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Malaria is considered an important cause of morbidity and mortality among people living with sickle cell disease (SCD). This has partly been attributed to the loss of splenic function that occurs early in the disease process. We conducted a cross-sectional study and determined the frequency of malaria infection among SCD patients and explored the association with spleen's presence on ultrasonography and spleen function assessed using the frequency of Howell-Jolly bodies (HJBs). A total of 395 participants consisting of 119 acutely-ill SCD patients, 168 steady-state SCD controls, and 108 healthy non-SCD controls were studied. The prevalence of Plasmodium falciparum parasitemia was 51.3% in acutely-ill SCD patients, 31.7% in steady-state SCD controls, and 11.0% in the healthy non-SCD controls; however, the mean parasite density was significantly higher in the non-SCD controls compared to both SCD groups ( p =  0.0001). Among the acutely-ill SCD patients, the prevalence of clinical malaria and severe malaria anemia were highest in children <5 years of age. The prevalence of parasitemia ( p =  0.540) and parasite density ( p =  0.975) showed no association with spleen presence or absence on ultrasonography. Similarly, the frequency of HJB red cells was not associated with the presence of parasitemia ( p =  0.183). Our study highlights the frequency and role of malaria infection in acutely-ill SCD patients, especially in those younger than five years. Although we have found no evidence of an increased risk of malaria parasitemia or parasite density with markers of hyposplenism, the role played by an underlying immunity to malaria among SCD patients in malaria-endemic region is not clear and needs further studies.

BACKGROUND Sickle cell disease (SCD) is an autosomal recessive hereditary condition characterized by chronic hemolytic anemia and painful vaso-occlusive episodes. Homozygous sickle cell patients are at increased risk of morbidity and mortality from malaria. Autoimmune hemolytic anemia (AIHA) secondary to, or in the setting of, malarial infection is rare. In our case, the concurrence of Plasmodium falciparum malarial parasitemia and AIHA led to severe hemolytic anemia with an extensive packed red blood cell transfusion requirement. The patient's underlying SCD also contributed to the severity of the anemia and persistence of the malarial infection. CASE REPORT We report the case of a 29-year-old woman in the second trimester of pregnancy, with a history of SCD, who presented with severe anemia beyond her typical baseline in the setting of P. falciparum malaria. Hemolysis markers, including lactate dehydrogenase and bilirubin, were elevated. Direct Coombs testing was positive for IgG and C3 antibodies. Treatment with antimalarial agents and steroids led to clinical improvement and eventual clearance of the parasitemia. CONCLUSIONS Our patient's clinical course was most compatible with P. falciparum malaria-induced AIHA. Although she received a short course of steroids, it was treatment and clearance of the parasitemia that led to resolution of the hemolysis and a return to baseline hemoglobin levels. While the exact mechanism of AIHA in malaria is not well characterized, several unique mechanisms have been proposed and should be considered in cases of P. falciparum malaria manifesting with particularly severe hemolytic anemia.

Decreased platelet count is an early phenomenon in asexual Plasmodium falciparum parasitemia, but its association with acute or long-term functional changes in platelets and coagulation is unknown. Moreover, the impact of gametocytemia on platelets and coagulation remains unclear. We investigated the changes in platelet number and function during early asexual parasitemia, gametocytemia and convalescence in 16 individuals participating in a controlled human malaria infection study, and studied its relationship with changes in total and active von Willebrand factor levels (VWF) and the coagulation system. Platelet activation and reactivity were determined by flow cytometry, and the coagulation system was assessed using different representative assays including antigen assays, activity assays and global functional assays. Platelet count was decreased during asexual blood stage infection but normalized during gametocytemia. Platelet P-selectin expression was slightly increased during asexual parasitemia, gametocytemia and at day 64. In contrast, platelet reactivity to different agonists remained unchanged, except a marked decrease in reactivity to low dose collagen-related peptide-XL. Thrombin generation and antigen assays did not show a clear activation of the coagulation during asexual parasitemia, whereas total and active VWF levels were markedly increased. During gametocytemia and on day 64, the endogenous thrombin potential, thrombin peak and velocity index were increased and prothrombin conversion and plasma prothrombin levels were decreased. We conclude that the decreased platelet count during asexual parasitemia is associated with increased active VWF levels (i.e. endothelial activation), but not platelet hyperreactivity or hypercoagulability, and that the increased platelet clearance in asexual parasitemia could cause spontaneous VWF-platelet complexes formation., Competing Interests: The authors have declared that no competing interests exist.

Background: Infants who are aged six months and below are often protected from malaria and usually present with light parasitaemia when infected. However, complications following heavy malaria parasitaemia in this age group are being increasingly reported. This study set out to determine the prevalence, determinants and the public health implications of heavy malaria parasitaemia in young infants (aged one to six months) at the Wesley Guild Hospital, Ilesa (a unit of the Obafemi Awolowo University Teaching Hospitals Complex)., Methods: Ill infants aged one to six months in out-patient and in-patient care were recruited over an 11-month period. Clinical examinations and blood film for malaria parasite were done for all the study participants. Heavy parasitaemia was defined as > 5000 parasites/µl. Clinical predictors of heavy parasitaemia were determined., Results: Heavy parasitaemia was observed in 16(23.9%) of the sixty-seven participants with malaria infection. Presence of fever at presentation (p=0.007), excessive crying (p=0.003) and pallor (p=0.001) were associated with heavy malaria parasitaemia. However, pallor (OR = 20.653; 95%CI 2.091-203.958; p=0.010) was the only independent predictor of heavy parasitaemia among the young infants., Conclusion: About one-in-four ill young infants with malaria had heavy parasitaemia, which was predicted by pallor. Hence, the presence of pallor and factors related to low parental socio-economic status should increase the suspicion of heavy malaria parasitaemia in ill young infants in malaria endemic settings., Competing Interests: The Authors declare that no competing interest exists., (Copyright © 2022 by West African Journal of Medicine.)

This cross-sectional study evaluated epidemiologic characteristics of persons living with HIV (PWH) coinfected with Trypanosoma cruzi in Cochabamba, Bolivia, and estimated T. cruzi parasitemia by real-time quantitative polymerase chain reaction (qPCR) in patients with and without evidence of reactivation by direct microscopy. Thirty-two of the 116 HIV patients evaluated had positive serology for T. cruzi indicative of chronic Chagas disease (27.6%). Sixteen of the 32 (50%) patients with positive serology were positive by quantitative polymerase chain reaction (qPCR), and four of the 32 (12.5%) were positive by direct microscopy. The median parasite load by qPCR in those with CD4+ < 200 was 168 parasites/mL (73-9951) compared with 28.5 parasites/mL (15-1,528) in those with CD4+ ≥ 200 (P = 0.89). There was a significant inverse relationship between the degree of parasitemia estimated by qPCR from blood clot and CD4+ count on the logarithmic scale (rsBC= -0.70, P = 0.007). The correlation between T. cruzi estimated by qPCR+ blood clot and HIV viral load was statistically significant with rsBC = 0.61, P = 0.047. Given the significant mortality of PWH and Chagas reactivation and that 57% of our patients with CD4+ counts < 200 cells/mm3 showed evidence of reactivation, we propose that screening for chronic Chagas disease be considered in PWH in regions endemic for Chagas disease and in the immigrant populations in nonendemic regions. Additionally, our study showed that PWH with advancing immunosuppression have higher levels of estimated parasitemia measured by qPCR and suggests a role for active surveillance for Chagas reactivation with consideration of treatment with antitrypanosomal therapy until immune reconstitution can be achieved.

