-based surveillance systems from 2008 to 2014. The data were categorised into clinical and confirmed cases each year. An analysis of the data on cases registered in three districts that reported approximately 70% of all malaria cases was performed, stratified by year, type of reporting health facilities and diagnostic method. Results: During 2008-2014, 50 487 cases of malaria were reported in Botswana, and the proportion of RDT and/or blood microscopy confirmed cases improved from 6% in 2008 to 89% in 2013. The total number of malaria cases decreased by 97% in the same period, then increased by 41% in 2013. Conclusion: This study shows that malaria diagnostic tests dramatically improved malaria diagnosis and consequently reduced the malaria burden in Botswana. The study identified a need to build capacity on microscopy for species identification, parasite quantification and guiding treatment choices.

Malaria control: achievements, problems and strategies.

PubMed

Nájera, J A

2001-06-01

Even if history has not always been the Magistra vitae, Cicero expected it to be, it should provide, as Baas said, a mirror in which to observe and compare the past and present in order to draw therefrom well-grounded conclusions for the future. Based on this belief, this paper aims to provide an overview of the foundations and development of malaria control policies during the XX century. It presents an analysis of the conflicting tendencies which shaped the development of these policies and which appear to have oscillated between calls for frontal attack in an all-out campaign and calls for sustainable gains, even if slow. It discusses the various approaches to the control of malaria, their achievements and their limitations, not only to serve as a background to understand better the foundations of current policies, but also to prevent that simplistic generalisations may again lead to exaggerated expectations and disillusion. The first part of the paper is devoted to the development of malaria control during the first half of the century, characterised by the ups and downs in the reliance on mosquito control as the control measure applicable everywhere. The proliferation of "man-made-malaria", which accompanied the push for economic development in most of the endemic countries, spurred the need for control interventions and, while great successes were obtained in many specific projects, the general campaigns proposed by the enthusiasts of vector control faced increasing difficulties in their practical implementation in the field. Important events, which may be considered representative of this period are, on the campaign approach, the success of Gorgas in the Panama Canal, but also the failure of the Mian Mir project in India; while on the developmental approach, the Italian and Dutch schools of malariology, the Tennessee Valley and the development of malaria sanitation, included the so called species sanitation. The projection of these developments to a global

Seasonal vaccination against malaria: a potential use for an imperfect malaria vaccine.

PubMed

Greenwood, Brian; Dicko, Alassane; Sagara, Issaka; Zongo, Issaka; Tinto, Halidou; Cairns, Matthew; Kuepfer, Irene; Milligan, Paul; Ouedraogo, Jean-Bosco; Doumbo, Ogobara; Chandramohan, Daniel

2017-05-02

In many parts of the African Sahel and sub-Sahel, where malaria remains a major cause of mortality and morbidity, transmission of the infection is highly seasonal. Seasonal malaria chemoprevention (SMC), which involves administration of a full course of malaria treatment to young children at monthly intervals during the high transmission season, is proving to be an effective malaria control measure in these areas. However, SMC does not provide complete protection and it is demanding to deliver for both families and healthcare givers. Furthermore, there is a risk of the emergence in the future of resistance to the drugs, sulfadoxine-pyrimethamine and amodiaquine, that are currently being used for SMC. Substantial progress has been made in the development of malaria vaccines during the past decade and one malaria vaccine, RTS,S/AS01, has received a positive opinion from the European Medicines Authority and will soon be deployed in large-scale, pilot implementation projects in sub-Saharan Africa. A characteristic feature of this vaccine, and potentially of some of the other malaria vaccines under development, is that they provide a high level of efficacy during the period immediately after vaccination, but that this wanes rapidly, perhaps because it is difficult to develop effective immunological memory to malaria antigens in subjects exposed previously to malaria infection. A potentially effective way of using malaria vaccines with high initial efficacy but which provide only a short period of protection could be annual, mass vaccination campaigns shortly before each malaria transmission season in areas where malaria transmission is confined largely to a few months of the year.

Management of uncomplicated malaria in febrile under five-year-old children by community health workers in Madagascar: reliability of malaria rapid diagnostic tests

PubMed Central

2012-01-01

Background Early diagnosis, as well as prompt and effective treatment of uncomplicated malaria, are essential components of the anti-malaria strategy in Madagascar to prevent severe malaria, reduce mortality and limit malaria transmission. The purpose of this study was to assess the performance of the malaria rapid diagnostic tests (RDTs) used by community health workers (CHWs) by comparing RDT results with two reference methods (microscopy and Polymerase Chain Reaction, PCR). Methods Eight CHWs in two districts, each with a different level of endemic malaria transmission, were trained to use RDTs in the management of febrile children under five years of age. RDTs were performed by CHWs in all febrile children who consulted for fever. In parallel, retrospective parasitological diagnoses were made by microscopy and PCR. The results of these different diagnostic methods were analysed to evaluate the diagnostic performance of the RDTs administered by the CHWs. The stability of the RDTs stored by CHWs was also evaluated. Results Among 190 febrile children with suspected malaria who visited CHWs between February 2009 and February 2010, 89.5% were found to be positive for malaria parasites by PCR, 51.6% were positive by microscopy and 55.8% were positive by RDT. The performance accuracy of the RDTs used by CHWs in terms of sensitivity, specificity, positive and negative predictive values was greater than 85%. Concordance between microscopy and RDT, estimated by the Kappa value was 0.83 (95% CI: 0.75-0.91). RDTs stored by CHWs for 24 months were capable of detecting Plasmodium falciparum in blood at a level of 200 parasites/μl. Conclusion Introduction of easy-to-use diagnostic tools, such as RDTs, at the community level appears to be an effective strategy for improving febrile patient management and for reducing excessive use of anti-malarial drugs. PMID:22443344

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

PubMed Central

Obiero, Joshua M.; Shekalaghe, Seif; Hermsen, Cornelus C.; Mpina, Maxmillian; Bijker, Else M.; Roestenberg, Meta; Teelen, Karina; Billingsley, Peter F.; Sim, B. Kim Lee; James, Eric R.; Daubenberger, Claudia A.; Hoffman, Stephen L.; Abdulla, Salim

2015-01-01

To understand the effect of previous malaria exposure on antiparasite immune responses is important for developing successful immunization strategies. Controlled human malaria infections (CHMIs) using cryopreserved Plasmodium falciparum sporozoites provide a unique opportunity to study differences in acquisition or recall of antimalaria immune responses in individuals from different transmission settings and genetic backgrounds. In this study, we compared antiparasite humoral and cellular immune responses in two cohorts of malaria-naive Dutch volunteers and Tanzanians from an area of low malarial endemicity, who were subjected to the identical CHMI protocol by intradermal injection of P. falciparum sporozoites. Samples from both trials were analyzed in parallel in a single center to ensure direct comparability of immunological outcomes. Within the Tanzanian cohort, we distinguished one group with moderate levels of preexisting antibodies to asexual P. falciparum lysate and another that, based on P. falciparum serology, resembled the malaria-naive Dutch cohort. Positive P. falciparum serology at baseline was associated with a lower parasite density at first detection by quantitative PCR (qPCR) after CHMI than that for Tanzanian volunteers with negative serology. Post-CHMI, both Tanzanian groups showed a stronger increase in anti-P. falciparum antibody titers than Dutch volunteers, indicating similar levels of B-cell memory independent of serology. In contrast to the Dutch, Tanzanians failed to increase P. falciparum-specific in vitro recall gamma interferon (IFN-γ) production after CHMI, and innate IFN-γ responses were lower in P. falciparum lysate-seropositive individuals than in seronegative individuals. In conclusion, positive P. falciparum lysate serology can be used to identify individuals with better parasite control but weaker IFN-γ responses in circulating lymphocytes, which may help to stratify volunteers in future CHMI trials in areas where malaria is

Impact of Malaria at the End of Pregnancy on Infant Mortality and Morbidity

PubMed Central

Sigauque, Betuel; Sanz, Sergi; Maixenchs, María; Ordi, Jaume; Aponte, John J; Mabunda, Samuel; Alonso, Pedro L; Menéndez, Clara

2011-01-01

Background. There is some consensus that malaria in pregnancy may negatively affect infant's mortality and malaria morbidity, but there is less evidence concerning the factors involved. Methods. A total of 1030 Mozambican pregnant women were enrolled in a randomized, placebo-controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, and their infants were followed up throughout infancy. Overall mortality and malaria morbidity rates were recorded. The association of maternal and fetal risk factors with infant mortality and malaria morbidity was assessed. Results. There were 58 infant deaths among 997 live-born infants. The risk of dying during infancy was increased among infants born to women with acute placental infection (odds ratio [OR], 5.08 [95% confidence interval (CI), 1.77–14.53)], parasitemia in cord blood (OR, 19.31 [95% CI, 4.44–84.02]), low birth weight (OR, 2.82 [95% CI, 1.27–6.28]) or prematurity (OR, 3.19 [95% CI, 1.14–8.95]). Infants born to women who had clinical malaria during pregnancy (OR, 1.96 [95% CI, 1.13–3.41]) or acute placental infection (OR, 4.63 [95% CI, 2.10–10.24]) had an increased risk of clinical malaria during infancy. Conclusions. Malaria infection at the end of pregnancy and maternal clinical malaria negatively impact survival and malaria morbidity in infancy. Effective clinical management and prevention of malaria in pregnancy may improve infant's health and survival. PMID:21199881

Human behavior and malaria.

PubMed

Hongvivatana, T

1986-09-01

Human behavior in malaria is often narrowly referred to behavior of the target populations in transmission and control of malaria. In this presentation it was discussed that such view is too narrow. A broader framework incorporating illness behavior and human behavior in malaria control bureaucracies is needed for the success of national malaria control programme. Literature under the three broad categories of human behavior in malaria is reviewed to justify future directions in human behavior research and their significance for successful malaria control.

Malaria epidemiology in Lihir Island, Papua New Guinea

PubMed Central

2013-01-01

Background Plasmodium vivax and Plasmodium falciparum malaria remain highly endemic in the Pacific Islands including Lihir Island, Papua New Guinea. Lihir Gold Limited is conducting mining activities and funded an integrated vector control intervention within the villages surrounding the mine. The aim of this study was to assess the impact of such programme by comparing the epidemiological trends of malaria in different parts of the island. Methods Two cross-sectional surveys were conducted before and after the intervention (2006–2010) to determine malaria prevalence in mine-impact (MI) and non-MI areas. Incidence of malaria was estimated for the Lihir Medical Centre catchment area using island population denominators and a health-centre passive case detection ongoing from 2006–2011. Results A total of 2,264 and 1,653 children < 15 were surveyed in the cross-sectional studies. The prevalence of any malaria parasitaemia initially was 31.5% in MI areas and, 34.9% in non-MI (POR 1.17; 95 CI 0.97 – 1.39). After four years there was a significant reduction in prevalence in the MI areas (5.8%; POR 0.13, 95 CI 0.09–0.20), but reduction was less marked in non-MI areas (26.9%; POR 0.69, 95 CI 0.58-0.81). 28,747 patients were included in the evaluation of incidence trends and overall malaria in local Lihirian population in MI areas declined over time, while it remained at similar high levels among migrants. The age-incidence analysis showed that for each higher age range the malaria incidence declines compared to that of the previous stratum. Conclusions There was a substantial reduction in prevalence and incidence rates of both P. vivax and P. falciparum in the mining area following implementation of a malaria control intervention, which was not seen in the area outside the mining activities. PMID:23497296

Seasonal genetic partitioning in the neotropical malaria vector, Anopheles darlingi

PubMed Central

2014-01-01

Background Anopheles darlingi is the main malaria mosquito vector in the Amazonia region. In spite of being considered a riverine, forest-dwelling species, this mosquito is becoming more abundant in peri-urban areas, increasing malaria risk. This has been associated with human-driven environmental changes such as deforestation. Methods Microsatellites were used to characterize A. darlingi from seven localities along the Madeira River, Rondônia (Brazil), collected in the early and late periods of the rainy season. Results Two genetically distinct subpopulations were detected: one (subpopulation A) was associated with the late rainfall period and seems to be ecologically closer to the typical forest A. darlingi; the other (subpopulation B) was associated with the early rainfall period and is probably more adapted to drier conditions by exploiting permanent anthropogenic breeding sites. Results suggest also a pattern of asymmetric introgression, with more subpopulation A alleles introgressed into subpopulation B. Both subpopulations (and admixed mosquitoes) presented similar malaria infection rates, highlighting the potential for perennial malaria transmission in the region. Conclusions The co-occurrence of two genetically distinct subpopulations of A. darlingi adapted to different periods of rainfall may promote a more perennial transmission of malaria throughout the year. These findings, in a context of strong environmental impact due to deforestation and dam construction, have serious implications for malaria epidemiology and control in the Amazonian region. PMID:24885508

Models for short term malaria prediction in Sri Lanka

PubMed Central

Briët, Olivier JT; Vounatsou, Penelope; Gunawardena, Dissanayake M; Galappaththy, Gawrie NL; Amerasinghe, Priyanie H

2008-01-01

Background Malaria in Sri Lanka is unstable and fluctuates in intensity both spatially and temporally. Although the case counts are dwindling at present, given the past history of resurgence of outbreaks despite effective control measures, the control programmes have to stay prepared. The availability of long time series of monitored/diagnosed malaria cases allows for the study of forecasting models, with an aim to developing a forecasting system which could assist in the efficient allocation of resources for malaria control. Methods Exponentially weighted moving average models, autoregressive integrated moving average (ARIMA) models with seasonal components, and seasonal multiplicative autoregressive integrated moving average (SARIMA) models were compared on monthly time series of district malaria cases for their ability to predict the number of malaria cases one to four months ahead. The addition of covariates such as the number of malaria cases in neighbouring districts or rainfall were assessed for their ability to improve prediction of selected (seasonal) ARIMA models. Results The best model for forecasting and the forecasting error varied strongly among the districts. The addition of rainfall as a covariate improved prediction of selected (seasonal) ARIMA models modestly in some districts but worsened prediction in other districts. Improvement by adding rainfall was more frequent at larger forecasting horizons. Conclusion Heterogeneity of patterns of malaria in Sri Lanka requires regionally specific prediction models. Prediction error was large at a minimum of 22% (for one of the districts) for one month ahead predictions. The modest improvement made in short term prediction by adding rainfall as a covariate to these prediction models may not be sufficient to merit investing in a forecasting system for which rainfall data are routinely processed. PMID:18460204

High proportion of knowlesi malaria in recent malaria cases in Malaysia

PubMed Central

2014-01-01

Background Plasmodium knowlesi is a simian parasite that has been recognized as the fifth species causing human malaria. Naturally-acquired P. knowlesi infection is widespread among human populations in Southeast Asia. The aim of this epidemiological study was to determine the incidence and distribution of malaria parasites, with a particular focus on human P. knowlesi infection in Malaysia. Methods A total of 457 microscopically confirmed, malaria-positive blood samples were collected from 22 state and main district hospitals in Malaysia between September 2012 and December 2013. Nested PCR assay targeting the 18S rRNA gene was used to determine the infecting Plasmodium species. Results A total of 453 samples were positive for Plasmodium species by using nested PCR assay. Plasmodium knowlesi was identified in 256 (56.5%) samples, followed by 133 (29.4%) cases of Plasmodium vivax, 49 (10.8%) cases of Plasmodium falciparum, two (0.4%) cases of Plasmodium ovale and one (0.2%) case of Plasmodium malariae. Twelve mixed infections were detected, including P. knowlesi/P. vivax (n = 10), P. knowlesi/P. falciparum (n = 1), and P. falciparum/P. vivax (n = 1). Notably, P. knowlesi (Included mixed infections involving P. knowlesi (P. knowlesi/P. vivax and P. knowlesi /P. falciparum)) showed the highest proportion in Sabah (84/115 cases, prevalence of 73.0%), Sarawak (83/120, 69.2%), Kelantan (42/56, 75.0%), Pahang (24/25, 96.0%), Johor (7/9, 77.8%), and Terengganu (4/5, 80.0%,). In contrast, the rates of P. knowlesi infection in Selangor and Negeri Sembilan were found to be 16.2% (18/111 cases) and 50.0% (5/10 cases), respectively. Sample of P. knowlesi was not obtained from Kuala Lumpur, Melaka, Perak, Pulau Pinang, and Perlis during the study period, while a microscopically-positive sample from Kedah was negative by PCR. Conclusion In addition to Sabah and Sarawak, which have been known for high prevalence of P. knowlesi infection, the findings from this study

Tempol, an intracellular antioxidant, inhibits tissue factor expression, attenuates dendritic cell function, and is partially protective in a murine model of cerebral malaria.

PubMed

Francischetti, Ivo M B; Gordon, Emile; Bizzarro, Bruna; Gera, Nidhi; Andrade, Bruno B; Oliveira, Fabiano; Ma, Dongying; Assumpção, Teresa C F; Ribeiro, José M C; Pena, Mirna; Qi, Chen-Feng; Diouf, Ababacar; Moretz, Samuel E; Long, Carole A; Ackerman, Hans C; Pierce, Susan K; Sá-Nunes, Anderson; Waisberg, Michael

2014-01-01

The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood. We undertook testing Tempol--a superoxide dismutase (SOD) mimetic and pleiotropic intracellular antioxidant--in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol inhibited LPS-induced production of TNF-α, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants-such as α-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ) and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (gp91(phox-/-)) or mice treated with inhibitors of SOD (diethyldithiocarbamate

Analyzing actual risk in malaria-deferred donors through selective serologic testing.

PubMed

Nguyen, Megan L; Goff, Tami; Gibble, Joan; Steele, Whitney R; Leiby, David A

2013-08-01

Approximately 150,000 US blood donors are deferred annually for travel to malaria-endemic areas. However, the majority do not travel to the high-risk areas of Africa associated with transfusion-transmitted malaria (TTM) but visit low-risk areas such as Mexico. This study tests for Plasmodium infection among malaria-deferred donors, particularly those visiting Mexico. Blood donors deferred for malaria risk (travel, residence, or previous infection) provided blood samples and completed a questionnaire. Plasma was tested for Plasmodium antibodies by enzyme immunoassay (EIA); repeat-reactive (RR) samples were considered positive and tested by real-time polymerase chain reaction (PCR). Accepted donors provided background testing data. During 2005 to 2011, a total of 5610 malaria-deferred donors were tested by EIA, including 5412 travel deferrals. Overall, 88 (1.6%) were EIA RR; none were PCR positive. Forty-nine (55.7%) RR donors previously had malaria irrespective of deferral category, including 34 deferred for travel. Among 1121 travelers to Mexico, 90% visited Quintana Roo (no or very low risk), but just 2.2% visited Oaxaca/Chiapas (moderate or high risk). Only two Mexican travelers tested RR; both previously had malaria not acquired in Mexico. Travel to Mexico represents a large percentage of US donors deferred for malaria risk; however, these donors primarily visit no- or very-low-risk areas. No malaria cases acquired in Mexico were identified thereby supporting previous risk estimates. Consideration should be given to allowing blood donations from U.S. donors who travel to Quintana Roo and other low-risk areas in Mexico. A more effective approach to preventing TTM would be to defer all donors with a history of malaria, even if remote. © 2012 American Association of Blood Banks.

Assessment of climate-driven variations in malaria incidence in Swaziland: toward malaria elimination.

PubMed

Chuang, Ting-Wu; Soble, Adam; Ntshalintshali, Nyasatu; Mkhonta, Nomcebo; Seyama, Eric; Mthethwa, Steven; Pindolia, Deepa; Kunene, Simon

2017-06-01

Swaziland aims to eliminate malaria by 2020. However, imported cases from neighbouring endemic countries continue to sustain local parasite reservoirs and initiate transmission. As certain weather and climatic conditions may trigger or intensify malaria outbreaks, identification of areas prone to these conditions may aid decision-makers in deploying targeted malaria interventions more effectively. Malaria case-surveillance data for Swaziland were provided by Swaziland's National Malaria Control Programme. Climate data were derived from local weather stations and remote sensing images. Climate parameters and malaria cases between 2001 and 2015 were then analysed using seasonal autoregressive integrated moving average models and distributed lag non-linear models (DLNM). The incidence of malaria in Swaziland increased between 2005 and 2010, especially in the Lubombo and Hhohho regions. A time-series analysis indicated that warmer temperatures and higher precipitation in the Lubombo and Hhohho administrative regions are conducive to malaria transmission. DLNM showed that the risk of malaria increased in Lubombo when the maximum temperature was above 30 °C or monthly precipitation was above 5 in. In Hhohho, the minimum temperature remaining above 15 °C or precipitation being greater than 10 in. might be associated with malaria transmission. This study provides a preliminary assessment of the impact of short-term climate variations on malaria transmission in Swaziland. The geographic separation of imported and locally acquired malaria, as well as population behaviour, highlight the varying modes of transmission, part of which may be relevant to climate conditions. Thus, the impact of changing climate conditions should be noted as Swaziland moves toward malaria elimination.

Neonatal and congenital malaria: a case series in malaria endemic eastern Uganda.

PubMed

Olupot-Olupot, Peter; Eregu, Emma I E; Naizuli, Ketty; Ikiror, Julie; Acom, Linda; Burgoine, Kathy

2018-04-20

Congenital malaria is the direct infection of an infant with malaria parasites from their mother prior to or during birth. Neonatal malaria is due to an infective mosquito bite after birth. Neonatal and congenital malaria (NCM) are potentially life-threatening conditions that are believed to occur at relatively low rates in malaria endemic regions. However, recent reports suggest that the number of NCM cases is increasing, and its epidemiology remains poorly described. NCM can mimic other neonatal conditions and because it is thought to be rare, blood film examinations for malaria are not always routinely performed. Consequently, many cases of NCM are likely to be undiagnosed. A retrospective chart review for all neonates admitted with suspected sepsis between January and July 2017 was conducted and noted four cases of NCM since routine malaria testing was introduced as part of standard of care for suspected sepsis at Mbale Regional Referral Hospital Neonatology Unit. This description highlights the need to conduct routine malaria diagnostic testing for febrile neonates in malaria endemic areas, and supports the urgent need to undertake pharmacological studies on therapeutic agents in this population. Four cases (two congenital malaria cases and two neonatal malaria cases) are described after presenting for care at the Mbale Regional Referral Hospital Neonatal Unit (Mbale RRH-NNU). The maternal age was similar across the cases, but both neonatal malaria cases were born to primigravidae. At presentation three cases had fever and history of fever, but one was hypothermic (34.8 °C) and no history of fever. One case of congenital malaria had low birth weight, while the other was born to an HIV positive mother. Both cases of congenital malaria presented with poor feeding, in addition one of them had clinical jaundice. The neonatal malaria cases presented in the third week compared to the congenital malaria cases that presented within 48 h after birth. All of the

Malaria in Children.

PubMed

Cohee, Lauren M; Laufer, Miriam K

2017-08-01

Malaria is a leading cause of morbidity and mortality in endemic areas, leading to an estimated 438,000 deaths in 2015. Malaria is also an important health threat to travelers to endemic countries and should be considered in evaluation of any traveler returning from a malaria-endemic area who develops fever. Considering the diagnosis of malaria in patients with potential exposure is critical. Prompt provision of effective treatment limits the complications of malaria and can be life-saving. Understanding Plasmodium species variation, epidemiology, and drug-resistance patterns in the geographic area where infection was acquired is important for determining treatment choices. Copyright © 2017 Elsevier Inc. All rights reserved.

Performance of "VIKIA Malaria Ag Pf/Pan" (IMACCESS®), a new malaria rapid diagnostic test for detection of symptomatic malaria infections.

PubMed

Chou, Monidarin; Kim, Saorin; Khim, Nimol; Chy, Sophy; Sum, Sarorn; Dourng, Dany; Canier, Lydie; Nguon, Chea; Ménard, Didier

2012-08-24

Recently, IMACCESS® developed a new malaria test (VIKIA Malaria Ag Pf/Pan™), based on the detection of falciparum malaria (HRP-2) and non-falciparum malaria (aldolase). The performance of this new malaria rapid diagnostic test (RDT) was assessed using 1,000 febrile patients seeking malaria treatment in four health centres in Cambodia from August to December 2011. The results of the VIKIA Malaria Ag Pf/Pan were compared with those obtained by microscopy, the CareStart Malaria™ RDT (AccessBio®) which is currently used in Cambodia, and real-time PCR (as "gold standard"). The best performances of the VIKIA Malaria Ag Pf/Pan™ test for detection of both Plasmodium falciparum and non-P. falciparum were with 20-30 min reading times (sensitivity of 93.4% for P. falciparum and 82.8% for non-P. falciparum and specificity of 98.6% for P. falciparum and 98.9% for non-P. falciparum) and were similar to those for the CareStart Malaria™ test. This new RDT performs similarly well as other commercially available tests (especially the CareStart Malaria™ test, used as comparator), and conforms to the World Health Organization's recommendations for RDT performance. It is a good alternative tool for the diagnosis of malaria in endemic areas.

Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study.

PubMed

Mallewa, Macpherson; Vallely, Pam; Faragher, Brian; Banda, Dan; Klapper, Paul; Mukaka, Mavuto; Khofi, Harriet; Pensulo, Paul; Taylor, Terrie; Molyneux, Malcolm; Solomon, Tom

2013-09-01

Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and 34 (13%) of 262 with neither (p<0�

Early malaria resurgence in pre-elimination areas in Kokap Subdistrict, Kulon Progo, Indonesia

PubMed Central

2014-01-01

Background Indonesia is among those countries committed to malaria eradication, with a continuously decreasing incidence of malaria. However, at district level the situation is different. This study presents a case of malaria resurgence Kokap Subdistrict of the Kulon Progo District in Yogyakarta Province, Java after five years of low endemicity. This study also aims to describe the community perceptions and health services delivery situation that contribute to this case. Methods All malaria cases (2007–2011) in Kulon Progo District were stratified to annual parasite incidence (API). Two-hundred and twenty-six cases during an outbreak (May 2011 to April 2012) were geocoded by household addresses using a geographic information system (GIS) technique and clusters were identified by SaTScan software analysis (Arc GIS 10.1). Purposive random sampling was conducted on respondents living inside the clusters to identify community perceptions and behaviour related to malaria. Interviews were conducted with malaria health officers to understand the challenges of malaria surveillance and control. Results After experiencing three consecutive years with API less than 1 per thousand, malaria in Kokap subdistrict increased almost ten times higher than API in the district level and five times higher than national API. Malaria cases were found in all five villages in 2012. One primary and two secondary malaria clusters in Hargotirto and Kalirejo villages were identified during the 2011–2012 outbreak. Most of the respondents were positively aware with malaria signs and activities of health workers to prevent malaria, although some social economic activities could not be hindered. Return transmigrants or migrant workers entering to their villages, reduced numbers of village malaria workers and a surge in malaria cases in the neighbouring district contributed to the resurgence. Conclusion Community perception, awareness and participation could constitute a solid foundation for

Low uptake of preventive interventions among malaria cases in Swaziland: towards malaria elimination

PubMed Central

Dlamini, N.; Zulu, Z.; Dlamini, S.; Kunene, S.; Sikhondze, W.; Owiti, P.; Geoffroy, E.; Zachariah, R.; Mengestu, T. K.

2018-01-01

Settings: Swaziland is striving to achieve sustainable malaria elimination. Three preventive interventions are vital for reaching this goal: 1) effective household utilisation of long-lasting insecticide nets (LLINs), 2) indoor residual spraying (IRS), and 3) provision of chemoprophylaxis for those travelling to malaria-endemic areas. Objectives: To assess the uptake of preventive intervention among confirmed malaria cases. Design: A longitudinal study using nation-wide programme data from 2010 to 2015. Data on malaria cases from health facilities were sourced from the Malaria Surveillance Database System. Results: Of a total 2568 confirmed malaria cases in Swaziland, 2034 (79%) had complete data on case investigations and were included in the analysis. Of 341 (17%) individuals who owned LLINs, 169 (8%) used them; 338 (17%) had IRS and 314 (15%) slept in sprayed structures. Of 1403 travellers to areas at high malaria risk, 59 (4%) used any form of malaria prevention, including chemoprophylaxis. Conclusion: The uptake of all three key malaria prevention interventions is low, and could threaten the progress made thus far toward malaria elimination. Efforts to improve this situation, including qualitative research to understand the reasons for low uptake, are urgently needed. PMID:29713591

Malaria control in South Sudan, 2006–2013: strategies, progress and challenges

PubMed Central

2013-01-01

Background South Sudan has borne the brunt of years of chronic warfare and probably has the highest malaria burden in sub-Saharan Africa. However, effective malaria control in post-conflict settings is hampered by a multiplicity of challenges. This manuscript reports on the strategies, progress and challenges of malaria control in South Sudan and serves as an example epitome for programmes operating in similar environments and provides a window for leveraging resources. Case description To evaluate progress and challenges of the national malaria control programme an in-depth appraisal was undertaken according to the World Health Organization standard procedures for malaria programme performance review. Methodical analysis of published and unpublished documents on malaria control in South Sudan was conducted. To ensure completeness, findings of internal thematic desk assessments were triangulated in the field and updated by external review teams. Discussion and evaluation South Sudan has strived to make progress in implementing the WHO recommended malaria control interventions as set out in the 2006–2013 National Malaria Strategic Plan. The country has faced enormous programmatic constraints including infrastructure, human and financial resource and a weak health system compounded by an increasing number of refugees, returnees and internally displaced people. The findings present a platform on which to tailor an evidence-based 2014–2018 national malaria strategic plan for the country and a unique opportunity for providing a model for countries in a post-conflict situation. Conclusions The prospects for effective malaria control and elimination are huge in South Sudan. Nevertheless, strengthened coordination, infrastructure and human resource capacity, monitoring and evaluation are required. To achieve all this, allocation of adequate local funding would be critical. PMID:24160336

Host immune response in returning travellers infected with malaria.

PubMed

MacMullin, Gregory; Mackenzie, Ronald; Lau, Rachel; Khang, Julie; Zhang, Haibo; Rajwans, Nimerta; Liles, W Conrad; Pillai, Dylan R

2012-05-03

Clinical observations suggest that Canadian-born (CB) travellers are prone to more severe malaria, characterized by higher parasite density in the blood, and severe symptoms, such as cerebral malaria and renal failure, than foreign-born travellers (FB) from areas of malaria endemicity. It was hypothesized that host cytokine and chemokine responses differ significantly in CB versus FB patients returning with malaria, contributing to the courses of severity. A more detailed understanding of the profiles of cytokines, chemokines, and endothelial activation may be useful in developing biomarkers and novel therapeutic approaches for malaria. The patient population for the study (n = 186) was comprised of travellers returning to Toronto, Canada between 2007 and 2011. The patient blood samples' cytokine, chemokine and angiopoietin concentrations were determined using cytokine multiplex assays, and ELISA assays. Significantly higher plasma cytokine levels of IL-12 (p40) were observed in CB compared to FB travellers, while epidermal growth factor (EGF) was observed to be higher in FB than CB travellers. Older travellers (55 years old or greater) with Plasmodium vivax infections had significantly higher mean cytokine levels for IL-6 and macrophage colony-stimulating factor (M-CSF) than other adults with P. vivax (ages 18-55). Patients with P. vivax infections had significantly higher mean cytokine levels for monocyte chemotactic protein-1 (MCP-1), and M-CSF than patients with Plasmodium falciparum. Angiopoietin 2 (Ang-2) was higher for patients infected with P. falciparum than P. vivax, especially when comparing just the FB groups. IL-12 (p40) was higher in FB patients with P. vivax compared to P. falciparum. Il-12 (p40) was also higher in patients infected with P. vivax than those infected with Plasmodium ovale. For patients travelling to West Africa, IFN-γ and IL-6 was lower than for patients who were in other regions of Africa. Significantly higher levels of IL-12 (p40

Epidemiological and clinical correlates of malaria-helminth co-infections in southern Ethiopia

PubMed Central

2013-01-01

Background In many areas of the world, including Ethiopia, malaria and helminths are co-endemic, therefore, co-infections are common. However, little is known how concurrent infections affect the epidemiology and/or pathogenesis of each other. Therefore, this study was conducted to assess the effects of intestinal helminth infections on the epidemiology and clinical patterns of malaria in southern Ethiopia where both infections are prevalent. Methods A cross-sectional study was conducted in 2006 at Wondo Genet Health Center and Bussa Clinic, southern Ethiopia. Consecutive blood film positive malaria patients (N=230) and malaria negative asymptomatic individuals (N=233) were recruited. Malaria parasite detection and quantification was diagnosed using Giemsa-stained thick and thin blood films, respectively. Helminths were detected using direct microscopy and formol-ether concentration techniques. Coarse quantification of helminths ova was made using Kato Katz method. Results The over all magnitude of intestinal parasitic infection was high irrespective of malaria infection (67% among malaria positive patients versus 53.1% among malaria non-infected asymptomatic individuals). Trichuris trichiura infection was associated with increased malaria prevalence while increased worm burden of helminths as expressed by egg intensity was associated with increased malaria parasitaemia which could be a potential factor for development of severe malarial infection with the course of the disease. Majority (77%) of the subjects had multiple helminths infection. T. trichiura, Ascaris lumbricoides, Schistosoma mansoni, and hookworm infestation accounted for 64.5, 57.7 %, 28.4%, and 12.2% of the infections, respectively. Conclusions Populations in malaria-endemic areas of southern Ethiopia are multi-parasitized with up to four helminths. Mass deworming may be a simple practical approach in endemic areas in reducing the risk of severe malarial attack particularly for those at high risk

Ranking malaria risk factors to guide malaria control efforts in African highlands.

PubMed

Protopopoff, Natacha; Van Bortel, Wim; Speybroeck, Niko; Van Geertruyden, Jean-Pierre; Baza, Dismas; D'Alessandro, Umberto; Coosemans, Marc

2009-11-25

Malaria is re-emerging in most of the African highlands exposing the non immune population to deadly epidemics. A better understanding of the factors impacting transmission in the highlands is crucial to improve well targeted malaria control strategies. A conceptual model of potential malaria risk factors in the highlands was built based on the available literature. Furthermore, the relative importance of these factors on malaria can be estimated through "classification and regression trees", an unexploited statistical method in the malaria field. This CART method was used to analyse the malaria risk factors in the Burundi highlands. The results showed that Anopheles density was the best predictor for high malaria prevalence. Then lower rainfall, no vector control, higher minimum temperature and houses near breeding sites were associated by order of importance to higher Anopheles density. In Burundi highlands monitoring Anopheles densities when rainfall is low may be able to predict epidemics. The conceptual model combined with the CART analysis is a decision support tool that could provide an important contribution toward the prevention and control of malaria by identifying major risk factors.

High prevalence of asymptomatic malaria in south-eastern Bangladesh

PubMed Central

2014-01-01

Background The WHO has reported that RDT and microscopy-confirmed malaria cases have declined in recent years. However, it is still unclear if this reflects a real decrease in incidence in Bangladesh, as particularly the hilly and forested areas of the Chittagong Hill Tract (CHT) Districts report more than 80% of all cases and deaths. surveillance and epidemiological data on malaria from the CHT are limited; existing data report Plasmodium falciparum and Plasmodium vivax as the dominant species. Methods A cross-sectional survey was conducted in the District of Bandarban, the southernmost of the three Hill Tracts Districts, to collect district-wide malaria prevalence data from one of the regions with the highest malaria endemicity in Bangladesh. A multistage cluster sampling technique was used to collect blood samples from febrile and afebrile participants and malaria microscopy and standardized nested PCR for diagnosis were performed. Demographic data, vital signs and splenomegaly were recorded. Results Malaria prevalence across all subdistricts in the monsoon season was 30.7% (95% CI: 28.3-33.2) and 14.2% (95% CI: 12.5-16.2) by PCR and microscopy, respectively. Plasmodium falciparum mono-infections accounted for 58.9%, P. vivax mono-infections for 13.6%, Plasmodium malariae for 1.8%, and Plasmodium ovale for 1.4% of all positive cases. In 24.4% of all cases mixed infections were identified by PCR. The proportion of asymptomatic infections among PCR-confirmed cases was 77.0%, oligosymptomatic and symptomatic cases accounted for only 19.8 and 3.2%, respectively. Significantly (p < 0.01) more asymptomatic cases were recorded among participants older than 15 years as compared to younger participants, whereas prevalence and parasite density were significantly (p < 0.01) higher in patients younger than 15 years. Spleen rate and malaria prevalence in two to nine year olds were 18.6 and 34.6%, respectively. No significant difference in malaria prevalence and

Malaria Diagnosis Using a Mobile Phone Polarized Microscope

NASA Astrophysics Data System (ADS)

Pirnstill, Casey W.; Coté, Gerard L.

2015-08-01

Malaria remains a major global health burden, and new methods for low-cost, high-sensitivity, diagnosis are essential, particularly in remote areas with low-resource around the world. In this paper, a cost effective, optical cell-phone based transmission polarized light microscope system is presented for imaging the malaria pigment known as hemozoin. It can be difficult to determine the presence of the pigment from background and other artifacts, even for skilled microscopy technicians. The pigment is much easier to observe using polarized light microscopy. However, implementation of polarized light microscopy lacks widespread adoption because the existing commercial devices have complicated designs, require sophisticated maintenance, tend to be bulky, can be expensive, and would require re-training for existing microscopy technicians. To this end, a high fidelity and high optical resolution cell-phone based polarized light microscopy system is presented which is comparable to larger bench-top polarized microscopy systems but at much lower cost and complexity. The detection of malaria in fixed and stained blood smears is presented using both, a conventional polarized microscope and our cell-phone based system. The cell-phone based polarimetric microscopy design shows the potential to have both the resolution and specificity to detect malaria in a low-cost, easy-to-use, modular platform.

Malaria Diagnosis Using a Mobile Phone Polarized Microscope

PubMed Central

Pirnstill, Casey W.; Coté, Gerard L.

2015-01-01

Malaria remains a major global health burden, and new methods for low-cost, high-sensitivity, diagnosis are essential, particularly in remote areas with low-resource around the world. In this paper, a cost effective, optical cell-phone based transmission polarized light microscope system is presented for imaging the malaria pigment known as hemozoin. It can be difficult to determine the presence of the pigment from background and other artifacts, even for skilled microscopy technicians. The pigment is much easier to observe using polarized light microscopy. However, implementation of polarized light microscopy lacks widespread adoption because the existing commercial devices have complicated designs, require sophisticated maintenance, tend to be bulky, can be expensive, and would require re-training for existing microscopy technicians. To this end, a high fidelity and high optical resolution cell-phone based polarized light microscopy system is presented which is comparable to larger bench-top polarized microscopy systems but at much lower cost and complexity. The detection of malaria in fixed and stained blood smears is presented using both, a conventional polarized microscope and our cell-phone based system. The cell-phone based polarimetric microscopy design shows the potential to have both the resolution and specificity to detect malaria in a low-cost, easy-to-use, modular platform. PMID:26303238

Persistent Parasitism: The Adaptive Biology of Malariae and Ovale Malaria.