Background: Children with severe falciparum malaria in malaria-endemic regions are predisposed to developing life-threatening bacterial co-infection. International guidelines therefore recommend empirical broad-spectrum antibacterial therapy in these children. Few studies have examined co-infection in adults, although it has been believed to be relatively rare; antibacterial therapy is therefore not routinely recommended in adults with falciparum malaria., Discussion: However, the fundamental pathophysiology of falciparum malaria in adults and children is the same; it is therefore unclear why adults would not also be predisposed to bacterial infection. Indeed, recent studies have identified bacteraemia in >10% of adults hospitalized with malaria. Some have suggested that these adults probably had bacterial sepsis, with the parasitaemia an incidental finding. However, it is usually impossible in resource-limited settings to determine-at presentation-whether critically ill, parasitaemic adults have severe malaria, bacterial sepsis, or both. Given the significant case-fatality rates of severe malaria and bacterial sepsis, the pragmatic initial approach would be to cover both possibilities., Conclusions: Life-threatening bacterial co-infection may be more common in critically ill adults with malaria than previously believed. While further prospective data are awaited to confirm these findings, it might be more appropriate to provide empirical aantibacterial cover in these patients than current guidelines suggest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alterations in the structure of haemoglobin (Hb) are usually brought about by point mutations affecting one or, in some cases, two codons encoding amino acids of the globin chains. One in three Ghanaians are said to have sickle cell disorders, whereas malaria continues to be one of the leading causes of mortality among children. This study determined the prevalence of sickle cell disorders and malaria infection among children aged 1-12 years in the Volta Region., Methods: This was a community-based cross-sectional survey that involved 938 children aged 1-12 years selected from three districts, one each from the 3 geographical zones of the Volta Region using a multistage sampling method. Demographic information was collected using a standard questionnaire and anthropometric indices were measured. Isoelectric focusing (IEF) electrophoresis was used to determine the Hb genotypes and sub-microscopic parasites were determined by PCR., Results: The prevalence of sickling screening positive was 16.0% with an overall prevalence of sickle cell disorders being 2.0%. Among the individual genotypes making up the sickle cell disorders, genotype HbSF was the highest (0.9% as compared to 0.2%; HbSS, 0.6%; HbSC and 0.3%; HbSCF). Microscopic Plasmodium falciparum parasitaemia was detected among 5.5% of the children and 14.2% sub-microscopic prevalence by PCR. Children with sickle cell disorders were more likely to have sub-microscopic parasitaemia (AOR = 5.51 95%CI (2.15, 14.10), p < 0.001) as well as anaemia (AOR = 3.03 95% CI (1.04, 8.82), p = 0.042), compared to those with normal genotypes. There was no significant difference observed between sickle cell disorders and growth and development of the children screened., Conclusions: Sickle cell disorders were significantly associated with sub-microscopic parasitaemia as well as anaemia in this study. Establishment of sickle cell clinics in the district and regional hospitals will help in the management of children with the disorder and also generate a national database on sickle cell disorders. National neonatal screening policies must also be put in place to help in early detection and management of these disorders.

Background: Few recent descriptions of severe childhood malaria have been published from high-transmission regions. In the current study, the clinical epidemiology of severe malaria in Mbale, Eastern Uganda, is described, where the entomological inoculation rate exceeds 100 infective bites per year., Methods: A prospective descriptive study was conducted to determine the prevalence, clinical spectrum and outcome of severe Plasmodium falciparum malaria at Mbale Regional Referral Hospital in Eastern Uganda. All children aged 2 months-12 years who presented on Mondays to Fridays between 8.00 am and 5.00 pm from 5th May 2011 until 30th April 2012 were screened for parasitaemia. Clinical and laboratory data were then collected from all P. falciparum positive children with features of WHO-defined severe malaria by use of a standardized proforma., Results: A total of 10 208 children were screened of which 6582 (64%) had a positive blood film. Of these children, 662 (10%) had clinical features of severe malaria and were consented for the current study. Respiratory distress was the most common severity feature (554; 83.7%), while 365/585 (62.4%) had hyperparasitaemia, 177/662 (26.7%) had clinical jaundice, 169 (25.5%) had severe anaemia, 134/660 (20.2%) had hyperlactataemia (lactate ≥ 5 mmol/L), 93 (14.0%) had passed dark red or black urine, 52 (7.9%) had impaired consciousness and 49/662 (7.4%) had hypoxaemia (oxygen saturations < 90%). In-hospital mortality was 63/662 (9.5%) overall but was higher in children with either cerebral malaria (33.3%) or severe anaemia (19.5%). Factors that were independently associated with mortality on multivariate analysis included severe anaemia [odds ratio (OR) 5.36; 2.16-1.32; P = 0.0002], hyperlactataemia (OR 3.66; 1.72-7.80; P = 0.001), hypoxaemia (OR) 3.64 (95% CI 1.39-9.52; P = 0.008), and hepatomegaly (OR 2.29; 1.29-4.06; P = 0.004). No independent association was found between mortality and either coma or hyperparasitaemia., Conclusions: Severe childhood malaria remains common in Eastern Uganda where it continues to be associated with high mortality. An unusually high proportion of children with severe malaria had jaundice or gave a history of having recently passed dark red or black urine, an issue worthy of further investigation.

Malaria-associated acute respiratory distress syndrome (ARDS) is an inflammatory disease causing alveolar-pulmonary barrier lesion and increased vascular permeability characterized by severe hypoxemia. Computed tomography (CT), among other imaging techniques, allows the morphological and quantitative identification of lung lesions during ARDS. This study aims to identify the onset of malaria-associated ARDS development in an experimental model by imaging diagnosis. Our results demonstrated that ARDS-developing mice presented decreased gaseous exchange and pulmonary insufficiency, as shown by the SPECT/CT technique. The pulmonary aeration disturbance in ARDS-developing mice on the 5th day post infection was characterized by aerated tissues decrease and nonaerated tissue accumulation, demonstrating increased vascular permeability and pleural effusion. The SPECT/CT technique allowed the early diagnosis in the experimental model, as well as the identification of the pulmonary aeration. Notwithstanding, despite the fact that this study contributes to better understand lung lesions during malaria-associated ARDS, further imaging studies are needed., Competing Interests: The authors have declared that no competing interests exist.