PubMed

Sutherland, Colin J

2016-10-01

Plasmodium malariae causes malaria in humans throughout the tropics and subtropics. Plasmodium ovale curtisi and Plasmodium ovale wallikeri are sympatric sibling species common in sub-Saharan Africa and also found in Oceania and Asia. Although rarely identified as the cause of malaria cases in endemic countries, PCR detection has confirmed all three parasite species to be more prevalent, and persistent, than previously thought. Chronic, low-density, multispecies asymptomatic infection is a successful biological adaptation by these Plasmodium spp., a pattern also observed among malaria parasites of wild primates. Current whole-genome analyses are illuminating the species barrier separating the ovale parasite species and reveal substantial expansion of subtelomeric gene families. The evidence for and against a quiescent pre-erythrocytic form of P. malariae is reviewed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Advances in malaria elimination in Botswana: a dramatic shift to parasitological diagnosis, 2008–2014

PubMed Central

Edwards, J. K.; Motlaleng, M.; Namboze, J.; Butt, W.; Obopile, M.; Mosweunyane, T.; Manzi, M.; Takarinda, K. C.; Owiti, P.

2018-01-01

Background: Malaria elimination requires infection detection using quality assured diagnostics and appropriate treatment regimens. Although Botswana is moving towards malaria elimination, reports of unconfirmed cases may jeopardise this effort. This study aimed to determine the proportion of cases treated for malaria that were confirmed by rapid diagnostic testing (RDT) and/or microscopy. Methods: This was a retrospective descriptive study using routine national data from the integrated disease surveillance and case-based surveillance systems from 2008 to 2014. The data were categorised into clinical and confirmed cases each year. An analysis of the data on cases registered in three districts that reported approximately 70% of all malaria cases was performed, stratified by year, type of reporting health facilities and diagnostic method. Results: During 2008–2014, 50 487 cases of malaria were reported in Botswana, and the proportion of RDT and/or blood microscopy confirmed cases improved from 6% in 2008 to 89% in 2013. The total number of malaria cases decreased by 97% in the same period, then increased by 41% in 2013. Conclusion: This study shows that malaria diagnostic tests dramatically improved malaria diagnosis and consequently reduced the malaria burden in Botswana. The study identified a need to build capacity on microscopy for species identification, parasite quantification and guiding treatment choices. PMID:29713592

The economic benefits of malaria elimination: do they include increases in tourism?

PubMed

Modrek, Sepideh; Liu, Jenny; Gosling, Roland; Feachem, Richard G A

2012-07-28

Policy makers have speculated that one of the economic benefits of malaria elimination includes increases in foreign direct investment, particularly tourism. This study examines the empirical relationship between the demand for travel and malaria cases in two countries with large tourism industries around the time in which they carried out malaria-elimination campaigns. In Mauritius, this analysis examines historical, yearly tourist arrivals and malaria cases from 1978-1999, accounting for the background secular trend of increasing international travel. In Dominican Republic, a country embarking upon malaria elimination, it employs a time-series analysis of the monthly, international tourist arrivals from 1998-2010 to determine whether the timing of significant deviations in tourist arrivals coincides with malaria outbreaks. While naïve relationships exist in both cases, the results show that the relationships between tourist arrivals and malaria cases are relatively weak and statistically insignificant once secular confounders are accounted for. This suggests that any economic benefits from tourism that may be derived from actively pursuing elimination in countries that have high tourism potential are likely to be small when measured at a national level. Rather, tourism benefits are likely to be experienced with greater impact in more concentrated tourist areas within countries, and future studies should seek to assess these relationships at a regional or local level.

Spatial trend, environmental and socioeconomic factors associated with malaria prevalence in Chennai

PubMed Central

2014-01-01

Background Urban malaria is considered to be one of the most significant infectious diseases due to varied socioeconomic problems especially in tropical countries like India. Among the south Indian cities, Chennai is endemic for malaria. The present study aimed to identify the hot spots of malaria prevalence and the relationship with other factors in Chennai during 2005-2011. Methods Data on zone-wise and ward-wise monthly malaria positive cases were collected from the Vector Control Office, Chennai Corporation, for the year 2005 to 2011 and verified using field data. This data was used to calculate the prevalence among thousand people. Hotspot analysis for all the years in the study period was done to observe the spatial trend. Association of environmental factors like altitude, population density and climatic variables was assessed using ArcGIS 9.3 version and SPSS 11.5. Pearson’s correlation of climate parameters at 95% and 99% was considered to be the most significant. Social parameters of the highly malaria prone region were evaluated through a structured random questionnaire field survey. Results Among the ten zones of Chennai Corporation, Basin Bridge zone showed high malaria prevalence during the study period. The ‘hotspot’ analysis of malaria prevalence showed the emergence of newer hotspots in the Adyar zone. These hotspots of high prevalence are places of moderately populated and moderately elevated areas. The prevalence of malaria in Chennai could be due to rainfall and temperature, as there is a significant correlation with monthly rainfall and one month lag of monthly mean temperature. Further it has been observed that the socioeconomic status of people in the malaria hotspot regions and unhygienic living conditions were likely to aggravate the malaria problem. Conclusion Malaria hotspots will be the best method to use for targeting malaria control activities. Proper awareness and periodical monitoring of malaria is one of the quintessential

Malaria in rural Mozambique. Part I: Children attending the outpatient clinic

PubMed Central

Guinovart, Caterina; Bassat, Quique; Sigaúque, Betuel; Aide, Pedro; Sacarlal, Jahit; Nhampossa, Tacilta; Bardají, Azucena; Nhacolo, Ariel; Macete, Eusébio; Mandomando, Inácio; Aponte, John J; Menéndez, Clara; Alonso, Pedro L

2008-01-01

Background Malaria represents a huge burden for the health care services across Africa. Describing malaria attending health services contributes to quantify the burden and describe the epidemiology and clinical presentation. Methods Retrospective analysis of data collected through the Manhiça morbidity surveillance system (Mozambique) on all paediatric visits (<15 years) to the outpatient clinic from June 2003 to May 2005. Age-specific minimum community-based incidence rates (MCBIRs) of malaria were calculated using demographic surveillance system data. Malaria was defined as fever or history of fever in the preceding 24 hours with asexual Plasmodium falciparum parasitaemia of any density in the blood smear. Results A total of 94,941 outpatient visits were seen during the study period, of which 30.5% had malaria. Children younger than three years accounted for almost half of the total malaria cases and children aged ≥ 5 years represented 36.4% of the cases. Among children who presented with malaria, 56.7% had fever and among children who presented with fever or a history of fever only 37.2% had malaria. The geometric mean parasitaemia in malaria cases was 8582.2 parasites/μL, peaking in children aged two to three years. 13% of malaria cases had a PCV<25% and the mean PCV in malaria cases increased gradually with age, ranging from 27.8% in children aged 2–12 months to 34.4% in ≥ 5 years. The percentage of cases admitted or transferred showed a clear decreasing trend with age. MCBIRs of outpatient malaria per 1,000 child years at risk for the whole study period were of 394 in infants, 630 in children aged 1 to <5 years and 237 in children aged five years or more. A clustering of the cases was observed, whereby most children never had malaria, some had a few episodes and very few had many episodes. Conclusion Preventive measures should be targeted at children younger than three years, as they carry the highest burden of malaria. Children aged 5–15 years

Malaria ecotypes and stratification.

PubMed

Schapira, Allan; Boutsika, Konstantina

2012-01-01

To deal with the variability of malaria, control programmes need to stratify their malaria problem into a number of smaller units. Such stratification may be based on the epidemiology of malaria or on its determinants such as ecology. An ecotype classification was developed by the World Health Organization (WHO) around 1990, and it is time to assess its usefulness for current malaria control as well as for malaria modelling on the basis of published research. Journal and grey literature was searched for articles on malaria or Anopheles combined with ecology or stratification. It was found that all malaria in the world today could be assigned to one or more of the following ecotypes: savanna, plains and valleys; forest and forest fringe; foothill; mountain fringe and northern and southern fringes; desert fringe; coastal and urban. However, some areas are in transitional or mixed zones; furthermore, the implications of any ecotype depend on the biogeographical region, sometimes subregion, and finally, the knowledge on physiography needs to be supplemented by local information on natural, anthropic and health system processes including malaria control. Ecotyping can therefore not be seen as a shortcut to determine control interventions, but rather as a framework to supplement available epidemiological and entomological data so as to assess malaria situations at the local level, think through the particular risks and opportunities and reinforce intersectoral action. With these caveats, it does however emerge that several ecotypic distinctions are well defined and have relatively constant implications for control within certain biogeographic regions. Forest environments in the Indo-malay and the Neotropics are, with a few exceptions, associated with much higher malaria risk than in adjacent areas; the vectors are difficult to control, and the anthropic factors also often converge to impose constraints. Urban malaria in Africa is associated with lower risk than savanna

Diagnostic performance of CareStart™ malaria HRP2/pLDH (Pf/pan) combo test versus standard microscopy on falciparum and vivax malaria between China-Myanmar endemic borders

PubMed Central

2013-01-01

Background Rapid diagnostic test (RDT) is becoming an alternative way of establishing quickly the diagnosis of malaria infections, by detecting specific malaria antigens in suspected patients’ blood between the China-Myanmar endemic borders areas, towards achieving the National Malaria Elimination programme by 2020. The objective of this study is to evaluate the performance of CareStart™ Malaria Pf/Pan RDT kit for the diagnosis of malaria infections in suspected patients. Blood examination by microscopy was taken as gold standard to evaluate CareStart™ kit’s sensitivity, specificity and predictive value and corrected with PCR assay. Results Overall 126 of 241 (52.28%) malaria cases were detected by microscopy compared to 115 of 241(47.72%) CareStart™ kit and 128 of 241 (53.11%) PCR corrected assay. CareStart™ kit’s sensitivity and specificity for the diagnosis of malaria were 89.68% and 98.26% respectively, compared to standard microscopy, whereas the sensitivity and specificity for falciparum malaria were 88.52% and 98.26%, and for vivax malaria: 90.77% and 100%. The CareStart™ positive predictive values were 98.26% (93.88-99.52%, 95% CI) compared to 100% (96.77-100%, 95% CI) for PCR-corrected, and the negative predictive values of 89.68% (83.15-93.87%, 95% CI) were the same in microscopy as PCR-corrected. The diagnostic accuracy of CareStart™ kit versus microscopy and PCR were 93.78% (89.99-96.19%, 95% CI) and 94.61% (90.99-96.82%, 95% CI) respectively. The likelihood of diagnostic of malaria positive was almost similar between microscopy and CareStart™ kit, with an entropy reduction of 60.0% compared to a weak likelihood of misdiagnosis of 0.10 (0.09-0.12, 95% CI), with an entropy reduction of 36.01%. Conclusion The accuracy of CareStart™ kit is comparable to gold standard microscopy in these areas, it is easy to perform and suitable for cross-border diagnosis and monitoring of local or imported malaria patterns by any local health staff in

Increasing malaria hospital admissions in Uganda between 1999 and 2009

PubMed Central

2011-01-01

Background Some areas of Africa are witnessing a malaria transition, in part due to escalated international donor support and intervention coverage. Areas where declining malaria rates have been observed are largely characterized by relatively low baseline transmission intensity and rapid scaling of interventions. Less well described are changing patterns of malaria burden in areas of high parasite transmission and slower increases in control and treatment access. Methods Uganda is a country predominantly characterized by intense, perennial malaria transmission. Monthly pediatric admission data from five Ugandan hospitals and their catchments have been assembled retrospectively across 11 years from January 1999 to December 2009. Malaria admission rates adjusted for changes in population density within defined catchment areas were computed across three time periods that correspond to periods where intervention coverage data exist and different treatment and prevention policies were operational. Time series models were developed adjusting for variations in rainfall and hospital use to examine changes in malaria hospitalization over 132 months. The temporal changes in factors that might explain changes in disease incidence were qualitatively examined sequentially for each hospital setting and compared between hospital settings Results In four out of five sites there was a significant increase in malaria admission rates. Results from time series models indicate a significant month-to-month increase in the mean malaria admission rates at four hospitals (trend P < 0.001). At all hospitals malaria admissions had increased from 1999 by 47% to 350%. Observed changes in intervention coverage within the catchments of each hospital showed a change in insecticide-treated net coverage from <1% in 2000 to 33% by 2009 but accompanied by increases in access to nationally recommended drugs at only two of the five hospital areas studied. Conclusions The declining malaria disease

Malaria Situation and Anopheline Mosquitoes in Qom Province, Central Iran

PubMed Central

Farzinnia, B; Saghafipour, A; Abai, MR

2010-01-01

Background: The aims of this study was to analysis the current situation of malaria and to find the distribution of anopheline mosquitoes, as probable vectors of the disease, in Qom Province, central Iran. Methods: This study was carried out in two parts. First stage was data collection about malaria cases using recorded documents of patients in the Province health center, during 2001–2008. The second stage was entomological survey conducted by mosquito larval collection method in 4 villages with different geographical positions in 2008. Data were analyzed using Excel software. Results: Of 4456 blood slides, 10.9% out were positive. Most of cases were imported from other countries (90.4%), mainly from Afghanistan (56.5%) and Pakistan (16.3%). Slide positive rate showed a maximum of 16.9% and a minimum of 2.9% in 2008 and 2007, respectively. Plasmodium vivax was causative agent of 93.75% of cases, followed by P. falciparum (6.25%). More than 15 years old age group contained the most malaria reported cases (66.7%). Two Anopheles species, An. superpictus and An. claviger were collected and identified. This is the first report of Anopheles claviger in Qom Province. Conclusion: Malaria is in the control stage in Qom Province. The rate of local transmission is very low (only 1 case), shows Anopheles superpictus, as the main malaria vector of central part of Iran, can play its role in malaria transmission in the area. PMID:22808402

Funding for malaria control 2006–2010: A comprehensive global assessment

PubMed Central

2012-01-01

Background The last decade has seen a dramatic increase in international and domestic funding for malaria control, coupled with important declines in malaria incidence and mortality in some regions of the world. As the ongoing climate of financial uncertainty places strains on investment in global health, there is an increasing need to audit the origin, recipients and geographical distribution of funding for malaria control relative to populations at risk of the disease. Methods A comprehensive review of malaria control funding from international donors, bilateral sources and national governments was undertaken to reconstruct total funding by country for each year 2006 to 2010. Regions at risk from Plasmodium falciparum and/or Plasmodium vivax transmission were identified using global risk maps for 2010 and funding was assessed relative to populations at risk. Those nations with unequal funding relative to a regional average were identified and potential explanations highlighted, such as differences in national policies, government inaction or donor neglect. Results US$8.9 billion was disbursed for malaria control and elimination programmes over the study period. Africa had the largest levels of funding per capita-at-risk, with most nations supported primarily by international aid. Countries of the Americas, in contrast, were supported typically through national government funding. Disbursements and government funding in Asia were far lower with a large variation in funding patterns. Nations with relatively high and low levels of funding are discussed. Conclusions Global funding for malaria control is substantially less than required. Inequity in funding is pronounced in some regions particularly when considering the distinct goals of malaria control and malaria elimination. Efforts to sustain and increase international investment in malaria control should be informed by evidence-based assessment of funding equity. PMID:22839432

Cost Effectiveness of Malaria Interventions from Preelimination through Elimination: a Study in Iran

PubMed Central

Rezaei-Hemami, Mohsen; Akbari-Sari, Ali; Raiesi, Ahmad; Vatandoost, Hassan; Majdzadeh, Reza

2014-01-01

Background Malaria still is considered as a public health problem in Iran. The aim of the National Malaria Control Department is to reach the elimination by 2024. By decreasing the number of malaria cases in preelimination phase the cost effectiveness of malaria interventions decreases considerably. This study estimated the cost effectiveness of various strategies to combat malaria in preelimination and elimination phases in Iran. Methods: running costs of the interventions at each level of intervention was estimated by using evidence and expert opinions. The effect of each intervention was estimated using the documentary evidence available and expert opinions. Using a point estimate and distribution of each variable the sensitivity was evaluated with the Monte Carlo method. Results: The most cost-effective interventions were insecticide treated net (ITN), larviciding, surveillance for diagnosis and treatment of patients less than 24 hours, and indoor residual spraying (IRS) respectively, No related evidence found for the effectiveness of the border facilities. Conclusion: This study showed that interventions in the elimination phase of malaria have low cost effectiveness in Iran like many other countries. However ITN is the most cost effective intervention among the available interventions. PMID:25629064

Re-imagining malaria--a platform for reflections to widen horizons in malaria control.

PubMed

Hausmann-Muela, Susanna; Eckl, Julian

2015-04-24

Ongoing political-economic discussions that take stock of social and societal determinants of health present an opportunity for productive dialogue on why current approaches to malaria control and elimination need to be broadened, and how this may be accomplished. They invite us, for example, to look beyond malaria as a disease, to appreciate the experiences of malaria-afflicted populations, to transcend techno-centric approaches, to investigate social conflicts around malaria, to give voice to the communities engaged in bottom-up approaches, and to revisit lessons learned in the past. While contributions from all disciplines are invited to this discussion, social scientists are particularly encouraged to participate. They have struggled in the past to find an appropriate platform within the malaria community that provides them the opportunity to address researchers from other disciplines, malaria practitioners, and policy makers. The Malaria Journal's new thematic series on 're-imagining malaria' offers them this opportunity. The goal of the series is to encourage transdisciplinary thinking, to stimulate discussion, to promote constructive criticism, and to gather overlooked experiences that help to reflect on implicit assumptions. Overall it aims at widening horizons in malaria control.

Is There a Risk of Suburban Transmission of Malaria in Selangor, Malaysia?

PubMed Central

Braima, Kamil A.; Sum, Jia-Siang; Ghazali, Amir-Ridhwan M.; Muslimin, Mustakiza; Jeffery, John; Lee, Wenn-Chyau; Shaker, Mohammed R.; Elamin, Alaa-Eldeen M.; Jamaiah, Ibrahim; Lau, Yee-Ling; Rohela, Mahmud; Kamarulzaman, Adeeba; Sitam, Frankie; Mohd-Noh, Rosnida; Abdul-Aziz, Noraishah M.

2013-01-01

Background The suburban transmission of malaria in Selangor, Malaysia’s most developed and populous state still remains a concern for public health in this region. Despite much successful control efforts directed at its reduction, sporadic cases, mostly brought in by foreigners have continued to occur. In addition, cases of simian malaria caused by Plasmodium knowlesi, some with fatal outcome have caused grave concern to health workers. The aim of this study was to investigate the possibility of local malaria transmission in suburban regions of Selangor, which are adjacent to secondary rainforests. Findings A malaria survey spanning 7 years (2006 - 2012) was conducted in Selangor. A total of 1623 laboratory confirmed malaria cases were reported from Selangor’s nine districts. While 72.6% of these cases (1178/1623) were attributed to imported malaria (cases originating from other countries), 25.5% (414/1623) were local cases and 1.9% (31/1623) were considered as relapse and unclassified cases combined. In this study, the most prevalent infection was P. vivax (1239 cases, prevalence 76.3%) followed by P. falciparum (211, 13.0%), P. knowlesi (75, 4.6%), P. malariae (71, 4.4%) and P. ovale (1, 0.06%). Mixed infections comprising of P. vivax and P. falciparum were confirmed (26, 1.6%). Entomological surveys targeting the residences of malaria patients’ showed that the most commonly trapped Anopheles species was An. maculatus. No oocysts or sporozoites were found in the An. maculatus collected. Nevertheless, the possibility of An. maculatus being the malaria vector in the investigated locations was high due to its persistent occurrence in these areas. Conclusions Malaria cases reported in this study were mostly imported cases. However the co-existence of local cases and potential Plasmodium spp. vectors should be cause for concern. The results of this survey reflect the need of maintaining closely monitored malaria control programs and continuous extensive malaria

The economic burden of malaria.

PubMed

Gallup, J L; Sachs, J D

2001-01-01

Malaria and poverty are intimately connected. Controlling for factors such as tropical location, colonial history, and geographical isolation, countries with intensive malaria had income levels in 1995 of only 33% that of countries without malaria, whether or not the countries were in Africa. The high levels of malaria in poor countries are not mainly a consequence of poverty. Malaria is geographically specific. The ecological conditions that support the more efficient malaria mosquito vectors primarily determine the distribution and intensity of the disease. Intensive efforts to eliminate malaria in the most severely affected tropical countries have been largely ineffective. Countries that have eliminated malaria in the past half century have all been either subtropical or islands. These countries' economic growth in the 5 years after eliminating malaria has usually been substantially higher than growth in the neighboring countries. Cross-country regressions for the 1965-1990 period confirm the relationship between malaria and economic growth. Taking into account initial poverty, economic policy, tropical location, and life expectancy, among other factors, countries with intensive malaria grew 1.3% less per person per year, and a 10% reduction in malaria was associated with 0.3% higher growth. Controlling for many other tropical diseases does not change the correlation of malaria with economic growth, and these diseases are not themselves significantly negatively correlated with economic growth. A second independent measure of malaria has a slightly higher correlation with economic growth in the 1980-1996 period. We speculate about the mechanisms that could cause malaria to have such a large impact on the economy, such as foreign investment and economic networks within the country.

B and T lymphocyte attenuator restricts the protective immune response against experimental malaria.

PubMed

Adler, Guido; Steeg, Christiane; Pfeffer, Klaus; Murphy, Theresa L; Murphy, Kenneth M; Langhorne, Jean; Jacobs, Thomas

2011-11-15

The immune response against the blood stage of malaria has to be tightly regulated to allow for vigorous antiplasmodial activity while restraining potentially lethal immunopathologic damage to the host like cerebral malaria. Coinhibitory cell surface receptors are important modulators of immune activation. B and T lymphocyte attenuator (BTLA) (CD272) is a coinhibitory receptor expressed by most leukocytes, with the highest expression levels on T and B cells, and is involved in the maintenance of peripheral tolerance by dampening the activation of lymphocytes. The function of BTLA is described in several models of inflammatory disorders and autoimmunity, but its function in infectious diseases is less well characterized. Also, little is known about the influence of BTLA on non-T cells. In this study, we analyzed the function of BTLA during blood-stage malaria infection with the nonlethal Plasmodium yoelii strain 17NL. We show that BTLA knockout mice exhibit strongly reduced parasitemia and clear the infection earlier compared with wild-type mice. This increased resistance was seen before the onset of adaptive immune mechanisms and even in the absence of T and B cells but was more pronounced at later time points when activation of T and B cells was observed. We demonstrate that BTLA regulates production of proinflammatory cytokines in a T cell-intrinsic way and B cell intrinsically regulates the production of P. yoelii 17NL-specific Abs. These results indicate that the coinhibitory receptor BTLA plays a critical role during experimental malaria and attenuates the innate as well as the subsequent adaptive immune response.

Community mobilization for malaria elimination: application of an open space methodology in Ruhuha sector, Rwanda

PubMed Central

2014-01-01

Background Despite the significant reduction of malaria transmission in Rwanda, Ruhuha sector is still a highly endemic area for malaria. The objective of this activity was to explore and brainstorm the potential roles of various community stakeholders in malaria elimination. Methods Horizontal participatory approaches such as ‘open space’ have been deployed to explore local priorities, stimulate community contribution to project planning, and to promote local capacity to manage programmes. Two open space meetings were conducted with 62 and 82 participants in years 1 and 2, respectively. Participants included purposively selected community and local organizations’ representatives. Results Malaria was perceived as a health concern by the respondents despite the reported reduction in prevalence from 60 to 20% for cases at the local health centre. Some misconceptions of the cause of malaria and misuse of preventive strategies were noted. Poverty was deemed to be a contributing factor to malaria transmission, with suggestions that improvement of living conditions for poor families might help malaria reduction. Participants expressed willingness to contribute to malaria elimination and underscored the need for constant education, sensitization and mobilization towards malaria control in general. Active diagnosis, preventative strategies and prompt treatment of malaria cases were all mentioned by participants as ways to reduce malaria. Participants suggested that partnership of stakeholders at various levels could speed up programme activities. A community rewards system was deemed important to motivate engaged participants, i.e., community health workers and households. Establishment of malaria clubs in schools settings was also suggested as crucial to speed up community awareness and increase skills towards further malaria reduction. Conclusions This bottom-up approach was found useful in engaging the local community, enabling them to explore issues related to

Malaria in India: The Center for the Study of Complex Malaria in India

PubMed Central

Das, Aparup; Anvikar, Anupkumar R.; Cator, Lauren J.; Dhiman, Ramesh C.; Eapen, Alex; Mishra, Neelima; Nagpal, Bhupinder N.; Nanda, Nutan; Raghavendra, Kamaraju; Read, Andrew F.; Sharma, Surya K.; Singh, Om P.; Singh, Vineeta; Sinnis, Photini; Srivastava, Harish C.; Sullivan, Steven A.; Sutton, Patrick L.; Thomas, Matthew B.; Carlton, Jane M.; Valecha, Neena

2012-01-01

Malaria is a major public health problem in India and one which contributes significantly to the overall malaria burden in Southeast Asia. The National Vector Borne Disease Control Program of India reported ~1.6 million cases and ~1100 malaria deaths in 2009. Some experts argue that this is a serious underestimation and that the actual number of malaria cases per year is likely between 9 and 50 times greater, with an approximate 13-fold underestimation of malaria-related mortality. The difficulty in making these estimations is further exacerbated by (i) highly variable malaria eco-epidemiological profiles, (ii) the transmission and overlap of multiple Plasmodium species and Anopheles vectors, (iii) increasing antimalarial drug resistance and insecticide resistance, and (iv) the impact of climate change on each of these variables. Simply stated, the burden of malaria in India is complex. Here we describe plans for a Center for the Study of Complex Malaria in India (CSCMi), one of ten International Centers of Excellence in Malaria Research (ICEMRs) located in malarious regions of the world recently funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The CSCMi is a close partnership between Indian and United States scientists, and aims to address major gaps in our understanding of the complexity of malaria in India, including changing patterns of epidemiology, vector biology and control, drug resistance, and parasite genomics. We hope that such a multidisciplinary approach that integrates clinical and field studies with laboratory, molecular, and genomic methods will provide a powerful combination for malaria control and prevention in India. PMID:22142788

Geo-additive modelling of malaria in Burundi

PubMed Central

2011-01-01

Background Malaria is a major public health issue in Burundi in terms of both morbidity and mortality, with around 2.5 million clinical cases and more than 15,000 deaths each year. It is still the single main cause of mortality in pregnant women and children below five years of age. Because of the severe health and economic burden of malaria, there is still a growing need for methods that will help to understand the influencing factors. Several studies/researches have been done on the subject yielding different results as which factors are most responsible for the increase in malaria transmission. This paper considers the modelling of the dependence of malaria cases on spatial determinants and climatic covariates including rainfall, temperature and humidity in Burundi. Methods The analysis carried out in this work exploits real monthly data collected in the area of Burundi over 12 years (1996-2007). Semi-parametric regression models are used. The spatial analysis is based on a geo-additive model using provinces as the geographic units of study. The spatial effect is split into structured (correlated) and unstructured (uncorrelated) components. Inference is fully Bayesian and uses Markov chain Monte Carlo techniques. The effects of the continuous covariates are modelled by cubic p-splines with 20 equidistant knots and second order random walk penalty. For the spatially correlated effect, Markov random field prior is chosen. The spatially uncorrelated effects are assumed to be i.i.d. Gaussian. The effects of climatic covariates and the effects of other spatial determinants are estimated simultaneously in a unified regression framework. Results The results obtained from the proposed model suggest that although malaria incidence in a given month is strongly positively associated with the minimum temperature of the previous months, regional patterns of malaria that are related to factors other than climatic variables have been identified, without being able to explain

The evil circle of poverty: a qualitative study of malaria and disability

PubMed Central

2012-01-01

Background This article discusses the link between disability and malaria in a poor rural setting. Global malaria programmes and rehabilitation programmes are organized as vertical and separate programmes, and as such they focus on prevention, cure and control, and disability respectively. When looking at specific conditions and illnesses, the impairing long-term consequences of illness incidents during childhood are not questioned. Methods The study design was ethnographic with an open, exploratory approach. Data were collected in Mangochi District in Malawi through qualitative in-depth interviews and participant observation. Results Despite a local-based health service system, people living in poor rural areas are confronted with a multitude of barriers when accessing malaria prevention and treatment. Lack of skilled health personnel and equipment add to the general burden of poverty: insufficient knowledge about health care, problems connected to accessing the health facility in time, insufficient initiatives to prevent malaria attacks, and a general lack of attention to the long term disabling effects of a malaria attack. Conclusions This study points to the importance of building malaria programmes, research and statistics that take into consideration the consequences of permanent impairment after a malaria attack, as well as the context of poverty in which they often occur. In order to do so, one needs to develop methods for detecting people whose disabilities are a direct result of not having received health services after a malaria episode. This may be done through qualitative approaches in local communities and should also be supplemented by suitable surveys in order to estimate the problem on a larger scale. PMID:22236358

Modern malaria chemoprophylaxis.

PubMed

Shanks, G Dennis; Edstein, Michael D

2005-01-01

Currently available medications for malaria chemoprophylaxis are efficacious but the problems of patient compliance, the advance of parasite drug resistance, and real or perceived serious adverse effects mean that new chemical compounds are needed.Primaquine, which has been widely used to treat relapsing malaria since the 1950s, has been shown to prevent malaria when taken daily. Tafenoquine is a new 8-aminoquinoline with a much longer half-life than primaquine. Field trials to date indicate that tafenoquine is efficacious and can be taken weekly or perhaps even less frequently. Both primaquine and tafenoquine require exact knowledge of a person's glucose 6-phosphate dehydrogenase status in order to prevent drug-induced haemolysis. Other potential malaria chemoprophylactic drugs such as third-generation antifol compounds and Mannich bases have reached advanced preclinical testing. Mefloquine has been seen to cause serious neuropsychiatric adverse effects on rare occasions. Recent public controversy regarding reputedly common serious adverse effects has made many Western travellers unwilling to take mefloquine. Special risk groups exposed to malaria, such as long-term travellers, children, pregnant women, aircrew and those requiring unimpeded psychomotor reactions, migrants returning to visit malarious countries of origin and febrile persons who have returned from malaria endemic areas, all require a nuanced approach to the use of drugs to prevent malaria. The carrying of therapeutic courses of antimalarial drugs to be taken only if febrile illness develops is indicated in very few travellers despite its appeal to some who fear adverse effects more than they fear potentially lethal malaria infection. Travellers with a significant exposure to malaria require a comprehensive plan for prevention that includes anti-mosquito measures but which is still primarily be based on the regular use of efficacious antimalarial medications.

Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care

PubMed Central

2011-01-01

Background An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. Methods Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection. The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating

Mapping malaria incidence distribution that accounts for environmental factors in Maputo Province - Mozambique

PubMed Central

2010-01-01

Background The objective was to study if an association exists between the incidence of malaria and some weather parameters in tropical Maputo province, Mozambique. Methods A Bayesian hierarchical model to malaria count data aggregated at district level over a two years period is formulated. This model made it possible to account for spatial area variations. The model was extended to include environmental covariates temperature and rainfall. Study period was then divided into two climate conditions: rainy and dry seasons. The incidences of malaria between the two seasons were compared. Parameter estimation and inference were carried out using MCMC simulation techniques based on Poisson variation. Model comparisons are made using DIC. Results For winter season, in 2001 the temperature covariate with estimated value of -8.88 shows no association to malaria incidence. In year 2002, the parameter estimation of the same covariate resulted in 5.498 of positive level of association. In both years rainfall covariate determines no dependency to malaria incidence. Malaria transmission is higher in wet season with both covariates positively related to malaria with posterior means 1.99 and 2.83 in year 2001. For 2002 only temperature is associated to malaria incidence with estimated value 2.23. Conclusions The incidence of malaria in year 2001, presents an independent spatial pattern for temperature in summer and for rainfall in winter seasons respectively. In year 2002 temperature determines the spatial pattern of malaria incidence in the region. Temperature influences the model in cases where both covariates are introduced in winter and summer season. Its influence is extended to the summer model with temperature covariate only. It is reasonable to state that with the occurrence of high temperatures, malaria incidence had certainly escalated in this year. PMID:20302674

Clinical malaria case definition and malaria attributable fraction in the highlands of western Kenya.

PubMed

Afrane, Yaw A; Zhou, Guofa; Githeko, Andrew K; Yan, Guiyun

2014-10-15

In African highland areas where endemicity of malaria varies greatly according to altitude and topography, parasitaemia accompanied by fever may not be sufficient to define an episode of clinical malaria in endemic areas. To evaluate the effectiveness of malaria interventions, age-specific case definitions of clinical malaria needs to be determined. Cases of clinical malaria through active case surveillance were quantified in a highland area in Kenya and defined clinical malaria for different age groups. A cohort of over 1,800 participants from all age groups was selected randomly from over 350 houses in 10 villages stratified by topography and followed for two-and-a-half years. Participants were visited every two weeks and screened for clinical malaria, defined as an individual with malaria-related symptoms (fever [axillary temperature≥37.5°C], chills, severe malaise, headache or vomiting) at the time of examination or 1-2 days prior to the examination in the presence of a Plasmodium falciparum positive blood smear. Individuals in the same cohort were screened for asymptomatic malaria infection during the low and high malaria transmission seasons. Parasite densities and temperature were used to define clinical malaria by age in the population. The proportion of fevers attributable to malaria was calculated using logistic regression models. Incidence of clinical malaria was highest in valley bottom population (5.0% cases per 1,000 population per year) compared to mid-hill (2.2% cases per 1,000 population per year) and up-hill (1.1% cases per 1,000 population per year) populations. The optimum cut-off parasite densities through the determination of the sensitivity and specificity showed that in children less than five years of age, 500 parasites per μl of blood could be used to define the malaria attributable fever cases for this age group. In children between the ages of 5-14, a parasite density of 1,000 parasites per μl of blood could be used to define the

A global model of malaria climate sensitivity: comparing malaria response to historic climate data based on simulation and officially reported malaria incidence.

PubMed

Edlund, Stefan; Davis, Matthew; Douglas, Judith V; Kershenbaum, Arik; Waraporn, Narongrit; Lessler, Justin; Kaufman, James H

2012-09-18

The role of the Anopheles vector in malaria transmission and the effect of climate on Anopheles populations are well established. Models of the impact of climate change on the global malaria burden now have access to high-resolution climate data, but malaria surveillance data tends to be less precise, making model calibration problematic. Measurement of malaria response to fluctuations in climate variables offers a way to address these difficulties. Given the demonstrated sensitivity of malaria transmission to vector capacity, this work tests response functions to fluctuations in land surface temperature and precipitation. This study of regional sensitivity of malaria incidence to year-to-year climate variations used an extended Macdonald Ross compartmental disease model (to compute malaria incidence) built on top of a global Anopheles vector capacity model (based on 10 years of satellite climate data). The predicted incidence was compared with estimates from the World Health Organization and the Malaria Atlas. The models and denominator data used are freely available through the Eclipse Foundation's Spatiotemporal Epidemiological Modeller (STEM). Although the absolute scale factor relating reported malaria to absolute incidence is uncertain, there is a positive correlation between predicted and reported year-to-year variation in malaria burden with an averaged root mean square (RMS) error of 25% comparing normalized incidence across 86 countries. Based on this, the proposed measure of sensitivity of malaria to variations in climate variables indicates locations where malaria is most likely to increase or decrease in response to specific climate factors. Bootstrapping measures the increased uncertainty in predicting malaria sensitivity when reporting is restricted to national level and an annual basis. Results indicate a potential 20x improvement in accuracy if data were available at the level ISO 3166-2 national subdivisions and with monthly time sampling. The

Clinical overlap between malaria and pneumonia: can malaria rapid diagnostic test play a role?

PubMed

Ukwaja, Kingsley Nnanna; Aina, Olufemi B; Talabi, Ademola A

2011-03-21

Malaria and pneumonia account for 40% of mortality among children under five years of age in sub-Saharan Africa. Due to lack of diagnostic facilities, their management is based on the integrated management of childhood illnesses (IMCI) strategy. Symptoms of malaria and pneumonia overlap in African children, necessitating dual IMCI classifications at health centres and treatment with both antibiotics and antimalarials. This study determined the prevalence of malaria-pneumonia symptom overlap and confirmed the diagnosis of malaria in these cases using a rapid diagnostic test. Consecutive consultations of 1,216 children (two months to five years old) were documented over a three-month period in a comprehensive health centre. Malaria rapid diagnostic tests were conducted only for children who had symptom overlap. Of the 1,216 children enrolled, 1,090 (90%) reported cough or fever. Among the children fulfilling the malaria case definition, 284 (30%) also met the pneumonia case definition. Twenty-three percent (284) of all children enrolled met the criteria for both malaria and pneumonia. However, only 130 (46%) of them had a positive result for malaria using a malaria rapid diagnostic test. During a malaria-pneumonia overlap, female children (chi-square 5.9, P = 0.01) and children ≥ one year (chi-square 4.8, P = 0.003) were more likely to seek care within two days of fever. Dual treatment with antimalarials and antibiotics in children with malaria-pneumonia overlap may result in unnecessary over-prescription of antimalarial medications. Use of rapid diagnostic tests in their management can potentially avoid over-prescribing of malaria medications.

Evaluation of a rapid diagnostic test (CareStart Malaria HRP-2/pLDH (Pf/pan) Combo Test) for the diagnosis of malaria in a reference setting.

PubMed

Maltha, Jessica; Gillet, Philippe; Bottieau, Emmanuel; Cnops, Lieselotte; van Esbroeck, Marjan; Jacobs, Jan

2010-06-18

Malaria Rapid Diagnostic Tests (RDTs) are widely used for diagnosing malaria. The present retrospective study evaluated the CareStart Malaria HRP-2/pLDH (Pf/pan) Combo Test targeting the Plasmodium falciparum specific antigen histidine-rich protein (HRP-2) and the pan-Plasmodium antigen lactate dehydrogenase (pLDH) in a reference setting. The CareStart Malaria HRP-2/pLDH (Pf/pan) Combo Test was evaluated on a collection of samples obtained in returned international travellers using microscopy corrected by PCR as the reference method. Included were P. falciparum (n = 320), Plasmodium vivax (n = 76), Plasmodium ovale (n = 76), Plasmodium malariae (n = 23) and Plasmodium negative samples (n = 95). Overall sensitivity for the detection of P. falciparum was 88.8%, increasing to 94.3% and 99.3% at parasite densities above 100 and 1,000/microl respectively. For P. vivax, P. ovale and P. malariae, overall sensitivities were 77.6%, 18.4% and 30.4% respectively. For P. vivax sensitivity reached 90.2% for parasite densities above 500/microl. Incorrect species identification occurred in 11/495 samples (2.2%), including 8/320 (2.5%) P. falciparum samples which generated only the pan-pLDH line. For P. falciparum samples, 205/284 (72.2%) HRP-2 test lines had strong or medium line intensities, while for all species the pan-pLDH lines were less intense, especially in the case of P. ovale. Agreement between observers was excellent (kappa values > 0.81 for positive and negative readings) and test results were reproducible. The test was easy to perform with good clearing of the background. The CareStart Malaria HRP-2/pLDH (Pf/pan) Combo Test performed well for the detection of P. falciparum and P. vivax, but sensitivities for P. ovale and P. malariae were poor.