Background: Blood smear microscopy remains the gold-standard method to diagnose and quantify malaria parasite density. In addition, parasite genotyping of select loci is the most utilized method for distinguishing recrudescent and new infections and to determine the number of strains per sample. In research settings, blood may be obtained from capillary or venous compartments, and results from these matrices have been used interchangeably. Our aim was to compare quantitative results for parasite density and strain complexity from both compartments., Methods: In a prospective observational study, children and adults presenting with uncomplicated Plasmodium falciparum malaria, simultaneous capillary and venous blood smears and dried blood spots were collected over 42-days following treatment with artemether-lumefantrine. Blood smears were read by two microscopists, any discrepancies resolved by a third reader. Parasite DNA fingerprinting was conducted using six microsatellites. Bland Altman analysis and paired t-test/McNemar's test were used to assess the difference in density readings and measurements., Results: Two hundred twenty-three participants were included in the analysis (177 children (35 HIV-infected/142 HIV-uninfected), 21 HIV-uninfected pregnant women, and 25 HIV-uninfected non-pregnant adults). Parasite density measurements did not statistically differ between capillary and venous blood smears at the time of presentation, nor over the course of 42-day follow-up. Characterization of merozoite surface protein-2 (MSP-2) genetic polymorphism demonstrated a higher level of strain diversity at the time of presentation in venous samples, as compared with capillary specimens (p = 0.02). There was a high degree of variability in genotype-corrected outcomes when pairs of samples from each compartment were compared using MSP-2 alone, although the variability was reduced with the use of multiple markers., Conclusions: Parasite density measurements do not statistically differ between capillary and venous compartments in all studied demographic groups at the time of presentation with malaria, or over the course of follow-up. More strains were detected by MSP-2 genotyping in venous samples than in capillary samples at the time of malaria diagnosis. The use of multiple polymorphic markers reduces the impact of variability in strain detection on genotype-corrected outcomes. This study confirms that both capillary and venous compartments can be used for sampling with confidence in the clinical research setting., Trial Registration: The trial was registered at ClinicalTrials.gov under registration no. NCT01717885 .

Background: Recent reductions in malaria burden have been attributed largely to long-lasting insecticidal nets (LLINs). In March-June 2017, approximately 3 years after a national LLIN distribution campaign, a cross-sectional community survey was conducted to investigate factors associated with malaria parasitaemia and anaemia, in advance of Uganda's 2017-2018 LLIN campaign., Methods: Households from 104 clusters in 48 districts were randomly selected using two-staged cluster sampling; 50 households were enrolled per cluster. Eligible children aged 2-10 years had blood obtained for a thick blood smear and those aged 2-4 years had haemoglobin measured. Associations between outcomes and variables of interest were assessed using log-binomial regression with generalized estimating equations to adjust for household clustering., Results: In total, 5196 households, 8834 children with blood smear results, and 3753 with haemoglobin results were included. Only 16% of children lived in households with adequate LLIN coverage. Overall, parasite prevalence was 26.0%, ranging from 8.0% in the South West to 53.1% in East Central. Limiting data to children 2-4 years of age, parasite prevalence was 21.4%, up from 16.9% in 2014-2015 following the national LLIN campaign. In a multivariate analysis, factors associated with parasitaemia included region (East-Central vs South-Western; adjusted prevalence ratio [aPR] 6.45, 95% CI 5.55-7.50; p < 0.001), older age (8-10 vs 2-3 years; aPR 1.57, 95% CI 1.43-1.72; p < 0.001), living in a poorer household (poorest vs least poor tercile; aPR 2.32, 95% CI 2.05-2.63; p < 0.001), one constructed of traditional materials (aPR 1.13, 95% CI 1.03-1.24; p = 0.008), or without adequate LLIN coverage (aPR 1.30, 95% CI 1.14-1.48; p < 0.001). Overall, the prevalence of anaemia (haemoglobin < 10 g/dL) was 15.1% and varied geographically. In a multivariate analysis, factors associated with anaemia included region, younger age, living in a traditional house, and parasitaemia, which was the strongest predictor (aPR 2.50, 95% CI 2.12-2.95; p < 0.001)., Conclusions: Three years after a national LLIN campaign, LLIN coverage was low and parasite prevalence had increased. Parasite prevalence varied widely across Uganda; older children, those living in poorer households, and those with inadequate LLIN coverage, were at highest risk of parasitaemia. LLINs may need to be distributed more frequently through mass campaigns or continuously through sustainable mechanisms. Targeting interventions to geographic areas and populations at highest risk should also be considered.

Background: Babesiosis is a disease caused by parasites that infect red blood cells; in infants it can be acquired from tick bites, blood transfusions, or congenitally via vertical transmission. It can present with thrombocytopenia, fevers, and parasitemia., Case Report: A case of vertically transmitted babesiosis in an infant is described. Thrombocytopenia and parasitemia > 4% developed in this well-appearing infant. The diagnosis was made by history and blood smear in both infant and mother, and the patient recovered fully with oral antibiotics. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Congenital babesiosis has been reported infrequently in the literature and is reviewed here. It is important to consider congenital tick-borne illness in endemic areas as a cause for febrile thrombocytopenia in neonates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Elimination of the helminth disease, river blindness, remains challenging due to ivermectin treatment-associated adverse reactions in loiasis co-infected patients. Here, we address a deficit in preclinical research tools for filarial translational research by developing Loa loa mouse infection models. We demonstrate that adult Loa loa worms in subcutaneous tissues, circulating microfilariae (mf) and presence of filarial biomarkers in sera occur following experimental infections of lymphopenic mice deficient in interleukin (IL)-2/7 gamma-chain signaling. A microfilaraemic infection model is also achievable, utilizing immune-competent or -deficient mice infused with purified Loa mf. Ivermectin but not benzimidazole treatments induce rapid decline (>90%) in parasitaemias in microfilaraemic mice. We identify up-regulation of inflammatory markers associated with allergic type-2 immune responses and eosinophilia post-ivermectin treatment. Thus, we provide validation of murine research models to identify loiasis biomarkers, to counter-screen candidate river blindness cures and to interrogate the inflammatory etiology of loiasis ivermectin-associated adverse reactions.

Background: Malaria transmission-blocking anti-malarial drugs, such as primaquine, offers an effective strategy for reducing the incidence of falciparum malaria. However, this drug induces haemolytic anaemia among glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. The distribution of G6PD deficiency in Brazzaville, Republic of Congo and the association of G6PD deficiency with haemoglobin levels and blood cell counts were investigated., Methods: A total of 212 febrile children were recruited for this study. Plasmodium falciparum diagnosis was conducted by microscopy and nested PCR. Sanger sequencing was used to assess G6PD deficiency by detecting 202G>A (rs1050828) and 376A>G (rs1050829) single nucleotide polymorphisms., Results: Two hundred and twelve children were successfully genotyped for G6PD variants. Overall, 13% (27/212) of the children were G6PD deficient and 25% (25/100) females were heterozygous (11 BA- and 14 A+A-). The remaining 160 children had a normal G6PD genotype. The mean red blood and mean platelet counts were significantly lower in hemizygous male (G6PD A-) participants than in normal male (G6PD A+ or B) participants (p < 0.05)., Conclusion: This study gives an update on G6PD deficiency among Congolese children. Understanding the distribution of G6PD deficiency in other geographical regions is recommended before primaquine is adopted in the malaria control programme.