An assessment of Lot Quality Assurance Sampling to evaluate malaria outcome indicators: extending malaria indicator surveys

PubMed Central

Biedron, Caitlin; Pagano, Marcello; Hedt, Bethany L; Kilian, Albert; Ratcliffe, Amy; Mabunda, Samuel; Valadez, Joseph J

2010-01-01

Background Large investments and increased global prioritization of malaria prevention and treatment have resulted in greater emphasis on programme monitoring and evaluation (M&E) in many countries. Many countries currently use large multistage cluster sample surveys to monitor malaria outcome indicators on a regional and national level. However, these surveys often mask local-level variability important to programme management. Lot Quality Assurance Sampling (LQAS) has played a valuable role for local-level programme M&E. If incorporated into these larger surveys, it would provide a comprehensive M&E plan at little, if any, extra cost. Methods The Mozambique Ministry of Health conducted a Malaria Indicator Survey (MIS) in June and July 2007. We applied LQAS classification rules to the 345 sampled enumeration areas to demonstrate identifying high- and low-performing areas with respect to two malaria program indicators—‘household possession of any bednet’ and ‘household possession of any insecticide-treated bednet (ITN)’. Results As shown by the MIS, no province in Mozambique achieved the 70% coverage target for household possession of bednets or ITNs. By applying LQAS classification rules to the data, we identify 266 of the 345 enumeration areas as having bednet coverage severely below the 70% target. An additional 73 were identified with low ITN coverage. Conclusions This article demonstrates the feasibility of integrating LQAS into multistage cluster sampling surveys and using these results to support a comprehensive national, regional and local programme M&E system. Furthermore, in the recommendations we outlined how to integrate the Large Country-LQAS design into macro-surveys while still obtaining results available through current sampling practices. PMID:20139435

Malaria in India: the center for the study of complex malaria in India.

PubMed

Das, Aparup; Anvikar, Anupkumar R; Cator, Lauren J; Dhiman, Ramesh C; Eapen, Alex; Mishra, Neelima; Nagpal, Bhupinder N; Nanda, Nutan; Raghavendra, Kamaraju; Read, Andrew F; Sharma, Surya K; Singh, Om P; Singh, Vineeta; Sinnis, Photini; Srivastava, Harish C; Sullivan, Steven A; Sutton, Patrick L; Thomas, Matthew B; Carlton, Jane M; Valecha, Neena

2012-03-01

Malaria is a major public health problem in India and one which contributes significantly to the overall malaria burden in Southeast Asia. The National Vector Borne Disease Control Program of India reported ∼1.6 million cases and ∼1100 malaria deaths in 2009. Some experts argue that this is a serious underestimation and that the actual number of malaria cases per year is likely between 9 and 50 times greater, with an approximate 13-fold underestimation of malaria-related mortality. The difficulty in making these estimations is further exacerbated by (i) highly variable malaria eco-epidemiological profiles, (ii) the transmission and overlap of multiple Plasmodium species and Anopheles vectors, (iii) increasing antimalarial drug resistance and insecticide resistance, and (iv) the impact of climate change on each of these variables. Simply stated, the burden of malaria in India is complex. Here we describe plans for a Center for the Study of Complex Malaria in India (CSCMi), one of ten International Centers of Excellence in Malaria Research (ICEMRs) located in malarious regions of the world recently funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The CSCMi is a close partnership between Indian and United States scientists, and aims to address major gaps in our understanding of the complexity of malaria in India, including changing patterns of epidemiology, vector biology and control, drug resistance, and parasite genomics. We hope that such a multidisciplinary approach that integrates clinical and field studies with laboratory, molecular, and genomic methods will provide a powerful combination for malaria control and prevention in India. Copyright © 2011 Elsevier B.V. All rights reserved.

Malaria Molecular Epidemiology: Lessons from the International Centers of Excellence for Malaria Research Network

PubMed Central

Escalante, Ananias A.; Ferreira, Marcelo U.; Vinetz, Joseph M.; Volkman, Sarah K.; Cui, Liwang; Gamboa, Dionicia; Krogstad, Donald J.; Barry, Alyssa E.; Carlton, Jane M.; van Eijk, Anna Maria; Pradhan, Khageswar; Mueller, Ivo; Greenhouse, Bryan; Andreina Pacheco, M.; Vallejo, Andres F.; Herrera, Socrates; Felger, Ingrid

2015-01-01

Molecular epidemiology leverages genetic information to study the risk factors that affect the frequency and distribution of malaria cases. This article describes molecular epidemiologic investigations currently being carried out by the International Centers of Excellence for Malaria Research (ICEMR) network in a variety of malaria-endemic settings. First, we discuss various novel approaches to understand malaria incidence and gametocytemia, focusing on Plasmodium falciparum and Plasmodium vivax. Second, we describe and compare different parasite genotyping methods commonly used in malaria epidemiology and population genetics. Finally, we discuss potential applications of molecular epidemiological tools and methods toward malaria control and elimination efforts. PMID:26259945

Migration and Malaria in Europe

PubMed Central

Monge-Maillo, Begoña; López-Vélez, Rogelio

2012-01-01

The proportion of imported malaria cases due to immigrants in Europe has increased during the lasts decades, with higher rates associated with settled immigrants who travel to visit friends and relatives (VFRs) in their country of origin. Cases are mainly due to P. falciparum and Sub-Saharan Africa is the most common origin. Clinically, malaria in immigrants is characterised by a mild clinical presentation including asymptomatic or delayed malaria cases and low parasitic levels. These characteristics may be explained by a semi-immunity acquired after long periods of time exposed to stable malaria transmission. Malaria cases among immigrants, even asymptomatic patients with sub-microscopic parasitemia, could increase the risk of transmission and cause the reintroduction of malaria in certain areas that have adequate vectors and climate conditions. Moreover, imported malaria cases in immigrants can also play an important role in the non-vector transmission out of endemic areas, through blood transfusions, organ transplantation or congenital transmission or occupational exposures. Consequently, outside of endemic areas, malaria screening should be carried out among recently arrived immigrants coming from malaria endemic countries. The aim of screening is to reduce the risk of clinical malaria in the individual as well as to prevent autochthonous transmission of malaria in areas where it has been eradicated. PMID:22536477

How well are malaria maps used to design and finance malaria control in Africa?

PubMed

Omumbo, Judy A; Noor, Abdisalan M; Fall, Ibrahima S; Snow, Robert W

2013-01-01

Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed. An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated. 91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control. The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be necessary to guide appropriate financing for malaria

Imported malaria in an area in southern Madrid, 2005-2008

PubMed Central

2010-01-01

Background In Spain, malaria cases are mostly due to migrants and travellers returning from endemic areas. The objective of this work was to describe the malaria cases diagnosed at the Severo Ochoa University Hospital (HUSO) in Leganés in the south of the Madrid Region from 2005 to 2008. Methods Descriptive retrospective study performed at HUSO. Data sources are registries from the Microbiology Department and malaria cases notified to the Preventive Medicine Department. Analysed parameters were: administrative, demographical, related to the stay at the endemic country, clinical, microbiological diagnosis method, pregnancy, treatment and prophylaxis, co-infections, and days of hospital stay. Results Fifty-seven patients diagnosed with malaria were studied. Case distribution per year was 13 in 2005, 15 in 2006, 15 in 2007 and 14 in 2008. Thirty-three patients were female (57.9%) and 24 male (42.1%). Mean age was 27.8 years. Most of the malaria cases were acquired in Nigeria (49.1%) and Equatorial Guinea (32.7%). 29.1% of the patients were immigrants who had arrived recently, and 61.8% acquired malaria when travelling to their countries of origin to visit friends and relatives (VFR). Majority of cases were diagnosed between June and September. Microscopy was positive in 39 cases (68.4%) immunochromatography in 42 (73.7%) and PCR in the 55 cases where performed. Plasmodium falciparum was responsible for 94.7% of the cases. The more frequent symptoms were fever (77.2%), followed by headache and gastrointestinal symptoms (33.3%). Nine cases needed hospital admittance, a pregnant woman, three children, four VFR and an African tourist, but all evolved favourably. Chemoprophylaxis data was known from 55 patients. It was taken correctly in one case (1.8%), in five (9.1%) the prophylaxis was improper while the others 49 (89.1%) cases had not followed any anti-malarial prophylaxis. Conclusions Children, pregnant women and the VFR have the highest risk to present severe

Spatio-temporal heterogeneity of malaria morbidity in Ghana: Analysis of routine health facility data

PubMed Central

Malm, Keziah; Peprah, Nana Yaw; Silal, Sheetal P.

2018-01-01

Background Malaria incidence is largely influenced by vector abundance. Among the many interconnected factors relating to malaria transmission, weather conditions such as rainfall and temperature are known to create suitable environmental conditions that sustain reproduction and propagation of anopheles mosquitoes and malaria parasites. In Ghana, climatic conditions vary across the country. Understanding the heterogeneity of malaria morbidity using data sourced from a recently setup data repository for routine health facility data could support planning. Methods Monthly aggregated confirmed uncomplicated malaria cases from the District Health Information Management System and average monthly rainfall and temperature records obtained from the Ghana Meteorological Agency from 2008 to 2016 were analysed. Univariate time series models were fitted to the malaria, rainfall and temperature data series. After pre-whitening the morbidity data, cross correlation analyses were performed. Subsequently, transfer function models were developed for the relationship between malaria morbidity and rainfall and temperature. Results Malaria morbidity patterns vary across zones. In the Guinea savannah, morbidity peaks once in the year and twice in both the Transitional forest and Coastal savannah, following similar patterns of rainfall at the zonal level. While the effects of rainfall on malaria morbidity are delayed by a month in the Guinea savannah and Transitional Forest zones those of temperature are delayed by two months in the Transitional forest zone. In the Coastal savannah however, incidence of malaria is significantly associated with two months lead in rainfall and temperature. Conclusion Data captured on the District Health Information Management System has been used to demonstrate heterogeneity in the dynamics of malaria morbidity across the country. Timing of these variations could guide the deployment of interventions such as indoor residual spraying, Seasonal Malaria

Community perceptions of a malaria vaccine in the Kintampo districts of Ghana

PubMed Central

2013-01-01

Background Malaria remains the leading cause of morbidity and mortality in sub-Saharan Africa despite tools currently available for its control. Making malaria vaccine available for routine use will be a major hallmark, but its acceptance by community members and health professionals within the health system could pose considerable challenge as has been found with the introduction of polio vaccinations in parts of West Africa. Some of these challenges may not be expected since decisions people make are many a time driven by a complex myriad of perceptions. This paper reports knowledge and perceptions of community members in the Kintampo area of Ghana where malaria vaccine trials have been ongoing as part of the drive for the first-ever licensed malaria vaccine in the near future. Methods Both qualitative and quantitative methods were used in the data collection processes. Women and men whose children were or were not involved in the malaria vaccine trial were invited to participate in focus group discussions (FGDs). Respondents, made up of heads of religious groupings in the study area, health care providers, traditional healers and traditional birth attendants, were also invited to participate in in-depth interviews (IDIs). A cross-sectional survey was conducted in communities where the malaria vaccine trial (Mal 047RTS,S) was carried out. In total, 12 FGDs, 15 IDIs and 466 household head interviews were conducted. Results Knowledge about vaccines was widespread among participants. Respondents would like their children to be vaccinated against all childhood illnesses including malaria. Knowledge of the long existing routine vaccines was relatively high among respondents compared to hepatitis B and Haemophilus influenza type B vaccines that were introduced more recently in 2002. There was no clear religious belief or sociocultural practice that will serve as a possible barrier to the acceptance of a malaria vaccine. Conclusion With the assumption that a malaria

Malaria.

PubMed

Ashley, Elizabeth A; Pyae Phyo, Aung; Woodrow, Charles J

2018-04-21

Following unsuccessful eradication attempts there was a resurgence of malaria towards the end of the 20th century. Renewed control efforts using a range of improved tools, such as long-lasting insecticide-treated bednets and artemisinin-based combination therapies, have more than halved the global burden of disease, but it remains high with 445 000 deaths and more than 200 million cases in 2016. Pitfalls in individual patient management are delayed diagnosis and overzealous fluid resuscitation in severe malaria. Even in the absence of drug resistance, parasite recurrence can occur, owing to high parasite densities, low host immunity, or suboptimal drug concentrations. Malaria elimination is firmly back as a mainstream policy but resistance to the artemisinin derivatives, their partner drugs, and insecticides present major challenges. Vaccine development continues on several fronts but none of the candidates developed to date have been shown to provide long-lasting benefits at a population level. Increased resources and unprecedented levels of regional cooperation and societal commitment will be needed if further substantial inroads into the malaria burden are to be made. Copyright © 2018 Elsevier Ltd. All rights reserved.

Reduction in malaria prevalence and increase in malaria awareness in endemic districts of Bangladesh.

PubMed

Alam, Mohammad Shafiul; Kabir, Mohammad Moktadir; Hossain, Mohammad Sharif; Naher, Shamsun; Ferdous, Nur E Naznin; Khan, Wasif Ali; Mondal, Dinesh; Karim, Jahirul; Shamsuzzaman, A K M; Ahmed, Be-Nazir; Islam, Akramul; Haque, Rashidul

2016-11-11

Malaria is endemic in 13 districts of Bangladesh. A baseline malaria prevalence survey across the endemic districts of Bangladesh was conducted in 2007, when the prevalence was reported around 39.7 per 1000 population. After two rounds of Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-funded intervention by the National Malaria Control Programme (NMCP) and a BRAC-led NGO consortium, a follow-up survey was conducted across the malaria-endemic districts of Bangladesh to measure the change in prevalence rate and in people's knowledge of malaria. The survey was carried out from August to November 2013 in 70 upazilas (sub-districts) of 13 malaria-endemic districts of Bangladesh, following the same multi-stage cluster sampling design and the same number of households enrolled during the baseline prevalence survey in 2007, to collect 9750 randomly selected blood samples. For on-the-spot diagnosis of malaria, a rapid diagnostic test was used. The household head or eldest person available was interviewed using a pre-coded structured questionnaire to collect data on the knowledge and awareness of malaria in the household. Based on a weighted calculation, the overall malaria prevalence was found to be 1.41 per 1000 population. The proportion of Plasmodium falciparum mono-infection was 77.78% while both Plasmodium vivax mono-infection and mixed infection of the two species were found to be 11.11%. Bandarban had the highest prevalence (6.67 per 1000 population). Knowledge of malaria signs, symptoms and mode of transmission were higher in the follow-up survey (97.26%) than the baseline survey. Use of bed nets for prevention of malaria was found to be high (90.15%) at respondent level. People's knowledge of selected parameters increased significantly during the follow-up survey compared to the baseline survey conducted in 2007. A reduced prevalence rate of malaria and increased level of knowledge were observed in the present malaria prevalence survey in Bangladesh.

[Global trends in malaria control. Progress and topical tasks in malaria control programs].

PubMed

Kondrashin, A V; Baranova, A M; Morozova, L F; Stepanova, E V

2011-01-01

This communication is the first in the series consisting of two publications describing the present state of malaria control and elimination in the world. The global malaria situation in 2009-2010 demonstrated a considerable situation as compared to the previous years. This improvement is associated with a considerable global increase of investments made by both national governments and world society to the malaria control programs. Spectacular progress has been achieved even in the areas of the most infection-affected African countries situated to the south of the Sahara Desert. It has been estimated that malaria cases in the world declined from 233, 000,000 in 2000 to 225,000,000 in 2009. Malaria mortality decreased from 985,000 in 2000 to 781,000 in 2009. To maintain the results achieved and to further reduce the problem of malaria worldwide, it is necessary to ensure a long-term political and financial support for malaria control programs at the national and international levels.

Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice

PubMed Central

Parra, Marcela; Derrick, Steven C.; Yang, Amy; Tian, JinHua; Kolibab, Kristopher; Oakley, Miranda; Perera, Liyanage P.; Jacobs, William R.; Kumar, Sanjai; Morris, Sheldon L.

2011-01-01

Background Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. Principal Findings Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naïve mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-γ, TNF-α, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. Conclusions Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the

Prevalence of Malaria and Anemia among Pregnant Women Attending a Traditional Birth Home in Benin City, Nigeria

PubMed Central

Oladeinde, Bankole Henry; Omoregie, Richard; Odia, Ikponmwosa; Oladeinde, Oladapo Babatunde

2012-01-01

Objectives To determine the prevalence of malaria and anemia among pregnant women attending a traditional birth center as well as the effect of herbal remedies, gravidity, age, educational background and malaria prevention methods on their prevalence. Methods Blood specimens were collected from 119 pregnant women attending a Traditional Birth Home in Benin City, Nigeria. Malaria parasitemia was diagnosed by microscopy while anemia was defined as hemoglobin concentration <11 g/dL. Results The prevalence of malaria infection was (OR=4.35 95% CI=1.213, 15.600; p=0.016) higher among primigravidae (92.1%). Pregnant women (38.5%) with tertiary level of education had significantly lower prevalence of malaria infection (p=0.002). Malaria significantly affected the prevalence of anemia (p<0.05). Anemia was associated with consumption of herbal remedies (OR=2.973; 95% CI=1.206, 7.330; p=0.017). The prevalence of malaria parasitemia and anemia were not affected by malaria prevention methods used by the participants. Conclusion The overall prevalence of malaria infection and anemia observed in this study were 78.9% and 46.2%, respectively. Higher prevalence of malaria infection was associated with primigravidae and lower prevalence with tertiary education of subjects. Anemia was associated with consumption of herbal remedies. There is urgent need to control the prevalence of malaria and anemia among pregnant women attending traditional birth homes. PMID:22811774

Knowledge, attitude, and practice about malaria: Socio-demographic implications for malaria control in rural Ghana.

PubMed

Assan, Abraham; Takian, Amirhossein; Hanafi-Bojd, Ahmad Ali; Rahimiforoushani, Abbas; Nematolahi, Shahrzad

2017-11-01

Despite continuing international attention to malaria prevention, the disease remains a global public health problem. We investigated socio-demographic factors influencing knowledge, attitudes, and practices about malaria in rural Ghana. Our survey looked at 354 households. Mean knowledge score was higher among individuals with a history of volunteers having visited their households to educate them about malaria; families with 4-6 members; and males. Households with at least one under-five-aged child also had significantly higher knowledge scores. Households with at least one pregnant woman evinced a positive attitude towards malaria prevention. National malaria control strategies have achieved positive results in the fight against malaria. Nonetheless, multipronged community-based health strategies that integrate malaria programs and population growth control initiatives may be able to reach by 2030 the sustainable development goal of eliminating malaria.

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria.

PubMed

Dell'agli, Mario; Galli, Germana V; Bulgari, Michela; Basilico, Nicoletta; Romeo, Sergio; Bhattacharya, Deepak; Taramelli, Donatella; Bosisio, Enrica

2010-07-19

The sun-dried rind of the immature fruit of pomegranate (Punica granatum) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by Plasmodium falciparum, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The in vitro anti-plasmodial activity of Punica granatum (Pg) was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response. From the methanolic extract of the fruit rind, a fraction enriched in tannins (Pg-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the Pg-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated. Pg-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. Pg-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription. The beneficial effect of the fruit rind of Punica granatum for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria.

Microvascular hemodynamics and in vivo evidence for the role of intercellular adhesion molecule-1 in the sequestration of infected red blood cells in a mouse model of lethal malaria.

PubMed

Kaul, D K; Liu, X D; Nagel, R L; Shear, H L

1998-02-01

The cytoadherence of infected red blood cells (IRBCs) to the vascular endothelium is the major cause of IRBC sequestration and vessel blockage in the cerebral form of human malaria. Among the rodent models of malaria, Plasmodium yoelii 17XL-infected mice show many similarities with the human cerebral malaria caused by P. falciparum. In both, the sequestration of IRBCs in the brain vessels is secondary to the cytoadherence of IRBCs to the vascular endothelium. Similar to P. falciparum infection in the human but in contrast to P. berghei ANKA infection in mice, P. yoelii 17XL results in little, if any, accumulation of monocytes in the brain. In vivo microcirculatory studies reported here were designed to further understand the hemodynamic aspects and mechanisms underlying cytoadherence of IRBCs in the P. yoelii model using the easily accessible cremaster muscle vasculature. The results show significant decreases in arteriovenous red blood cell velocities (Vrbc) and wall shear rates in the microcirculation of P. yoelii-infected mice, with a maximal decrease occurring in small-diameter postcapillary venules, the main sites of cytoadherence. This reflects contributions from IRBC cytoadherence as well as from increased rigidity of parasitized red blood cells. No cytoadherence is observed in arterioles of the infected mice despite decreased wall shear rates, indicating that endothelial receptors for cytoadherence are restricted to venules. Infusion of a monoclonal antibody (MAb) against the intercellular adhesion molecule-1 (ICAM-1) resulted in significant increases in both arteriolar and venular Vrbc and wall shear rates, accompanied by detachment of adhered IRBCs at some venular sites. The peripheral blood smears taken after the MAb infusion showed a distinct increase in the percentage of schizonts, again indicating detachment and/or prevention of cytoadherence. An MAb against the vascular cell adhesion molecule-1 (VCAM-1) as well as an irrelevant control antibody had

Prevalence of cerebral palsy in Uganda: a population-based study.

PubMed

Kakooza-Mwesige, Angelina; Andrews, Carin; Peterson, Stefan; Wabwire Mangen, Fred; Eliasson, Ann Christin; Forssberg, Hans

2017-12-01

97) diagnosed with cerebral palsy were born preterm. Post-neonatal events were the probable cause of cerebral palsy in 24 (25%) of 97 children. Cerebral palsy prevalence was higher in rural Uganda than in high-income countries (HICs), where prevalence is about 1·8-2·3 cases per 1000 children. Children younger than 8 years were more likely to have severe cerebral palsy than older children. Fewer older children than younger children with cerebral palsy suggested a high mortality in severely affected children. The small number of preterm-born children probably resulted from low preterm survival. About five times more children with post-neonatal cerebral palsy in Uganda than in HICs suggested that cerebral malaria and seizures were prevalent risk factors in this population. Swedish Research Council, Promobilia. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Malaria Molecular Epidemiology: Lessons from the International Centers of Excellence for Malaria Research Network.

PubMed

Escalante, Ananias A; Ferreira, Marcelo U; Vinetz, Joseph M; Volkman, Sarah K; Cui, Liwang; Gamboa, Dionicia; Krogstad, Donald J; Barry, Alyssa E; Carlton, Jane M; van Eijk, Anna Maria; Pradhan, Khageswar; Mueller, Ivo; Greenhouse, Bryan; Pacheco, M Andreina; Vallejo, Andres F; Herrera, Socrates; Felger, Ingrid

2015-09-01

Molecular epidemiology leverages genetic information to study the risk factors that affect the frequency and distribution of malaria cases. This article describes molecular epidemiologic investigations currently being carried out by the International Centers of Excellence for Malaria Research (ICEMR) network in a variety of malaria-endemic settings. First, we discuss various novel approaches to understand malaria incidence and gametocytemia, focusing on Plasmodium falciparum and Plasmodium vivax. Second, we describe and compare different parasite genotyping methods commonly used in malaria epidemiology and population genetics. Finally, we discuss potential applications of molecular epidemiological tools and methods toward malaria control and elimination efforts. © The American Society of Tropical Medicine and Hygiene.

Presumptive Treatment of Malaria from Formal and Informal Drug Vendors in Nigeria

PubMed Central

Isiguzo, Chinwoke; Anyanti, Jennifer; Ujuju, Chinazo; Nwokolo, Ernest; De La Cruz, Anna; Schatzkin, Eric; Modrek, Sepideh; Montagu, Dominic; Liu, Jenny

2014-01-01

Background Despite policies that recommend parasitological testing before treatment for malaria, presumptive treatment remains widespread in Nigeria. The majority of Nigerians obtain antimalarial drugs from two types of for-profit drug vendors—formal and informal medicine shops—but little is known about the quality of malaria care services provided at these shops. Aims This study seeks to (1) describe the profile of patients who seek treatment at different types of drug outlets, (2) document the types of drugs purchased for treating malaria, (3) assess which patients are purchasing recommended drugs, and (4) estimate the extent of malaria over-treatment. Methods In urban, peri-urban, and rural areas in Oyo State, customers exiting proprietary and patent medicine vendor (PPMV) shops or pharmacies having purchased anti-malarial drugs were surveyed and tested with malaria rapid diagnostic test. A follow-up phone survey was conducted four days after to assess self-reported drug administration. Bivariate and multivariate regression analysis was conducted to determine the correlates of patronizing a PPMV versus pharmacy, and the likelihood of purchasing an artemisinin-combination therapy (ACT) drug. Results Of the 457participants who sought malaria treatment in 49 enrolled outlets, nearly 92% had diagnosed their condition by themselves, a family member, or a friend. Nearly 60% pharmacy customers purchased an ACT compared to only 29% of PPMV customers, and pharmacy customers paid significantly more on average. Multivariate regression results show that patrons of PPMVs were younger, less wealthy, waited fewer days before seeking care, and were less likely to be diagnosed at a hospital, clinic, or laboratory. Only 3.9% of participants tested positive with a malaria rapid diagnostic test. Conclusions Poorer individuals seeking care at PPMVs are more likely to receive inappropriate malaria treatment when compared to those who go to pharmacies. Increasing accessibility to

Spatial heterogeneity of malaria in Indian reserves of Southwestern Amazonia, Brazil

PubMed Central

Souza-Santos, Reinaldo; de Oliveira, Maurício VG; Escobar, Ana Lúcia; Santos, Ricardo Ventura; Coimbra, Carlos EA

2008-01-01

Background Malaria constitutes a major cause of morbidity in the Brazilian Amazon where an estimated 6 million people are considered at high risk of transmission. Indigenous peoples in the Amazon are particularly vulnerable to potentially epidemic disease such as malaria; notwithstanding, very little is known about the epidemiology of malaria in Indian reservations of the region. The aim of this paper is to present a spatial analysis of malaria cases over a four-year time period (2003–2006) among indigenous peoples of the Brazilian State of Rondônia, southwestern Amazon, by using passive morbidity data (results from Giemsa-stained thick blood smears) gathered from the National Malaria Epidemiologic Surveillance System databank. Results A total of 4,160 cases of malaria were recorded in 14 Indian reserves in the State of Rondônia between 2003 and 2006. In six reservations no cases of malaria were reported in the period. Overall, P. vivax accounted for 76.18 of malaria cases reported in the indigenous population of Rondônia. The P. vivax/P. falciparum ratio for the period was 3.78. Two reserves accounted for over half of the cases reported for the total indigenous population in the period – Roosevelt and Pacaas Novas – with a total of 1,646 (39.57%) and 1,145 (27.52%) cases, respectively. Kernel mapping of malaria mean Annual Parasite Index – API according to indigenous reserves and environmental zones revealed a heterogeneous pattern of disease distribution, with one clear area of high risk of transmission comprising reservations of west Rondônia along the Guaporé-Madeira River basins, and another high risk area to the east, on the Roosevelt reserve. Conclusion By means of kernel mapping, it was shown that malaria risk varies widely between Indian reserves and environmental zones defined on the basis of predominant ecologic characteristics and land use patterns observed in the southwestern Brazilian Amazon. The geographical approach in this paper helped

Accuracy of rapid tests for malaria and treatment outcomes for malaria and non-malaria cases among under-five children in rural Ghana.

PubMed

Baiden, Frank; Webster, Jayne; Tivura, Mathilda; Delimini, Rupert; Berko, Yvonne; Amenga-Etego, Seeba; Agyeman-Budu, Akua; Karikari, Akosua B; Bruce, Jane; Owusu-Agyei, Seth; Chandramohan, Daniel

2012-01-01

WHO now recommends test-based management of malaria across all transmission settings. The accuracy of rapid diagnostic test (RDT) and the outcome of treatment based on the result of tests will influence acceptability of and adherence to the new guidelines. We conducted a study at the Kintampo hospital in rural Ghana to evaluate the performance of CareStart, a HRP-2 based RDT, using microscopy as reference. We applied IMCI treatment guidelines, restricted ACT to RDT-positive children and followed-up both RDT-positive (malaria) and RDT-negative (non-malaria) cases over 28 days. 436 children were enrolled in the RDT evaluation and 391 (children with haemoglobin >8.0 gm/dl) were followed-up to assess treatment outcomes. Mean age was 25.4 months (s.d. 14.6). Sensitivity and specificity of the RDT were 100.0% and 73.0% respectively. Over the follow-up period, 32 (18.5%) RDT-negative children converted to positive, with 7 (4.0%) of them presenting with fever. More children in the non-malaria group made unscheduled visits than children in the malaria group (13.3% versus 7.7%) On all scheduled follow-up visits, proportion of children having a temperature higher than that recorded on day 0 was higher in the non-malaria group compared to the malaria group. Reports of unfavourable treatment outcomes by caregivers were higher among the non-malaria group than the malaria group. The RDT had good sensitivity and specificity. However a minority of children who will not receive ACT based on RDT results may develop clinical malaria within a short period in high transmission settings. This could undermine caregivers' and health workers' confidence in the new guidelines. Improving the quality of management of non-malarial febrile illnesses should be a priority in the era of test-based management of malaria. ClinicalTrials.gov NCT00832754.

HIV-malaria interactions in North-East India: A prospective cohort study

PubMed Central

Mohapatra, Pradhyumn K.; Pachuau, Elsa; Kumar, Chandra; Borkakoty, Biswajit; Zomawia, Eric; Singh, Achouba; Walia, Kamini; Arora, Rashmi; Mahanta, Jagdish; Subbarao, Sarala K.

2017-01-01

Background & objectives: The interactions between HIV and malaria co-infection have been shown to influence each other in their clinical outcomes in Sub-Saharan Africa. This study was carried out in the two States of north east India endemic for both HIV and malaria infections, to study the interactions between the two diseases in the HIV-infected population. Methods: In this prospective study, a total of 333 HIV-infected individuals were followed up for a period of 6-18 months in Mizoram and Manipur during 2010-2011. The study assessed the changes in viral load and also the therapeutic efficacy of artesunate plus sulphadoxine-pyrimethamine (AS+SP) combination therapy in HIV-infected and HIV-uninfected individuals with Plasmodium falciparum malaria. Results: Viral load in HIV-infected malaria patients on day zero (D0) ranged from 1110 to 147,000 copies/ml. The log transformation of the geometric means of HIV viral loads revealed no significant difference on different days of follow up. There was 100 per cent adequate clinical and parasitological response (ACPR) after treating with artemisinin based combination therapy (ACT) both in HIV-infected and HIV-uninfected P. falciparum-positive individuals. Similarly, chloroquine showed 100 per cent ACPR in P. vivax HIV-infected individuals. Interpretation & conclusion: The study showed no significant increase in HIV viral load in malaria cases. All HIV-infected and HIV-uninfected P. falciparum malaria-positive cases responded to the treatment with 100 per cent ACPR. PMID:28749403

Challenges for malaria elimination in Zanzibar: pyrethroid resistance in malaria vectors and poor performance of long-lasting insecticide nets

PubMed Central

2013-01-01

Background Long-lasting insecticide treated nets (LLINs) and indoor residual house spraying (IRS) are the main interventions for the control of malaria vectors in Zanzibar. The aim of the present study was to assess the susceptibility status of malaria vectors against the insecticides used for LLINs and IRS and to determine the durability and efficacy of LLINs on the island. Methods Mosquitoes were sampled from Pemba and Unguja islands in 2010–2011 for use in WHO susceptibility tests. One hundred and fifty LLINs were collected from households on Unguja, their physical state was recorded and then tested for efficacy as well as total insecticide content. Results Species identification revealed that over 90% of the Anopheles gambiae complex was An. arabiensis with a small number of An. gambiae s.s. and An. merus being present. Susceptibility tests showed that An. arabiensis on Pemba was resistant to the pyrethroids used for LLINs and IRS. Mosquitoes from Unguja Island, however, were fully susceptible to all pyrethroids tested. A physical examination of 150 LLINs showed that two thirds were damaged after only three years in use. All used nets had a significantly lower (p < 0.001) mean permethrin concentration of 791.6 mg/m2 compared with 944.2 mg/m2 for new ones. Their efficacy decreased significantly against both susceptible An. gambiae s.s. colony mosquitoes and wild-type mosquitoes from Pemba after just six washes (p < 0.001). Conclusion The sustainability of the gains achieved in malaria control in Zanzibar is seriously threatened by the resistance of malaria vectors to pyrethroids and the short-lived efficacy of LLINs. This study has revealed that even in relatively well-resourced and logistically manageable places like Zanzibar, malaria elimination is going to be difficult to achieve with the current control measures. PMID:23537463

Prevalence of malaria from blood smears examination: a seven-year retrospective study from metema hospital, northwest ethiopia.

PubMed

Ferede, Getachew; Worku, Abiyu; Getaneh, Alemtegna; Ahmed, Ali; Haile, Tarekegn; Abdu, Yenus; Tessema, Belay; Wondimeneh, Yitayih; Alemu, Abebe

2013-01-01

Background. Malaria is a major public health problem in Ethiopia where an estimated 68% of the population lives in malarious areas. Studying its prevalence is necessary to implement effective control measures. Therefore, the aim of this study was to determine seven-year slide positive rate of malaria. Methods. A retrospective study was conducted at Metema Hospital from September 2006 to August 2012. Seven-year malaria cases data had been collected from laboratory registration book. Results. A total of 55,833 patients were examined for malaria; of these, 9486 (17%) study subjects were positive for malaria. The predominant Plasmodium species detected was P. falciparum (8602) (90.7%) followed by P. vivax (852) (9%). A slide positive rate of malaria within the last seven years (2006-2012) was almost constant with slight fluctuation. The age groups of 5-14 years old were highly affected by malariainfection (1375) (20.1%), followed by 15-29 years old (3986) (18.5%). High slide positive rate of malaria occurred during spring (September-November), followed by summer (June-August). Conclusion. Slide positive rate of malaria was high in study area. Therefore, health planners and administrators should give intensive health education for the community.

[Plasmodium malariae malaria with more than a 4-month incubation period: difficult to distinguish from a relapse of Plasmodium vivax malaria].

PubMed

Hase, Ryota; Uwamino, Yoshifumi; Muranaka, Kiyoharu; Tochitani, Kentaro; Sogi, Misa; Kitazono, Hidetaka; Hosokawa, Naoto

2013-07-01

We report herein on a case of Plasmodium malariae malaria with more than a 4-month incubation period. A 35-year-old Japanese man who first presented to our clinic with fever and history of travel to Papua New Guinea was suspected of having Plasmodium vivax malaria based on peripheral smear results. We admitted him and initiated treatment with mefloquine. After two days of therapy, he became afebrile. We discharged him, and P. vivax was later confirmed with PCR. We started mefloquine prophylaxis for a planned trip to Papua New Guinea. After his return, a standard dose of primaquine (15 mg x 14 days) was prescribed for a radical cure of P. vivax. About 4 months after his last visit to Papua New Guinea, he returned to our clinic with fever. We suspected a relapse of P. vivax malaria and admitted him for a second time. After two days of mefloquine therapy, his symptoms improved. We discharged him and restarted a higher dose of primaquine (30 mg x 14 days) therapy for a radical cure of P. vivax. Subsequently, the PCR test revealed the parasite was P. malariae and not P. vivax. Only 13 cases of Plasmodium malariae malaria have been reported in Japan during the past 10 years. Blood-stage schizonticides such as mefloquine is not active against the liver stage. Therefore, the use of these drugs for prophylaxis will not be effective for prevention of malaria if its liver stage is longer than the duration of effective chemoprophylaxis. Although the incubation period of P. malariae is typically 13 to 28 days, it occasionally lasts for months or even years. Careful attention should be given to the possibility that P. malariae occasionally has a long incubation period even in the absence of the hypnozoite stage.

Transfusion-transmitted malaria in Ghana.

PubMed

Owusu-Ofori, Alex K; Betson, Martha; Parry, Christopher M; Stothard, J Russell; Bates, Imelda

2013-06-01

In sub-Saharan Africa, the prevalence of malaria parasitemia in blood donors varies from 0.6% to 50%. Although the burden of TTM in malaria-endemic countries is unknown, it is recommended that all donated blood is screened for malaria parasites. This study aimed to establish the incidence of TTM and identify a suitable screening test. Pregnant women, children, and immunocompromised malaria-negative transfusion recipients in a teaching hospital in Ghana were recruited over the course of 1 year. Parasites detected in recipients within 14 days of the transfusion were genotyped and compared to parasites in the transfused blood. The presence of genotypically identical parasites in the recipient and the transfused blood confirmed transfusion-transmitted malaria. Four malaria screening tests were compared to assess their usefulness in the context of African blood banks. Of the 50 patients who received transfusions that were positive for Plasmodium falciparum by polymerase chain reaction (PCR), 7 recipients developed PCR-detectable parasitemia. In only 1 of the 50 recipients (2%) was the parasite identical to that in the transfused blood. The prevalence of P. falciparum malaria in transfused blood was 4.7% (21/445) by microscopy, 13.7% (60/440) by rapid diagnostic test, 18% (78/436) by PCR, and 22.2% (98/442) by enzyme immunoassay. Although malaria parasites are commonly detected in blood donors in malaria-endemic areas, transfusion-transmitted malaria occurs infrequently. Policies recommend screening blood donors for malaria, but none of the commonly used methods is sufficiently sensitive to be used by blood banks in malaria-endemic countries.

Chronic Malaria Revealed by a New Fluorescence Pattern on the Antinuclear Autoantibodies Test

PubMed Central

Hommel, Benjamin; Charuel, Jean-Luc; Jaureguiberry, Stéphane; Arnaud, Laurent; Courtin, Regis; Kassab, Petra; Prendki, Virginie; Paris, Luc; Ghillani-Dalbin, Pascale; Thellier, Marc; Caumes, Eric; Amoura, Zahir; Mazier, Dominique; Musset, Lucile; Buffet, Pierre; Miyara, Makoto

2014-01-01

Background Several clinical forms of malaria such as chronic carriage, gestational malaria or hyper-reactive malarial splenomegaly may follow a cryptic evolution with afebrile chronic fatigue sometimes accompanied by anemia and/or splenomegaly. Conventional parasitological tests are often negative or not performed, and severe complications may occur. Extensive explorations of these conditions often include the search for antinuclear autoantibodies (ANA). Methods We analysed fluorescence patterns in the ANA test in patients with either chronic cryptic or acute symptomatic malaria, then conducted a one-year prospective study at a single hospital on all available sera drawn for ANA detections. We then identified autoantibodies differentially expressed in malaria patients and in controls using human protein microarray. Results We uncovered and defined a new, malaria-related, nucleo-cytoplasmic ANA pattern displaying the specific association of a nuclear speckled pattern with diffuse cytoplasmic perinuclearly-enhanced fluorescence. In the one-year prospective analysis, 79% of sera displaying this new nucleo-cytoplasmic fluorescence were from patients with malaria. This specific pattern, not seen in other parasitic diseases, allowed a timely reorientation of the diagnosis toward malaria. To assess if the autoantibody immune response was due to autoreactivity or molecular mimicry we isolated 42 autoantigens, targets of malarial autoantibodies. BLAST analysis indicated that 23 of recognized autoantigens were homologous to plasmodial proteins suggesting autoimmune responses directly driven by the plasmodial infection. Conclusion In patients with malaria in whom parasitological tests have not been performed recognition of this new, malaria-related fluorescence pattern on the ANA test is highly suggestive of the diagnosis and triggers immediate, easy confirmation and adapted therapy. PMID:24551116

Maternal malaria and gravidity interact to modify infant susceptibility to malaria.