Background: Malaria remains a leading cause of childhood mortality in sub-Saharan Africa. Identifying patients who are at risk for severe manifestations at presentation still remains challenging. This study examines whether a semi-quantitative test on C-Reactive Protein (CRP) could be useful for rapidly predicting the presence or absence of malarial parasitemia in febrile children., Method: Data were collected from children with fever or a history of fever at the Agogo Presbyterian Hospital in the Ashanti Region of Ghana. Haematological measurements, microscopic detection of plasmodium species and semi-quantitative CRP measurements with a membrane-based immunoassay for whole blood were performed. CRP was classified as positive when the measured level was ≥ 10 mg/l., Results: During 548 visits, thick blood film results could be obtained from 541 patients, 270 (49.3%) yielded parasitemia with Plasmodium spp. Whereas malaria parasites were detected in only a few patients (7.1%) with normal CRP levels (< 10mg/l), more than a half of patients with an increased CRP concentration (≥ 10 mg/l) were parasite positive (OR 14.5 [CI 4.4-47.6], p<0.001). Patients with increased CRP levels had more than an eight-fold likelihood for parasitemia after correction for other parameters (adjusted OR 8.7 [CI 2.5-30.5], p<0.001). Sensitivity, specificity as well as positive predictive and negative predictive values of CRP for malaria were 99.3% (CI 96.2%-100%), 9.2% (CI 6.4%-12.8%), 31.7% (CI 27.4%-36.1%) and 97.0% (CI 84.2%-99.9%), respectively., Conclusion: The semi-quantitative method of measuring CRP is cheap, rapid and easy to perform but not useful in predicting parasitemia and malaria. However, due to its high negative predictive value, it could have a role in identifying those patients unlikely to be presenting with clinical malaria., Competing Interests: The authors have declared that no competing interests exist.

Background: Human immunodeficiency virus (HIV) and malaria are leading causes of morbidity and mortality among under-fives in sub-Saharan Africa. HIV infection could affect development of antimalarial immunity by impaired parasite clearance with predisposition to higher malaria parasitaemia., Objective: The objective of this study is to assess asymptomatic malaria parasite density (AMPD) in HIV-1-infected under-fives in a holoendemic zone., Methods: HIV-1-positive and -negative children <5 years on follow-up care were recruited and AMPD and CD4 counts were determined., Results: A total of 358 children were studied. Significantly higher malaria parasitaemia was found in HIV-infected individuals (118.7 vs. 87.3 parasite/μl, p = 0.021). Disparity in AMPD was most pronounced at infancy with similar distribution at all age brackets and consistently higher parasitaemia in the subjects., Conclusion: Parasitaemia is higher in HIV-infected than uninfected children. The burden is highest at infancy. Acquisition of antimalarial immunity is similar in both groups. Parasitaemia is not significantly affected by clinical disease stage or worsening immunosuppression.

Background: Blackwater fever is a complication of malaria infection consisting of a syndrome of febrile intra-vascular haemolysis with severe anaemia and intermittent passage of dark-red to black colour urine. Despite numerous reports and studies of this condition, its pathogenesis remains incompletely understood., Case Presentation: This report describes a case of classic blackwater fever in a returning traveller, without prior history of malaria infection nor usage of anti-malarial prophylaxis, treated with two courses of oral artemether-lumefantrine combination therapy. Unusual persistence of submicroscopic Plasmodium falciparum parasitaemia was detected by PCR for 18 days after initiation of treatment., Conclusion: To the authors' knowledge this is the first reported occurrence of a case of blackwater fever associated with prolonged submicroscopic parasitaemia. This unusual case challenges the current knowledge of the pathogenesis of this condition and opens questions that may have important diagnostic and treatment implications.

Delayed onset haemolysis occurring post-artesunate and post-artemisinin combination therapy is secondary to delayed clearance of infected erythrocytes spared by pitting during treatment. We report a case of severe post-treatment delayed haemolytic anaemia with a positive direct antiglobulin test and a positive response to corticosteroid therapy, suggesting an associated immune mechanism., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.

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).

Background: In severe malaria, intravenous artesunate may cause delayed haemolytic anaemia but there has been little evaluation of the propensity of oral artemisinin-based combination treatments (ACTs) to cause late-appearing anaemia., Methods: The frequency of anaemia (haematocrit <30%), and temporal changes in haematocrit were evaluated in 1,191 malarious children following ACTs. "Haematocrit conservation" was evaluated by using the fall in haematocrit/1,000 asexual parasites cleared from the peripheral blood (FIH/1,000 asexual parasites cpb), and the ratio of the average haematocrit (on the first 3 days of starting treatment):total parasitaemia cleared., Results: The frequency of anaemia decreased significantly following treatment. FIH/1,000 asexual parasites cpb, average haematocrit:total parasitaemia cleared, and mean haematocrit 5 weeks after treatment began were significantly lower in hyperparasitaemic children than in children without hyperparasitaemia, suggesting haematocrit conservation during treatment followed later by a loss of haematocrit. Asymptomatic late-appearing anaemia occurred in 6% of the children., Conclusion: Artesunate-amodiaquine and artemether-lumefantrine contribute to haematocrit conservation at high parasitaemias but may cause late-appearing anaemia., (© 2017 S. Karger AG, Basel.)

Extralymphatic filarial disease has varied clinical manifestations and is largely underestimated worldwide. We report an autopsy case of extralymphatic filarial disease with coronary and pulmonary circulations being involved and causing sudden death. Such an isolated event is, perhaps, rare and has not been reported so far to the best of our knowledge. Microfilaremia on autopsy may be easily missed or overlooked due to unawareness. The present report emphasizes the importance of extensive careful scrutiny of autopsy sections.

Submicroscopic Plasmodium infections are an important parasite reservoir, but their clinical relevance is poorly defined. A cross-sectional household survey was conducted in southern Papua, Indonesia, using cluster random sampling. Data were recorded using a standardized questionnaire. Blood samples were collected for haemoglobin measurement. Plasmodium parasitaemia was determined by blood film microscopy and PCR. Between April and July 2013, 800 households and 2,830 individuals were surveyed. Peripheral parasitaemia was detected in 37.7% (968/2,567) of individuals, 36.8% (357) of whom were identified by blood film examination. Overall the prevalence of P. falciparum parasitaemia was 15.4% (396/2567) and that of P. vivax 18.3% (471/2567). In parasitaemic individuals, submicroscopic infection was significantly more likely in adults (adjusted odds ratio (AOR): 3.82 [95%CI: 2.49-5.86], p<0.001) compared to children, females (AOR = 1.41 [1.07-1.86], p = 0.013), individuals not sleeping under a bednet (AOR = 1.4 [1.0-1.8], p = 0.035), and being afebrile (AOR = 3.2 [1.49-6.93], p = 0.003). The risk of anaemia (according to WHO guidelines) was 32.8% and significantly increased in those with asymptomatic parasitaemia (AOR 2.9 [95% 2.1-4.0], p = 0.007), and submicroscopic P. falciparum infections (AOR 2.5 [95% 1.7-3.6], p = 0.002). Asymptomatic and submicroscopic infections in this area co-endemic for P. falciparum and P. vivax constitute two thirds of detectable parasitaemia and are associated with a high risk of anaemia. Novel public health strategies are needed to detect and eliminate these parasite reservoirs, for the benefit both of the patient and the community., Competing Interests: The authors have declared that no competing interests exist.

Currently there are no biological markers to indicate which individuals with chronic indeterminate period of Chagas disease develop heart disease and who will remain all his life in this phase. The aim of this survey was to determine if Trypanosoma cruzi burden is related to the presence of heart disease in patients with chronic Chagas disease. 200 patients who had not been treated, 100 with cardiopathy and 100 without, groups A and B respectively, were submitted to clinical study and electrocardiogram, Echo-Doppler was performed for group A in which all important known causes of cardiopathy were discarded. In both groups xenodiagnosis, conventional PCR and quantitative PCR were undertaken. The 100 cardiopaths had 133 electrocardiographic alterations most of them in grade II of the New York Heart Association classification. 98 cardiopaths were classified in grade I by Echo-Doppler and only 2 cases were in grade III due to low ejection fraction. The difference in average parasitemia in patients of group A and B was not significant and no statistically differences were observed between average parasitemia of cardiopaths grade II versus grade I of NYHA. This results allow to characterize same clinical, electrocardiographical and parasitological features in chagasic cardiopaths of Chile., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Iron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria., Objectives: To evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in areas with hyperendemic or holoendemic malaria transmission., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, MEDLINE (up to August 2015) and LILACS (up to February 2015). We also checked the metaRegister of Controlled Trials (mRCT) and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2015. We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials. We scanned references of included trials, pertinent reviews, and previous meta-analyses for additional references., Selection Criteria: We included individually randomized controlled trials (RCTs) and cluster RCTs conducted in hyperendemic and holoendemic malaria regions or that reported on any malaria-related outcomes that included children younger than 18 years of age. We included trials that compared orally administered iron, iron with folic acid, and iron with antimalarial treatment versus placebo or no treatment. We included trials of iron supplementation or fortification interventions if they provided at least 80% of the Recommended Dietary Allowance (RDA) for prevention of anaemia by age. Antihelminthics could be administered to either group, and micronutrients had to be administered equally to both groups., Data Collection and Analysis: The primary outcomes were clinical malaria, severe malaria, and death from any cause. We assessed the risk of bias in included trials with domain-based evaluation and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes, and adjusted analyses for cluster RCTs. We based the subgroup analyses for anaemia at baseline, age, and malaria prevention or management services on trial-level data., Main Results: Thirty-five trials (31,955 children) met the inclusion criteria. Overall, iron does not cause an excess of clinical malaria (risk ratio (RR) 0.93, 95% confidence intervals (CI) 0.87 to 1.00; 14 trials, 7168 children, high quality evidence). Iron probably does not cause an excess of clinical malaria in both populations where anaemia is common and those in which anaemia is uncommon. In areas where there are prevention and management services for malaria, iron (with or without folic acid) may reduce clinical malaria (RR 0.91, 95% CI 0.84 to 0.97; seven trials, 5586 participants, low quality evidence), while in areas where such services are unavailable, iron (with or without folic acid) may increase the incidence of malaria, although the lower CIs indicate no difference (RR 1.16, 95% CI 1.02 to 1.31; nine trials, 19,086 participants, low quality evidence). Iron supplementation does not cause an excess of severe malaria (RR 0.90, 95% CI 0.81 to 0.98; 6 trials, 3421 children, high quality evidence). We did not observe any differences for deaths (control event rate 1%, low quality evidence). Iron and antimalarial treatment reduced clinical malaria (RR 0.54, 95% CI 0.43 to 0.67; three trials, 728 children, high quality evidence). Overall, iron resulted in fewer anaemic children at follow up, and the end average change in haemoglobin from base line was higher with iron., Authors' Conclusions: Iron treatment does not increase the risk of clinical malaria when regular malaria prevention or management services are provided. Where resources are limited, iron can be administered without screening for anaemia or for iron deficiency, as long as malaria prevention or management services are provided efficiently.

Background: 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., Objective: To assess the safety and clinical benefit of intravenous artesunate as an alternative to quinidine., Design: Retrospective case series., Setting: U.S. hospitals., Patients: 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., Measurements: 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., Results: 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., Limitation: Potential late-presenting safety issues might occur outside the 7-day follow-up., Conclusion: Artesunate was a safe and clinically beneficial alternative to quinidine.

Background: Malaria and HIV infections are both highly prevalent in sub-Saharan Africa, with HIV-infected patients being at higher risk of acquiring malaria. HIV-1 infection is known to impair the immune response and may increase the incidence of clinical malaria. However, a positive association between HIV-1 and malaria parasitaemia is still evolving. Equally, the effect of malaria on HIV-1 disease stage has not been well established, but when fever and parasitemia are high, malaria may be associated with transient increases in HIV-1 viral load, and progression of HIV-1 asymptomatic disease phase to AIDS., Objective: To determine the effects of HIV-1 infection on malaria parasitaemia among consented residents of Milo sub-location, Bungoma County in western Kenya., Study Design: Census study evaluating malaria parasitaemia in asymptomatic individuals with unknown HIV-1 status., Methods: After ethical approvals from both Moi University and MTRH research ethics committees, data of 3,258 participants were retrieved from both Webuye health demographic surveillance system (WHDSS), and Academic Model Providing Access to Healthcare (AMPATH) in the year 2010. The current study was identifying only un-diagnosed HIV-1 individuals at the time the primary data was collected. The data was then analysed for significant statistical association for malaria parasitemia and HIV-1 infection, using SPSS version 19. Demographic characteristics such as age and sex were summarized as means and percentages, while relationship between malaria parasitaemia and HIV-1 (serostatus) was analyzed using Chi square., Results: Age distribution for the 3,258 individuals ranged between 2 and 94 years, with a mean age of 26 years old. Females constituted 54.3%, while males were 45.8%. In terms of age distribution, 2-4 years old formed 15.1% of the study population, 5-9 years old were 8.8%, 10-14 years old were 8.6% while 15 years old and above were 67.5%. Of the 3,258 individuals whose data was eligible for analysis, 1.4% was newly diagnosed HIV-1 positive. Our findings showed a higher prevalence of malaria in children aged 2-10 years (73.4%), against the one reported in children in lake Victoria endemic region by the Kenya malaria indicator survey in the year 2010 (38.1%). There was no significant associations between the prevalence of asymptomatic malaria and HIV-1 status (p = 0.327). However, HIV-1/malaria co-infected individuals showed elevated mean malaria parasite density, compared to HIV-1 negative individuals, p = 0.002., Conclusion: HIV-1 status was not found to have effect on malaria infection, but the mean malaria parasite density was significantly higher in HIV-1 positive than the HIV-1 negative population.

Background: Indoor residual spraying (IRS) is considered a valuable transmission control measure against malaria but exact efficacy data are not available for many epidemiological settings. This study was conducted to determine indicators for malaria epidemiology and transmission among school children as baseline assessment before IRS implementation in Ghana., Methods: A cross-sectional study was conducted in Adansi South District of the Ashanti Region and Wa West District of the Upper West Region of Ghana. Malarial parasitaemia and anaemia were determined in pupils between the ages of 2 and 14 years from Early Childhood Development Centres and primary schools. Plasmodium falciparum parasitaemia was detected by light microscopy., Results: Out of 1,649 pupils who were enrolled at participating schools, 684 were positive for plasmodia resulting in a baseline parasitaemia prevalence of 41.5%. Parasite rate was similar in the two districts (42.0% in Adansi South and 40.7% in Wa West), but differed across the nine sentinel schools ranging from 21 to 63% (p < 0.001). The mean haemoglobin concentration was 11.3 g/dl [standard deviation (SD) ±2.1]. Pupils who had moderate to mild anaemia (7.0-10.9 g/dl) constituted 41.7% of the study sample., Conclusion: The burden of parasitaemia, malaria and anaemia is a major public health problem among school children in rural Ghana with extensive heterogeneity between schools and warrants further investment in intervention measures.