PubMed

Mutabingwa, Theonest K; Bolla, Melissa C; Li, Jin-Long; Domingo, Gonzalo J; Li, Xiaohong; Fried, Michal; Duffy, Patrick E

2005-12-01

In endemic areas, placental malaria due to Plasmodium falciparum is most frequent and severe in first-time mothers, and increases the risk of infant mortality in their offspring. Placental malaria may increase the susceptibility of infants to malaria parasitemia, but evidence for this effect is inconclusive. During 2002-2004, we monitored parasitemia in 453 infants, including 69 who were born to mothers with placental malaria, in a region of northeastern Tanzania where malaria transmission is intense. We used a Cox proportional hazards model to evaluate the time from birth to first parasitemia, and a generalized estimating equations logistic regression model to evaluate risk of any parasitemia throughout the first year of life. Compared with infants whose mothers did not have placental malaria at delivery ("PM-negative"), offspring of mothers with placental malaria at delivery ("PM-positive") were 41% more likely to experience their first parasitemia at a younger age (adjusted hazard ratio [AHR] = 1.41, 95% confidence interval [CI] 1.01-1.99). The odds of parasitemia throughout infancy were strongly modified by the interaction between placental malaria and gravidity (p for interaction = 0.008, Type 3 likelihood ratio test). Offspring of PM-negative primigravidae had lower odds of parasitemia during infancy (adjusted odds ratio [AOR] = 0.67, 95% CI 0.50-0.91) than offspring of PM-negative multigravidae, and offspring of PM-positive primigravidae had the lowest odds (AOR = 0.21, 95% CI 0.09-0.47). In contrast, offspring of PM-positive multigravidae had significantly higher odds of parasitemia (AOR = 1.59, 95% CI 1.16-2.17). Although parasitemia is more frequent in primigravid than multigravid women, the converse is true in their offspring, especially in offspring of PM-positive women. While placental malaria is known to increase mortality risk for first-born infants, it surprisingly reduced their risk of parasitemia in this study. Placental malaria of multigravidae

Ecology, economics and political will: the vicissitudes of malaria strategies in Asia.

PubMed

Kidson, C; Indaratna, K

1998-06-01

The documented history of malaria in parts of Asia goes back more than 2,000 years, during which the disease has been a major player on the socioeconomic stage in many nation states as they waxed and waned in power and prosperity. On a much shorter time scale, the last half century has seen in microcosm a history of large fluctuations in endemicity and impact of malaria across the spectrum of rice fields and rain forests, mountains and plains that reflect the vast ecological diversity inhabited by this majority aggregation of mankind. That period has seen some of the most dramatic changes in social and economic structure, in population size, density and mobility, and in political structure in history: all have played a part in the changing face of malaria in this extensive region of the world. While the majority of global malaria cases currently reside in Africa, greater numbers inhabited Asia earlier this century before malaria programs savored significant success, and now Asia harbors a global threat in the form of the epicenter of multidrug resistant Plasmodium falciparum which is gradually encompassing the tropical world. The latter reflects directly the vicissitudes of economic change over recent decades, particularly the mobility of populations in search of commerce, trade and personal fortunes, or caught in the misfortunes of physical conflicts. The period from the 1950s to the 1990s has witnessed near "eradication" followed by resurgence of malaria in Sri Lanka, control and resurgence in India, the influence of war and postwar instability on drug resistance in Cambodia, increase in severe and cerebral malaria in Myanmar during prolonged political turmoil, the essential disappearance of the disease from all but forested border areas of Thailand where it remains for the moment intractable, the basic elimination of vivax malaria from many provinces of central China. Both positive and negative experiences have lessons to teach in the debate between eradication

The challenge of maintaining microscopist capacity at basic levels for malaria elimination in Jiangsu Province, China.

PubMed

Ding, Guisheng; Zhu, Guoding; Cao, Caiqun; Miao, Ping; Cao, Yuanyuan; Wang, Weiming; Gu, Yaping; Xu, Sui; Wang, Shengqiang; Zhou, Huayun; Cao, Jun

2018-04-12

Local malaria transmission has decreased rapidly since the National Malaria Elimination Action Plan was launched in China in 2010. However, imported malaria cases from Africa and Southeast Asia still occur in China due to overseas laborers. Diagnosis by microscopy is the gold standard for malaria and is used in most hospitals in China. However, the current capacity of microscopists to manage malaria cases in hospitals and public health facilities to meet the surveillance needs to eliminate and prevent the reintroduction of malaria is unknown. Malaria diagnoses were assessed by comparing the percentage of first visit and confirmed malaria diagnoses at Centers for Disease Control and Prevention (CDCs) and hospitals. The basic personnel information for public health departments and hospitals at different levels was investigated. The skills of microscopists for blood smear preparation and slide interpretation were also examined at the county and township levels. Inaccurate rate with 13.49% and 7.32%, respectively, in 2013 and 2014, from 341 and 355 reported cases from sub-provincial levels in Jiangsu province. Most of the 523 malaria cases reported in Nantong Prefecture from 2000 to 2014 involved patients who first visited county CDCs seeking treatment, however, none of these cases received confirmed diagnosis of malaria in townships or villages.The staff at county CDCs and hospitals with a higher education background performed better at making and interpreting blood smears than staff from townships. The network for malaria elimination in an entire province has been well established. However, an insufficient capacity for malaria diagnosis was observed, especially the preparing and reading the blood smears at the township and village levels, which is a challenge to achieving and maintaining malaria elimination.

Targeting imported malaria through social networks: a potential strategy for malaria elimination in Swaziland.

PubMed

Koita, Kadiatou; Novotny, Joseph; Kunene, Simon; Zulu, Zulizile; Ntshalintshali, Nyasatu; Gandhi, Monica; Gosling, Roland

2013-06-27

Swaziland has made great progress towards its goal of malaria elimination by 2015. However, malaria importation from neighbouring high-endemic Mozambique through Swaziland's eastern border remains a major factor that could prevent elimination from being achieved. In order to reach elimination, Swaziland must rapidly identify and treat imported malaria cases before onward transmission occurs. A nationwide formative assessment was conducted over eight weeks to determine if the imported cases of malaria identified by the Swaziland National Malaria Control Programme could be linked to broader social networks and to explore methods to access these networks. Using a structured format, interviews were carried out with malaria surveillance agents (6), health providers (10), previously identified imported malaria cases (19) and people belonging to the networks identified through these interviews (25). Most imported malaria cases were Mozambicans (63%, 12/19) making a living in Swaziland and sustaining their families in Mozambique. The majority of imported cases (73%, 14/19) were labourers and self-employed contractors who travelled frequently to Mozambique to visit their families and conduct business. Social networks of imported cases with similar travel patterns were identified through these interviews. Nearly all imported cases (89%, 17/19) were willing to share contact information to enable network members to be interviewed. Interviews of network members and key informants revealed common congregation points, such as the urban market places in Manzini and Malkerns, as well as certain bus stations, where people with similar travel patterns and malaria risk behaviours could be located and tested for malaria. This study demonstrated that imported cases of malaria belonged to networks of people with similar travel patterns. This study may provide novel methods for screening high-risk groups of travellers using both snowball sampling and time-location sampling of networks to

Pregnancy-associated malaria and malaria in infants: an old problem with present consequences.

PubMed

Moya-Alvarez, Violeta; Abellana, Rosa; Cot, Michel

2014-07-11

Albeit pregnancy-associated malaria (PAM) poses a potential risk for over 125 million women each year, an accurate review assessing the impact on malaria in infants has yet to be conducted. In addition to an effect on low birth weight (LBW) and prematurity, PAM determines foetal exposure to Plasmodium falciparum in utero and is correlated to congenital malaria and early development of clinical episodes during infancy. This interaction plausibly results from an ongoing immune tolerance process to antigens in utero, however, a complete explanation of this immune process remains a question for further research, as does the precise role of protective maternal antibodies. Preventive interventions against PAM modify foetal exposure to P. falciparum in utero, and have thus an effect on perinatal malaria outcomes. Effective intermittent preventive treatment in pregnancy (IPTp) diminishes placental malaria (PM) and its subsequent malaria-associated morbidity. However, emerging resistance to sulphadoxine-pyrimethamine (SP) is currently hindering the efficacy of IPTp regimes and the efficacy of alternative strategies, such as intermittent screening and treatment (IST), has not been accurately evaluated in different transmission settings. Due to the increased risk of clinical malaria for offspring of malaria infected mothers, PAM preventive interventions should ideally start during the preconceptual period. Innovative research examining the effect of PAM on the neurocognitive development of the infant, as well as examining the potential influence of HLA-G polymorphisms on malaria symptoms, is urged to contribute to a better understanding of PAM and infant health.

Malaria chemotherapy.

PubMed

Winstanley, Peter; Ward, Stephen

2006-01-01

Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.

Malaria vaccine: WHO position paper, January 2016 - Recommendations.

PubMed

2018-06-14

This article presents the World Health Organization's (WHO) recommendations on the use of malaria vaccine excerpted from the WHO position paper on malaria vaccine published in the Weekly epidemiological Record in January 2016 [1]. The current document is the first WHO position paper on malaria vaccination and focuses primarily on the available evidence concerning the only malaria vaccine having received a positive regulation assessment from the European Medicines Agency (EMA) [2]. The position paper gives consideration to the epidemiological features of the disease and assesses the potential use of the vaccine for public health benefits. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence to recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the joint recommendation of the WHO's Strategic Advisory Group of Experts (SAGE) on immunization and the Malaria Policy Advisory Committee (MPAC). These recommendations were discussed by SAGE and MPAC at the October 2015 SAGE meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. Copyright © 2016 Elsevier Ltd. All rights reserved.

Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

PubMed Central

2010-01-01

Background Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. Methods The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. Results Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Conclusions These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis. PMID:20955613

Rodent malaria-resistant strains of the mosquito, Anopheles gambiae, have slower population growth than -susceptible strains

PubMed Central

Voordouw, Maarten J; Anholt, Bradley R; Taylor, Pam J; Hurd, Hilary

2009-01-01

Background Trade-offs between anti-parasite defence mechanisms and other life history traits limit the evolution of host resistance to parasites and have important implications for understanding diseases such as malaria. Mosquitoes have not evolved complete resistance to malaria parasites and one hypothesis is that anti-malaria defence mechanisms are costly. Results We used matrix population models to compare the population growth rates among lines of Anopheles gambiae that had been selected for resistance or high susceptibility to the rodent malaria parasite, Plasmodium yoelii nigeriensis. The population growth rate of the resistant line was significantly lower than that of the highly susceptible and the unselected control lines, regardless of whether mosquitoes were infected with Plasmodium or not. The lower population growth of malaria-resistant mosquitoes was caused by reduced post blood-feeding survival of females and poor egg hatching. Conclusion With respect to eradicating malaria, the strategy of releasing Plasmodium-resistant Anopheles mosquitoes is unlikely to be successful if the costs of Plasmodium-resistance in the field are as great as the ones measured in this study. High densities of malaria-resistant mosquitoes would have to be maintained by continuous release from captive breeding facilities. PMID:19379508

The Efficacy of the Canter Background Interference Procedure in Identifying Children with Cerebral Dysfunction

ERIC Educational Resources Information Center

Adams, Jerry; Kenny, Thomas J.

1973-01-01

In this study, BIP records previously reported by Kenny (1971) were reused to determine the accuracy of identification of children with cerebral dysfunction and to update the results of using the revised BIP scoring system. (Author)

The effect of dams and seasons on malaria incidence and anopheles abundance in Ethiopia

PubMed Central

2013-01-01

Background Reservoirs created by damming rivers are often believed to increase malaria incidence risk and/or stretch the period of malaria transmission. In this paper, we report the effects of a mega hydropower dam on P. falciparum malaria incidence in Ethiopia. Methods A longitudinal cohort study was conducted over a period of 2 years to determine Plasmodium falciparum malaria incidence among children less than 10 years of age living near a mega hydropower dam in Ethiopia. A total of 2080 children from 16 villages located at different distances from a hydropower dam were followed up from 2008 to 2010 using active detection of cases based on weekly house to house visits. Of this cohort of children, 951 (48.09%) were females and 1059 (51.91%) were males, with a median age of 5 years. Malaria vectors were simultaneously surveyed in all the 16 study villages. Frailty models were used to explore associations between time-to-malaria and potential risk factors, whereas, mixed-effects Poisson regression models were used to assess the effect of different covariates on anopheline abundance. Results Overall, 548 (26.86%) children experienced at least one clinical malaria episode during the follow up period with mean incidence rate of 14.26 cases/1000 child-months at risk (95% CI: 12.16 - 16.36). P. falciparum malaria incidence showed no statistically significant association with distance from the dam reservoir (p = 0.32). However, P. falciparum incidence varied significantly between seasons (p < 0.01). The malaria vector, Anopheles arabiensis, was however more abundant in villages nearer to the dam reservoir. Conclusions P. falciparum malaria incidence dynamics were more influenced by seasonal drivers than by the dam reservoir itself. The findings could have implications in timing optimal malaria control interventions and in developing an early warning system in Ethiopia. PMID:23566411

Malaria and pregnancy: the perspective in Pakistan.

PubMed

Bhatti, Maqsood A; Azharuddin, Muhammad; Bhatti, Samreen; Islam, Muhammad; Khan, Muhammad Aslam

2007-01-01

To study the effects of malaria on pregnancy outcome. A case control study conducted on patients identified by ICD-9 coding system of the hospital medical records. Demographic and clinical data recorded on standardized data sheet and analyzed using SPSS 11.5 software. Of the total patients, 67.4% were multigravid and 32.6% were primigravid with 78.6% of patients having platelets < 150,000. Mean haemoglobin was 9.4 gm/dl in patients and 12.2 gm/dl in controls. Plasmodium Vivax was accounted for 55.8%, P. Falciparum for 41.9%, and P. Ovale 2.3% of infections. In all, 48.8% of patients received oral Chloroquine, 16.3% oral Quinine, 30.3% intravenous Quinine, 20.9% of patients received combination treatment with IV Clindamycin, and one each patient received oral Artemether or oral halofantrine. Two patients had an abortion. One of the following complications including, threatened abortion, preterm labour, ARDS or Cerebral malaria, was observed in one patient each. Mean weight of babies born to cases was 2.8 kg (range 1.4-3.8) and of control babies was 3.2 kg (range 2.5-4.0 kg). No congenital malformations were reported. Plasmodium falciparum sp, moderate parasitic load, haemoglobin < 10 gm/dL, platelet count < 50,000/mm3 and IV quinine with loading dose of 20 mg/kg are identified as few of the potential risk factors for poor outcome in pregnancy.

Driving towards malaria elimination in Botswana by 2018: progress on case-based surveillance, 2013-2014.

PubMed

Motlaleng, M; Edwards, J; Namboze, J; Butt, W; Moakofhi, K; Obopile, M; Manzi, M; Takarinda, K C; Zachariah, R; Owiti, P; Oumer, N; Mosweunyane, T

2018-04-25

Background: Reliable information reporting systems ensure that all malaria cases are tested, treated and tracked to avoid further transmission. Botswana aimed to eliminate malaria by 2018, and surveillance is key. This study focused on assessing the uptake of the new malaria case-based surveillance (CBS) system introduced in 2012, which captures information on malaria cases reported in the Integrated Disease Surveillance and Response (IDSR) system. Methods: This was a retrospective descriptive study based on routine data focusing on Ngami, Chobe and Okavango, three high-risk districts in Botswana. Aggregated data variables were extracted from the IDSR and compared with data from the CBS. Results: The IDSR reported 456 malaria cases in 2013 and 1346 in 2014, of which respectively only 305 and 884 were reported by the CBS. The CBS reported 34% fewer cases than the IDSR system, indicating substantial differences between the two systems. The key malaria indicators with the greatest variability among the districts included in the study were case identification number and date of diagnosis. Conclusion: The IDSR and CBS systems are essential for malaria elimination, as shown by the significant gaps in reporting between the two systems. These findings highlight the need for further investigation into these discrepancies. Strengthening the CBS system will help to reach the objective of malaria elimination in Botswana.

Evolution of malaria mortality and morbidity after the emergence of chloroquine resistance in Niakhar, Senegal

PubMed Central

2009-01-01

Background Recently, it has been assumed that resistance of Plasmodium to chloroquine increased malaria mortality. The study aimed to assess the impact of chemoresistance on mortality attributable to malaria in a rural area of Senegal, since the emergence of resistance in 1992, whilst chloroquine was used as first-line treatment of malaria, until the change in national anti-malarial policy in 2003. Methods The retrospective study took place in the demographic surveillance site (DSS) of Niakhar. Data about malaria morbidity were obtained from health records of three health care facilities, where diagnosis of malaria was based on clinical signs. Source of data concerning malaria mortality were verbal autopsies performed by trained fieldworkers and examined by physicians who identified the probable cause of death. Results From 1992 to 2004, clinical malaria morbidity represented 39% of total morbidity in health centres. Mean malaria mortality was 2.4‰ and 10.4‰ among total population and children younger than five years, respectively, and was highest in the 1992-1995 period. It tended to decline from 1992 to 2003 (Trend test, total population p = 0.03, children 0-4 years p = 0.12 - children 1-4 years p = 0.04- children 5-9 years p = 0.01). Conclusion Contrary to what has been observed until 1995, mortality attributable to malaria did not continue to increase dramatically in spite of the growing resistance to chloroquine and its use as first-line treatment until 2003. Malaria morbidity and mortality followed parallel trends and rather fluctuated accordingly to rainfall. PMID:19943921

Predictors of fetal anemia and cord blood malaria parasitemia among newborns of HIV-positive mothers

PubMed Central

2013-01-01

Background Malaria and HIV infections during pregnancy can individually or jointly unleash or confound pregnancy outcomes. Two of the probable outcomes are fetal anemia and cord blood malaria parasitemia. We determined clinical and demographic factors associated with fetal anemia and cord blood malaria parasitemia in newborns of HIV-positive women from two districts in Ghana. Results We enrolled 1,154 antenatal attendees (443 HIV-positive and 711 HIV-negative) of which 66% were prospectively followed up at delivery. Maternal malaria parasitemia, and anemia rates among HIV+ participants at enrolment were 20.3% and 78.7% respectively, and 12.8% and 51.6% among HIV- participants. Multivariate linear and logistic regression models were used to study associations. Prevalence of fetal anemia (cord hemoglobin level < 12.5 g/dL) and cord parasitemia (presence of P. falciparum in cord blood at delivery) were 57.3% and 24.4% respectively. Factors found to be associated with fetal anemia were maternal malaria parasitemia and maternal anemia. Infant cord hemoglobin status at delivery was positively and significantly associated with maternal hemoglobin and gestational age whilst female gender of infant was negatively associated with cord hemoglobin status. Maternal malaria parasitemia status at recruitment and female gender of infant were positively associated with infant cord malaria parasitemia status. Conclusions Our data show that newborns of women infected with HIV and/or malaria are at increased risk of anemia and also cord blood malaria parasitemia. Prevention of malaria infection during pregnancy may reduce the incidence of both adverse perinatal outcomes. PMID:24007344

Quality of Malaria Case Management in Malawi: Results from a Nationally Representative Health Facility Survey

PubMed Central

Steinhardt, Laura C.; Chinkhumba, Jobiba; Wolkon, Adam; Luka, Madalitso; Luhanga, Misheck; Sande, John; Oyugi, Jessica; Ali, Doreen; Mathanga, Don; Skarbinski, Jacek