Background: Severe falciparum malaria may be complicated by haemolysis after parasite clearance, however the mechanisms remain unclear. Recent reports describe a pattern of delayed onset haemolysis among non-immune travellers with hyperparasitaemia treated with intravenous artesunate, termed post-artesunate delayed haemolysis (PADH). The occurrence and clinical impact of PADH following severe malaria infections in areas of unstable transmission are unknown., Case: A 45-year-old Bangladeshi male was initially admitted to a local hospital with severe falciparum malaria complicated by hyperparasitaemia and treated with intravenous artesunate. Twenty days from his first presentation he was readmitted with delayed onset haemolytic anaemia and acute kidney injury. Multiple blood transfusions and haemodialysis were required. Renal biopsy revealed acute tubular injury and haem pigment nephropathy. His haemoglobin and renal function recovered to baseline after 62 days from his second admission., Discussion: This case highlights the differential diagnosis of post-malaria delayed onset haemolysis, including the recently described syndrome of post-artemisinin delayed haemolysis. The pathophysiology contributing to acute kidney injury in this patient and the limited treatment options are discussed., Conclusions: This report describes PADH complicated by acute kidney injury in an adult patient living in a malaria hypoendemic region who subsequently required blood transfusions and haemodialysis. This case emphasizes the importance of routine follow up of haemoglobin and renal function in artesunate-treated patients who have recovered from severe malaria.

Background: Anaemia is an increasingly recognized health problem in Africa, particularly in infants and pregnant women. Although malaria is known to be the main risk factor of anaemia in both groups, the consequences of maternal factors, particularly malaria in pregnancy (MiP), on infant haemoglobin (Hb) concentrations during the first months of life are still unclear., Methods: We followed-up a cohort of 1005 Beninese pregnant women from the beginning of pregnancy until delivery. A subsample composed of the first 400 offspring of these women were selected at birth and followed until the first year of life. Placental histology and blood smear at 1st clinical antenatal visit (ANC), 2nd ANC and delivery were used to assess malaria during pregnancy. Infant Hb concentrations were measured at birth, 6, 9 and 12 months of age. A mixed multi-level model was used to assess the association between MiP and infant Hb variations during the first 12 months of life., Results: Placental malaria (difference mean [dm] = - 2.8 g/L, 95% CI [-5.3, -0.3], P = 0.03) and maternal peripheral parasitaemia at delivery (dm = - 4.6 g/L, 95% CI [-7.9, -1.3], P = 0.007) were the main maternal factors significantly associated with infant Hb concentrations during the first year of life. Poor maternal nutritional status and malaria infection during infancy were also significantly associated with a decrease in infant Hb., Conclusion: Antimalarial control and nutritional interventions before and during pregnancy should be reinforced to reduce specifically the incidence of infant anaemia, particularly in Sub-Saharan countries.

Background: Understanding the current epidemiology of malaria and the relationship between intervention coverage, transmission intensity, and burden of disease is important to guide control activities. We aimed to determine the prevalence of anemia, parasitemia, and serological responses to P. falciparum antigens, and factors associated with these indicators, in three different epidemiological settings in Uganda., Methods and Findings: In 2012, cross-sectional surveys were conducted in 200 randomly selected households from each of three sites: Walukuba, Jinja district (peri-urban); Kihihi, Kanungu district (rural); and Nagongera, Tororo district (rural) with corresponding estimates of annual entomologic inoculation rates (aEIR) of 3.8, 26.6, and 125.0, respectively. Of 2737 participants, laboratory testing was done in 2227 (81.4%), including measurement of hemoglobin, parasitemia using microscopy, and serological responses to P. falciparum apical membrane antigen 1 (AMA-1) and merozoite surface protein 1, 19 kilodalton fragment (MSP-119). Analysis of laboratory results was restricted to 1949 (87.5%) participants aged ≤ 40 years. Prevalence of anemia (hemoglobin < 11.0 g/dL) was significantly higher in Walukuba (18.9%) and Nagongera (17.4%) than in Kihihi (13.1%), and was strongly associated with decreasing age for those ≤ 5 years at all sites. Parasite prevalence was significantly higher in Nagongera (48.3%) than in Walukuba (12.2%) and Kihihi (12.8%), and significantly increased with age to 11 years, and then significantly decreased at all sites. Seropositivity to AMA-1 was 53.3% in Walukuba, 63.0% in Kihihi, and 83.7% in Nagongera and was associated with increasing age at all sites. AMA-1 seroconversion rates strongly correlated with transmission intensity, while serological responses to MSP-119 did not., Conclusion: Anemia was predominant in young children and parasitemia peaked by 11 years across 3 sites with varied transmission intensity. Serological responses to AMA-1 appeared to best reflect transmission intensity, and may be a more accurate indicator for malaria surveillance than anemia or parasitemia.

Background: Evans syndrome (ES) is characterized by the simultaneous or sequential presence of multiple autoimmune cytopenias. It is often secondary to rheumatologic disorders or lymphoid malignancies, but has not previously been associated with babesiosis. Here we present two cases of severe cytopenias in asplenic patients precipitated by active babesiosis., Case Report: The first patient had a history of Hodgkin's lymphoma in remission and autoimmune hemolytic anemia (AIHA) treated by splenectomy 12 years prior who presented with severe AIHA and thrombocytopenia after Babesia infection. The second patient had a history of ES requiring splenectomy, which relapsed after Babesia infection., Results: The complex presentation and medical histories of both patients made the diagnosis challenging. Both patients' cytopenias responded to therapy, although the use of immunosuppressive agents in patients with active hematologic infections was challenging and required a multidisciplinary approach., Conclusion: These two cases illustrate the possibility of babesiosis to not only reactivate ES in asplenic patients, but also precipitate increased levels of immune deregulation, potentially provoking ES, a phenomenon not previously reported., (© 2014 AABB.)

Plasmodium vivax can cause severe malaria, however its pathogenesis is poorly understood. In contrast to P. falciparum, circulating vivax parasitemia is low, with minimal apparent sequestration in endothelium-lined microvasculature, and pathogenesis thought unrelated to parasite biomass. However, the relationships between vivax disease-severity and total parasite biomass, endothelial autocrine activation and microvascular dysfunction are unknown. We measured circulating parasitemia and markers of total parasite biomass (plasma parasite lactate dehydrogenase [pLDH] and PvLDH) in adults with severe (n = 9) and non-severe (n = 53) vivax malaria, and examined relationships with disease-severity, endothelial activation, and microvascular function. Healthy controls and adults with non-severe and severe falciparum malaria were enrolled for comparison. Median peripheral parasitemia, PvLDH and pLDH were 2.4-fold, 3.7-fold and 6.9-fold higher in severe compared to non-severe vivax malaria (p = 0.02, p = 0.02 and p = 0.015, respectively), suggesting that, as in falciparum malaria, peripheral P. vivax parasitemia underestimates total parasite biomass, particularly in severe disease. P. vivax schizonts were under-represented in peripheral blood. Severe vivax malaria was associated with increased angiopoietin-2 and impaired microvascular reactivity. Peripheral vivax parasitemia correlated with endothelial activation (angiopoietin-2, von-Willebrand-Factor [VWF], E-selectin), whereas markers of total vivax biomass correlated only with systemic inflammation (IL-6, IL-10). Activity of the VWF-cleaving-protease, ADAMTS13, was deficient in proportion to endothelial activation, IL-6, thrombocytopenia and vivax disease-severity, and associated with impaired microvascular reactivity in severe disease. Impaired microvascular reactivity correlated with lactate in severe vivax malaria. Findings suggest that tissue accumulation of P. vivax may occur, with the hidden biomass greatest in severe disease and capable of mediating systemic inflammatory pathology. The lack of association between total parasite biomass and endothelial activation is consistent with accumulation in parts of the circulation devoid of endothelium. Endothelial activation, associated with circulating parasites, and systemic inflammation may contribute to pathology in vivax malaria, with microvascular dysfunction likely contributing to impaired tissue perfusion.

Objective: To assess the effectiveness of IPTp in two areas with different malaria transmission intensities., Methods: Prospective observational study recruiting pregnant women in two health facilities in areas with high and low malaria transmission intensities. A structured questionnaire was used for interview. Maternal clinic cards and medical logs were assessed to determine drug intake. Placental parasitaemia was screened using both light microscopy and real-time quantitative PCR., Results: Of 350 pregnant women were recruited and screened for placental parasitaemia, 175 from each area. Prevalence of placental parasitaemia was 16.6% (CI 11.4-22.9) in the high transmission area and 2.3% (CI 0.6-5.7) in the low transmission area. Being primigravida and residing in a high transmission area were significant risk factors for placental malaria (OR 2.4; CI 1.1-5.0; P = 0.025) and (OR 9.4; CI 3.2-27.7; P < 0.001), respectively. IPTp was associated with a lower risk of placental malaria (OR 0.3; CI 0.1-1.0; P = 0.044); the effect was more pronounced in the high transmission area (OR 0.2; CI 0.06-0.7; P = 0.015) than in the low transmission area (OR 0.4; CI 0.04-4.5; P = 0.478). IPTp use was not associated with reduced risk of maternal anaemia or low birthweight, regardless of transmission intensity. The number needed to treat (NNT) was four (CI 2-6) women in the high transmission area and 33 (20-50) in the low transmission area to prevent one case of placental malaria., Conclusion: IPTp may have an effect on lowering the risk of placental malaria in areas of high transmission, but this effect did not translate into a benefit on risks of maternal anaemia or low birthweight. The NNT needs to be considered, and weighted against that of other protective measures, eventually targeting areas which are above a certain threshold of malaria transmission to maximise the benefit., (© 2014 John Wiley & Sons Ltd.)

Risk factors for progression from acute malaria to multiple organ dysfunction syndrome (MODS) are poorly understood. The MODS is commonly diagnosed with the sequential organ failure assessment (SOFA) scale, but this scale has been understudied in patients with severe malaria. We conducted a cohort study among 426 adult males admitted to hospital with malaria in Bogotá, Colombia. We estimated SOFA scores and relative risks (RRs) for MODS during hospitalization according to patients' characteristics on admission. Risk of MODS was 7.3% over a median 6.0 days in hospital. Baseline hemoglobin was strongly, inversely associated with MODS (adjusted RR for hemoglobin ≤ 8.5 g/dL versus hemoglobin > 11 g/dL = 9.5, 95% confidence interval [CI]: 3.6, 25.3). Plasmodium falciparum malaria and parasitemia were positively associated with MODS. There was a strong interaction between baseline parasitemia and hemoglobin on MODS risk. In conclusion, the use of parasitemia and hemoglobin on admission to identify high-risk patients deserves consideration., (© The American Society of Tropical Medicine and Hygiene.)

Although malnutrition and malaria co-occur among individuals and populations globally, effects of nutritional status on risk for parasitemia and clinical illness remain poorly understood. We investigated associations between Plasmodium falciparum infection, nutrition, and food security in a cross-sectional survey of 365 Batwa pygmies in Kanungu District, Uganda in January of 2013. We identified 4.1% parasite prevalence among individuals over 5 years old. Severe food insecurity was associated with increased risk for positive rapid immunochromatographic test outcome (adjusted relative risk [ARR] = 13.09; 95% confidence interval [95% CI] = 2.23-76.79). High age/sex-adjusted mid-upper arm circumference was associated with decreased risk for positive test among individuals who were not severely food-insecure (ARR = 0.37; 95% CI = 0.19-0.69). Within Batwa pygmy communities, where malnutrition and food insecurity are common, individuals who are particularly undernourished or severely food-insecure may have elevated risk for P. falciparum parasitemia. This finding may motivate integrated control of malaria and malnutrition in low-transmission settings., (© The American Society of Tropical Medicine and Hygiene.)

Aims and Objectives: The objective of this study was to determine an algorithm for malaria diagnosis using presenting signs and symptoms of children (aged 0-13 years) with uncomplicated malaria in Gwagwalada Area Council of Abuja, Nigeria., Materials and Methods: A validated questionnaire was used to obtain relevant data from 400 children diagnosed presumptively of simple malaria by clinicians and 400 other children of similar sex and age considered as not having malaria. Giemsa-stained thick blood films were used to determine parasitaemia. Data obtained was analysed using Epi-Info version 3.3.2., Results: Thirty-eight per cent of children with presumptive diagnosis of malaria had parasitaemia. Fever, rigor, vomiting, jaundice, pallor and spleen enlargement had significant statistical relationship with parasitaemia on bivariate analysis, but only fever (p=0.00), rigor (p=0.00), vomiting (p=0.00), and pallor (p=0.00) maintained the relationship when subjected to logistic regression analysis. But these symptoms individually had low sensitivity and/or specificity. Candidate algorithms (combinations of symptoms) were then successively subjected to bivariate, logistic and validity analyses. Fever with vomiting gave the highest sensitivity (56.2%), specificity (76.4%) and PPV (60.0%) and were therefore adopted as the algorithm of choice., Conclusion and Recommendations: Children presenting with fever and vomiting without any other obvious cause in health facilities without laboratory support in the research area should receive antimalarial treatment, to help reduce the malaria scourge. This algorithm should be field-tested and if found reliable should be adopted to ease the problem of malaria diagnosis in peripheral health facilities.

Background: Oxygen saturation is a good marker for disease severity in emergency care. However, studies have not considered its use in identifying individuals infected with Plasmodium falciparum at risk of deaths., Objective: To investigate the prevalence and predictive value of hypoxaemia for deaths in under-5s with severe falciparum malaria infection., Methods: Oxygen saturation was prospectively measured alongside other indicators of disease severity in 369 under-5s admitted to a tertiary hospital in Nigeria. Participants were children in whom falciparum malaria parasitaemia was confirmed with blood film microscopy in the presence of any of the World Health Organization-defined life-threatening features for malaria., Results: Overall mortality rate was 8.1%. Of the 16 indicators of the disease severity assessed, hypoxaemia (OR=7.54; 95% CI=2.80, 20.29), co-morbidity with pneumonia (OR=19.27; 95% CI=2.87, 29.59), metabolic acidosis (OR=6.21; 95% CI=2.21, 17.47) and hypoglycaemia (OR=19.71; 95% CI=2.61, 25.47) were independent predictors of death. Cerebral malaria, male gender, wasting, hypokalaemia, hyponatriaemia, azotaemia and renal impairment were significantly associated with death in univariate analysis but not logistic regression model., Conclusions: Hypoxaemia predicts deaths in Nigerian children with severe malaria, irrespective of other features. Efforts should always be made to measure oxygen saturation as part of the treatments for severe malaria in children.