2014-01-01

Background Malaria is endemic throughout Malawi, but little is known about quality of malaria case management at publicly-funded health facilities, which are the major source of care for febrile patients. Methods In April–May 2011, we conducted a nationwide, geographically-stratified health facility survey to assess the quality of outpatient malaria diagnosis and treatment. We enrolled patients presenting for care and conducted exit interviews and re-examinations, including reference blood smears. Moreover, we assessed health worker readiness (e.g., training, supervision) and health facility capacity (e.g. availability of diagnostics and antimalarials) to provide malaria case management. All analyses accounted for clustering and unequal selection probabilities. We also used survey weights to produce estimates of national caseloads. Results At the 107 facilities surveyed, most of the 136 health workers interviewed (83%) had received training on malaria case management. However, only 24% of facilities had functional microscopy, 15% lacked a thermometer, and 19% did not have the first-line artemisinin-based combination therapy (ACT), artemether-lumefantrine, in stock. Of 2,019 participating patients, 34% had clinical malaria (measured fever or self-reported history of fever plus a positive reference blood smear). Only 67% (95% confidence interval (CI): 59%, 76%) of patients with malaria were correctly prescribed an ACT, primarily due to missed malaria diagnosis. Among patients without clinical malaria, 31% (95% CI: 24%, 39%) were prescribed an ACT. By our estimates, 1.5 million of the 4.4 million malaria patients seen in public facilities annually did not receive correct treatment, and 2.7 million patients without clinical malaria were inappropriately given an ACT. Conclusions Malawi has a high burden of uncomplicated malaria but nearly one-third of all patients receive incorrect malaria treatment, including under- and over-treatment. To improve malaria case

Plasmodium knowlesi malaria in humans is widely distributed and potentially life-threatening

PubMed Central

Cox-Singh, Janet; Davis, Timothy M. E.; Lee, Kim-Sung; Shamsul, Sunita S. G.; Matusop, Asmad; Ratnam, Shanmuga; Rahman, Hasan A.; Conway, David J; Singh, Balbir

2008-01-01

Background Until recently, Plasmodium knowlesi malaria in humans was misdiagnosed as P. malariae. The present objectives were to determine the geographic distribution of P. knowlesi in the human population in Malaysia and to investigate four suspected fatal cases. Methods Sensitive and specific nested-PCR was used to identify all Plasmodium species present in blood from i) 960 patients with malaria hospitalized in Sarawak, Malaysian Borneo from 2001-2006, ii) 54 P. malariae archival blood-films from 15 districts in Sabah, Malaysian Borneo (2003–2005) and four districts in Pahang, Peninsular Malaysia (2004–2005), and iii) suspected knowlesi fatalities. In the four latter cases, available clinical and laboratory data were reviewed. Results P. knowlesi DNA was detected in 266 of 960 (27·7%) of the samples from Sarawak hospitals, 41 of 49 (83·7%) from Sabah and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 fatal cases. All were hyperparasitemic and developed marked hepatorenal dysfunction. Conclusions Human infections with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 hours, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for knowlesi malaria, we recommend that patients in, or who have travelled to, South-east Asia who are ill with a ‘P. malariae’ hyperparasitemia diagnosis by microscopy should receive intensive management as appropriate for severe falciparum malaria. PMID:18171245

Malaria indicator survey 2007, Ethiopia: coverage and use of major malaria prevention and control interventions

PubMed Central

2010-01-01

Background In 2005, a nationwide survey estimated that 6.5% of households in Ethiopia owned an insecticide-treated net (ITN), 17% of households had been sprayed with insecticide, and 4% of children under five years of age with a fever were taking an anti-malarial drug. Similar to other sub-Saharan African countries scaling-up malaria interventions, the Government of Ethiopia set an ambitious national goal in 2005 to (i) provide 100% ITN coverage in malarious areas, with a mean of two ITNs per household; (ii) to scale-up indoor residual spraying of households with insecticide (IRS) to cover 30% of households targeted for IRS; and (iii) scale-up the provision of case management with rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT), particularly at the peripheral level. Methods A nationally representative malaria indicator survey (MIS) was conducted in Ethiopia between September and December 2007 to determine parasite and anaemia prevalence in the population at risk and to assess coverage, use and access to scaled-up malaria prevention and control interventions. The survey used a two-stage random cluster sample of 7,621 households in 319 census enumeration areas. A total of 32,380 people participated in the survey. Data was collected using standardized Roll Back Malaria Monitoring and Evaluation Reference Group MIS household and women's questionnaires, which were adapted to the local context. Results Data presented is for households in malarious areas, which according to the Ethiopian Federal Ministry of Health are defined as being located <2,000 m altitude. Of 5,083 surveyed households, 3,282 (65.6%) owned at least one ITN. In ITN-owning households, 53.2% of all persons had slept under an ITN the prior night, including 1,564/2,496 (60.1%) children <5 years of age, 1,891/3,009 (60.9%) of women 15 - 49 years of age, and 166/266 (65.7%) of pregnant women. Overall, 906 (20.0%) households reported to have had IRS in the past 12 months. Of 747

Anophelism in a Former Malaria Area of Northeastern Spain

PubMed Central

Bueno-Marí, Rubén; Jiménez-Peydró, Ricardo

2013-01-01

Background: A field study on diversity and distribution of anophelines currently present in a past endemic malaria area of Spain was carried out in order to identify possible risk areas of local disease transmission. Methods: Multiple larval sites were sampled from June to October of 2011 in the Region of Somontano de Barbastro (Northeastern Spain). The sampling effort was fixed at 10 minutes which included the active search for larvae in each biotope visited. Results: A total of 237 larval specimens belonging to four Anopheles species (Anopheles atroparvus, An. claviger, An. maculipennis and An. petragnani) were collected and identified. Conclusions: Malaria receptivity in the study area is high, especially in the area of Cinca river valley, due to the abundance of breeding sites of An. atroparvus very close to human settlements. Although current socio-economic conditions in Spain reduce possibilities of re-emergence of malaria transmission, it is evident that certain entomological and epidemiological vigilance must be maintained and even increased in the context of current processes of climate change and globalization. PMID:24409440

Malaria rapid diagnostic tests.

PubMed

Wilson, Michael L

2012-06-01

Global efforts to control malaria are more complex than those for other infectious diseases, in part because of vector transmission, the complex clinical presentation of Plasmodium infections, >1 Plasmodium species causing infection, geographic distribution of vectors and infection, and drug resistance. The World Health Organization approach to global malaria control focuses on 2 components: vector control and diagnosis and treatment of clinical malaria. Although microscopy performed on peripheral blood smears remains the most widely used diagnostic test and the standard against which other tests are measured, rapid expansion of diagnostic testing worldwide will require use of other diagnostic approaches. This review will focus on the malaria rapid diagnostic test (MRDT) for detecting malaria parasitemia, both in terms of performance characteristics of MRDTs and how they are used under field conditions. The emphasis will be on the performance and use of MRDTs in regions of endemicity, particularly sub-Saharan Africa, where most malaria-related deaths occur.

Intraerythrocytic Killing of Malaria Parasites

DTIC Science & Technology

1989-05-12

immunity (23, 24) and its relevance to human malaria (25). 4. The effect of the B- thalassemia mutation on ralaria-infectcd mice arid the role of the spleen...detected. Thus, Pc96 shares a cross-reactive epitope with these three primate malaria antigens. 4. Effect of B- thalassemia on malaria-infected mice and...B- thalassemia against malaria, rodent malaria parasites were studied in C57BL/6J mice with B- thalassemia , in mice in which the thalassemia had been

Self-diagnosis of malaria by travellers: a cohort study on the use of malaria rapid diagnostic tests provided by a Swiss travel clinic.

PubMed

Berthod, Delphine; Rochat, Jacynthe; Voumard, Rachel; Rochat, Laurence; Genton, Blaise; D'Acremont, Valérie

2017-10-28

The WHO recommends that all suspect malaria cases be tested before receiving treatment. Rapid diagnostic tests (RDT) for malaria can be performed reliably by community health workers with no formal medical background and thus, RDTs could also be provided to travellers for self-diagnosis during visits to endemic regions. RDTs were proposed during pre-travel consultations to pre-defined categories of travellers. A training run on their own blood was performed and, if carried out correctly, the traveller was given a written procedure on how to perform the test and act on its result. The travellers were then proposed to buy a malaria RDT kit and were interviewed upon their return. From February 2012 to February 2017, 744 travellers were proposed RDTs and 692 performed the training run (one could not complete it due to a hand tremor). Among the 691 subjects included, 69% travelled to moderate- or low-risk areas of malaria, 18% to high-risk areas and 13% to mixed-risk areas. The two most frequent categories of travellers to whom RDTs were proposed were long-term travellers (69%) and those travelling to remote areas (57%). 543 travellers (79%) were interviewed upon return. During their trip, 17% (91/543) had a medical problem with fever and 12% (65/543) without fever. Among 91 febrile patients, 57% (52/91) performed an RDT, 22% (20/91) consulted immediately without using the test, and 21% (19/91) did neither. Four RDTs (4/52; 8%) were positive: 2 in low-risk and 2 in high-risk areas (0.7% attack rate of self-documented malaria). Two travellers could not perform the test correctly and attended a facility or took standby emergency treatment. Four travellers with negative results repeated the test after 24 h; all were still negative. Carrying RDTs made travellers feel more secure, especially when travelling with children. 1/6 travellers experienced fever and 4/5 of those reacted appropriately: more than half used RDTs and a quarter consulted immediately. Four travellers

New treatment policy of malaria as a part of malaria control program in Indonesia.

PubMed

Kusriastuti, Rita; Surya, Asik

2012-07-01

Malaria control program is one of the oldest program in the Ministry of Health (MoH) Republic of Indonesia. Started with effort to eradicate malaria in 1959 through Malaria Eradication Command well known as KOPEM (Komando Pembasmian Malaria) then it evolves to Malaria Control Program, Roll Back Malaria Program, and the current Malaria Elimination Program. In terms of diagnostic and treatment, the policy has formulated by strictly follow evidence-based principles as well as technical guided from World Health Organization (WHO). In 2004, based on numerous researches conducted in Indonesia the use of chloroquine was stopped and artemisinin-based combination therapy (ACT) was then initiated. For severe cases the use of intravenous (iv) Artesunate for cases treated in hospitals and intramuscular (im) Arthemeter for cases treated in the primary care setting were also introduced. ACT, Artesunate iv, and Artemether im, all are provided nationwide through the procurement system. For radical treatment, the recommendation in Indonesia is to add primaquine (PQ) to ACT for Plasmodium vivax and Plasmodium ovale infections to prevent relapses and for Plasmodium Falciparum infection to kill the gametocytes. These recommendations put hope to reduce malaria mortality to zero and eventually with other interventions will eliminate malaria from the country by 2030. The dissemination of this information is important for the policy to apply in practice across the country.

Relative importance of climatic, geographic and socio-economic determinants of malaria in Malawi

PubMed Central

2013-01-01

Background Malaria transmission is influenced by variations in meteorological conditions, which impact the biology of the parasite and its vector, but also socio-economic conditions, such as levels of urbanization, poverty and education, which impact human vulnerability and vector habitat. The many potential drivers of malaria, both extrinsic, such as climate, and intrinsic, such as population immunity are often difficult to disentangle. This presents a challenge for the modelling of malaria risk in space and time. Methods A statistical mixed model framework is proposed to model malaria risk at the district level in Malawi, using an age-stratified spatio-temporal dataset of malaria cases from July 2004 to June 2011. Several climatic, geographic and socio-economic factors thought to influence malaria incidence were tested in an exploratory model. In order to account for the unobserved confounding factors that influence malaria, which are not accounted for using measured covariates, a generalized linear mixed model was adopted, which included structured and unstructured spatial and temporal random effects. A hierarchical Bayesian framework using Markov chain Monte Carlo simulation was used for model fitting and prediction. Results Using a stepwise model selection procedure, several explanatory variables were identified to have significant associations with malaria including climatic, cartographic and socio-economic data. Once intervention variations, unobserved confounding factors and spatial correlation were considered in a Bayesian framework, a final model emerged with statistically significant predictor variables limited to average precipitation (quadratic relation) and average temperature during the three months previous to the month of interest. Conclusions When modelling malaria risk in Malawi it is important to account for spatial and temporal heterogeneity and correlation between districts. Once observed and unobserved confounding factors are allowed for

The Gates Malaria Partnership: a consortium approach to malaria research and capacity development.

PubMed

Greenwood, Brian; Bhasin, Amit; Targett, Geoffrey

2012-05-01

Recently, there has been a major increase in financial support for malaria control. Most of these funds have, appropriately, been spent on the tools needed for effective prevention and treatment of malaria such as insecticide-treated bed nets, indoor residual spraying and artemisinin combination therapy. There has been less investment in the training of the scientists from malaria-endemic countries needed to support these large and increasingly complex malaria control programmes, especially in Africa. In 2000, with support from the Bill & Melinda Gates Foundation, the Gates Malaria Partnership was established to support postgraduate training of African scientists wishing to pursue a career in malaria research. The programme had three research capacity development components: a PhD fellowship programme, a postdoctoral fellowship programme and a laboratory infrastructure programme. During an 8-year period, 36 African PhD students and six postdoctoral fellows were supported, and two research laboratories were built in Tanzania. Some of the lessons learnt during this project--such as the need to improve PhD supervision in African universities and to provide better support for postdoctoral fellows--are now being applied to a successor malaria research capacity development programme, the Malaria Capacity Development Consortium, and may be of interest to other groups involved in improving postgraduate training in health sciences in African universities. © 2012 Blackwell Publishing Ltd.

The clinical burden of malaria in Nairobi: a historical review and contemporary audit

PubMed Central

2011-01-01

Background Widespread urbanization over the next 20 years has the potential to drastically change the risk of malaria within Africa. The burden of the disease, its management, risk factors and appropriateness of targeted intervention across varied urban environments in Africa remain largely undefined. This paper presents a combined historical and contemporary review of the clinical burden of malaria within one of Africa's largest urban settlements, Nairobi, Kenya. Methods A review of historical reported malaria case burdens since 1911 within Nairobi was undertaken using archived government and city council reports. Contemporary information on out-patient case burdens due to malaria were assembled from the National Health Management and Information System (HMIS). Finally, an audit of 22 randomly selected health facilities within Nairobi was undertaken covering 12 months 2009-2010. The audit included interviews with health workers, and a checklist of commodities and guidelines necessary to diagnose, treat and record malaria. Results From the 1930's through to the mid-1960's malaria incidence declined coincidental with rapid population growth. During this period malaria notification and prevention were a priority for the city council. From 2001-2008 reporting systems for malaria were inadequate to define the extent or distribution of malaria risk within Nairobi. A more detailed facility review suggests, however that malaria remains a common diagnosis (11% of all paediatric diagnoses made) and where laboratories (n = 15) exist slide positivity rates are on average 15%. Information on the quality of diagnosis, slide reading and whether those reported as positive were imported infections was not established. The facilities and health workers included in this study were not universally prepared to treat malaria according to national guidelines or identify foci of risks due to shortages of national first-line drugs, inadequate record keeping and a view among some health

Establishing a China malaria diagnosis reference laboratory network for malaria elimination.

PubMed

Yin, Jian-hai; Yan, He; Huang, Fang; Li, Mei; Xiao, Hui-hui; Zhou, Shui-sen; Xia, Zhi-gui

2015-01-28

In China, the prevalence of malaria has reduced dramatically due to the elimination programme. The continued success of the programme will depend upon the accurate diagnosis of the disease in the laboratory. The basic requirements for this are a reliable malaria diagnosis laboratory network and quality management system to support case verification and source tracking. The baseline information of provincial malaria laboratories in the China malaria diagnosis reference laboratory network was collected and analysed, and a quality-assurance activity was carried out to assess their accuracies in malaria diagnosis by microscopy using WHO standards and PCR. By the end of 2013, nineteen of 24 provincial laboratories have been included in the network. In the study, a total of 168 staff were registered and there was no bias in their age, gender, education level, and position. Generally Plasmodium species were identified with great accuracy by microscopy and PCR. However, Plasmodium ovale was likely to be misdiagnosed as Plasmodium vivax by microscopy. China has established a laboratory network for primary malaria diagnosis which will cover a larger area. Currently, Plasmodium species can be identified fairly accurately by microscopy and PCR. However, laboratory staff need additional trainings on accurate identification of P. ovale microscopically and good performance of PCR operations.

Rapid case-based mapping of seasonal malaria transmission risk for strategic elimination planning in Swaziland

PubMed Central

2013-01-01

Background As successful malaria control programmes move towards elimination, they must identify residual transmission foci, target vector control to high-risk areas, focus on both asymptomatic and symptomatic infections, and manage importation risk. High spatial and temporal resolution maps of malaria risk can support all of these activities, but commonly available malaria maps are based on parasite rate, a poor metric for measuring malaria at extremely low prevalence. New approaches are required to provide case-based risk maps to countries seeking to identify remaining hotspots of transmission while managing the risk of transmission from imported cases. Methods Household locations and travel histories of confirmed malaria patients during 2011 were recorded through routine surveillance by the Swaziland National Malaria Control Programme for the higher transmission months of January to April and the lower transmission months of May to December. Household locations for patients with no travel history to endemic areas were compared against a random set of background points sampled proportionate to population density with respect to a set of variables related to environment, population density, vector control, and distance to the locations of identified imported cases. Comparisons were made separately for the high and low transmission seasons. The Random Forests regression tree classification approach was used to generate maps predicting the probability of a locally acquired case at 100 m resolution across Swaziland for each season. Results Results indicated that case households during the high transmission season tended to be located in areas of lower elevation, closer to bodies of water, in more sparsely populated areas, with lower rainfall and warmer temperatures, and closer to imported cases than random background points (all p < 0.001). Similar differences were evident during the low transmission season. Maps from the fit models suggested better predictive

Malaria Diagnostics in Clinical Trials

PubMed Central

Murphy, Sean C.; Shott, Joseph P.; Parikh, Sunil; Etter, Paige; Prescott, William R.; Stewart, V. Ann

2013-01-01

Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests. PMID:24062484

Economic burden of malaria on businesses in Ghana: a case for private sector investment in malaria control.

PubMed

Nonvignon, Justice; Aryeetey, Genevieve Cecilia; Malm, Keziah L; Agyemang, Samuel Agyei; Aubyn, Vivian N A; Peprah, Nana Yaw; Bart-Plange, Constance N; Aikins, Moses

2016-09-06

Despite the significant gains made globally in reducing the burden of malaria, the disease remains a major public health challenge, especially in sub-Saharan Africa (SSA) including Ghana. There is a significant gap in financing malaria control globally. The private sector could become a significant source of financing malaria control. To get the private sector to appreciate the need to invest in malaria control, it is important to provide evidence of the economic burden of malaria on businesses. The objective of this study, therefore, was to estimate the economic burden on malaria on businesses in Ghana, so as to stimulate the sector's investment in malaria control. Data covering 2012-2014 were collected from 62 businesses sampled from Greater Accra, Ashanti and Western Regions of Ghana, which have the highest concentration of businesses in the country. Data on the cost of businesses' spending on treatment and prevention of malaria in staff and their dependants as well as staff absenteeism due to malaria and expenditure on other health-related activities were collected. Views of business leaders on the effect of malaria on their businesses were also compiled. The analysis was extrapolated to cover 5828 businesses across the country. The results show that businesses in Ghana lost about US$6.58 million to malaria in 2014, 90 % of which were direct costs. A total of 3913 workdays were lost due to malaria in firms in the study sample during the period 2012-2014. Businesses in the study sample spent an average of 0.5 % of the annual corporate returns on treatment of malaria in employees and their dependants, 0.3 % on malaria prevention, and 0.5 % on other health-related corporate social responsibilities. Again business leaders affirmed that malaria affects their businesses' efficiency, employee attendance and productivity and expenses. Finally, about 93 % of business leaders expressed the need private sector investment in malaria control. The economic burden of