Background: Co-infection with falciparum malaria and HIV-1 increases the severity and mortality of both infections in unstable malaria-transmission areas. In contrast, in stable transmission areas, HIV co-infection increases the severity of both infections but has not been found to influence malaria mortality., Methods: In a prospective cross-sectional study, clinical and laboratory data were consecutively collected for all adults admitted with fever and/or suspected malaria to the medical department of the Central Hospital of Maputo, Mozambique, during two malaria seasons from January 2011. Malaria and HIV PCRs were performed, and risk factors for fatal outcomes were analysed. The impact of HIV on the clinical presentation and mortality of malaria was assessed., Findings: A total of 212 non-pregnant adults with fever and/or suspected malaria and 56 healthy controls were included in the study. Of the 131 patients with confirmed falciparum malaria, 70 were co-infected with HIV-1. The in-hospital mortality of the co-infected patients was 13.0% (9/69) compared with 1.7% (1/59) in the patients without HIV (p = 0.018). Malaria severity (p = 0.016) and co-infection with HIV (p = 0.064) were independent risk factors for death although the association with HIV did not reach statistical significance. The co-infected patients had significantly more frequent respiratory distress, bleeding disturbances, hypoglycaemia, liver and renal failure and high malaria parasitemia compared with the patients with malaria alone., Interpretations: HIV co-infection is associated with increased disease severity in and mortality from malaria in an area of stable malaria transmission. This finding was not observed earlier and should motivate doctors working in malaria-endemic areas to consider early HIV testing and a closer follow-up of patients with malaria and HIV co-infection.

Introduction: Malaria and anaemia have adverse effects in pregnant women and on the birth weight of infants in malaria endemic areas. P. falciparum malaria, the most virulent species continues to be a major health problem in sub-Saharan Africa. This study was carried out to establish the prevalence of pregnancy-associated malaria and its associated consequences including maternal anaemia and low birthweight (LBW) deliveries and placental malaria among pregnant women in a sub-urban area in coastal Ghana., Methods: A facility-based investigation was carried out among 320 pregnant women seeking antenatal care in a hospital in suburban coastal Ghana. Information on the use of Insecticide Treated Nets (ITNs) and Intermittent Preventive Treatment in pregnancy (IPTp) were collected using a structured questionnaire at enrollment. Venous blood was collected for microscopy and screening for Glucose 6-phosphate dehydrogenase (G6PD) deficiency. Haemoglobin concentration was obtained from an automatic blood analyzer. Placental smears and birth weight measurements were taken at delivery., Results: The prevalence of Plasmodium falciparum parasitaemia was 5%. The mean haemoglobin (Hb) level at registration was 11.44 g/dL (95% CI 11.29 - 11.80). Placental blood parasitaemia and low birthweight were 2.5% and 3% respectively. ITN possession was 31.6% with 5.4% usage. The IPTp coverage was 55%., Conclusion: The prevalence of malaria and anaemia among the pregnant women were low at enrollment. Placental blood parasitaemia and LBW at delivery were also low. These are clear indications of the high coverage of the IPTp. Increase in ITN use will further improve birthweight outcomes and reduce placental malaria.

Background: There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda., Methods: Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities., Results: 2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18-4.24) and seizures (aPRR 1.12; CI 1.09-1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91-0.93), HIV infected children (aPRR 0.60 CI 0.52-0.71), and children with diarrhea (aPRR 0.76; CI 0.65-0.90). The overall prevalence of anemia (Hgb<10 g/dl) was 56.3% and severe anemia (Hgb<6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%., Conclusion: There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population.

Background: The study assessed aspects of malaria infection, prevention and treatment in a population of resettled pregnant women in South Sudan., Methods: During April and May 2008, a cross-sectional study was carried out to estimate malaria prevalence and to assess the use of malaria risk reduction measures and their associations with selected background characteristics. Two hundred and twenty women were tested for malaria parasitaemia and questioned about their malaria prevention and treatment practices., Results: The results showed a prevalence of Plasmodium falciparum parasitaemia of 9.1%. No statistically significant associations were observed between selected background characteristics and malaria infection status. However, school attendance was significantly associated with insecticide-treated net ownership (OR = 6.52, 95% CI 2.37-17.94; p = 0.001) and access to malaria diagnosis and treatment (OR = 3.20, 95% CI 1.26-8.16; p = 0.015)., Conclusions: The results suggest that educational attainment need not be very advanced to affect practices of malaria prevention and treatment. Primary school attendance was a stronger predictor for use of malaria risk reduction measures than any of the other selected background characteristics. Educational attainment, information and communication about malaria prevention and control play a pivotal role in increasing and improving use of malaria risk reduction measures.

The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.

Background: Although thrombocytopenia is a hematological disorder commonly reported in malarial patients, its mechanisms are still poorly understood, with only a few studies focusing on the role of platelets phagocytosis., Methods and Findings: Thirty-five malaria vivax patients and eight healthy volunteers (HV) were enrolled in the study. Among vivax malaria patients, thrombocytopenia (<150,000 platelets/µL) was found in 62.9% (22/35). Mean platelet volume (MPV) was higher in thrombocytopenic patients as compared to non-thrombocytopenic patients (p = 0.017) and a negative correlation was found between platelet count and MPV (r = -0.483; p = 0.003). Platelets from HV or patients were labeled with 5-chloromethyl fluorescein diacetate (CMFDA), incubated with human monocytic cell line (THP-1) and platelet phagocytosis index was analyzed by flow cytometry. The phagocytosis index was higher in thrombocytopenic patients compared to non-thrombocytopenic patients (p = 0.042) and HV (p = 0.048). A negative correlation was observed between platelet count and phagocytosis index (r = -0.402; p = 0.016). Platelet activation was assessed measuring the expression of P-selectin (CD62-P) in platelets' surface by flow cytometry. No significant difference was found in the expression of P-selectin between thrombocytopenic patients and HV (p = 0.092). After evaluating the cytokine profile (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17) in the patients' sera, levels of IL-6, IL-10 and IFN-γ were elevated in malaria patients compared to HV. Moreover, IL-6 and IL-10 values were higher in thrombocytopenic patients than non-thrombocytopenic ones (p = 0.044 and p = 0.017, respectively. In contrast, TNF-α levels were not different between the three groups, but a positive correlation was found between TNF-α and phagocytosis index (r = -0.305; p = 0.037)., Conclusion/significance: Collectively, our findings indicate that platelet phagocytosis may contribute to thrombocytopenia found in vivax malaria. Finally, we believe that this study opens new avenues to explore the mechanisms involved in platelet dysfunction, commonly found in vivax malaria patients.

Degenerative and demyelinating diseases are known to alter the mechanical properties of brain tissue. While few studies have characterized these biomechanical changes, it is clear that accurate characterization of the mechanical properties of diseased brain tissue could be a substantial asset to neuronavigation and surgery simulation through haptic devices. In this study, samples of brain tissue from rats infected with Plasmodium berghei ANKA, an African murine malaria parasite, are evaluated using a uniaxial tensile test machine. Infected brains having different levels of parasitemia are mounted on the testing machine and extended until failure of the tissue. The stress-strain curve of each sample is obtained and compared to healthy rat brain tissue. Young's modulus of each sample is extracted from the Hookean part of the stress-strain diagram. Young's modulus of rats' brain shows considerable difference among the samples having various levels of parasitemia compared with the controls. For instance, the brains with 0% (control), 1.5%, and 9% parasitemia showed a Young's modulus of 46.15, 54.54, and 266.67 kPa, respectively. This suggests sequestration of the stiffened and less deformable parasitized red blood cells in the brain microvasculature.