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Background Rapid diagnostic tests (RDTs) have been extensively evaluated and play an important role in malaria diagnosis. However, the accuracy of RDTs for malaria diagnosis in patients with sickle cell disease (SCD) is unknown. Methods We compared the performance of a histidine rich protein 2 (HRP-2)-based RDT (First Response) and a lactate dehydrogenase (LDH)-based RDT (Optimal) with routine microscopy as reference standard in 445 children with SCD and an acute febrile illness in Accra, Ghana. Results The overall sensitivity, specificity, and positive and negative predictive values of the HRP-2-based RDTs were 100%, 95.7%, 73.8%, and 100%, respectively. Comparable values for the LDH-based RDTs were 91.7%, 99.5%, 95.7%, and 99.0%, respectively. A total of 423 results were true in both tests, 1 result was false in both tests, 16 results were false in the HRP-2 test only, and 5 were false in the LDH test only (McNemar test, P  = .03). At follow-up, 73.7% (28/38), 52.6% (20/38), 48.6% (17/35), and 13.2% (5/38) of study participants were HRP-2 positive on days 14, 28, 35, and 42, respectively, compared with 0%, 2.6% (1/38), 2.9% (1/35), and 2.6% (1/38) for LDH. Conclusion The HRP2-based RDT fulfilled World Health Organization criteria for malaria diagnosis in patients with SCD and may provide diagnostic evidence for treatment to begin in cases in which treatment would otherwise have begun presumptively based on symptoms, whereas LDH-based RDTs may be more suitable as a confirmatory test in low-parasitemic subgroups, such as patients with SCD. [ABSTRACT FROM AUTHOR]

Abstract Background Several anti-malarial drugs are associated with adverse cardiovascular effects. These effects may be exacerbated when different anti-malarials are used in combination. There has been no report yet on the potential cardiac effects of the combination artesunate-amodiaquine. Methods Electrocardiographic (ECG) intervals in Ghanaian children with uncomplicated malaria treated with artesunate-amodiaquine (n=47), were compared with that of children treated with artemether-lumefantrine (n=30). The ECG measurements were repeated one, two, three, seven and 28 days after treatment. The ECG intervals of artesunate-amodiaquine treated subjects were correlated with plasma concentrations of desethylamodiaquine (DEAQ), the main metabolite of amodiaquine. Results The mean ECG intervals were similar in both groups before treatment. After treatment (day 3), ECG intervals changed significantly from baseline in all subjects, but there were no differences between the two treatment groups. A significantly higher proportion of children treated with artesunate-amodiaquine developed sinus bradycardia compared with artemether-lumefantrine treated subjects (7/47 vs 0/30; χ2 p=0.03). Subjects who developed bradycardia were significantly older, and had higher DEAQ concentrations than those who did not develop bradycardia. The proportion of subjects with QTc interval prolongations did not differ significantly between the groups, and no relationship between prolonged QTc intervals and DEAQ levels were observed. No clinically significant rhythm disturbances were observed in any of the subjects. Conclusion Artesunate-amodiaquine treatment resulted in a higher incidence of sinus bradycardia than artemether-lumefantrine treatment in children with uncomplicated malaria, but no clinically significant rhythm disturbances were induced by combining artesunate with amodiaquine. These findings, although reassuring, may imply that non-amodiaquine based artemisinin combination therapy may be preferable for malaria treatment in patients who are otherwise at risk of cardiac effects.

Child assent is recommended in addition to parental consent when enrolling children in clinical research; however, appreciation and relevance ascribed to these concepts vary in different contexts, and information on attitudes towards storage of biological samples for future research is limited, especially in developing countries. We assessed caregivers' understanding and appreciation of consent and assent procedures, and their attitudes towards use of stored blood samples for future research prior to enrolling a child in clinical research. A total of 17 in-depth interviews were conducted with primary caregivers of children (fathers [n = 3], mothers [n = 12], and grandmothers [n = 2]) at enrolment or on the immediate follow-up date. All caregivers recalled significant amount information from the study information sheet and were able to appropriately link such information to the consent process. While all participants confirmed information received prior to blood sampling as adequate, a few noted that the purpose was not sufficiently well communicated. Caregivers felt children were cognitively vulnerable, and prone to decisions that were not necessarily in their best interest. Nearly all caregivers felt it was their right and responsibility to overrule objections from their ward's regarding enrolment into specific study or receipt of a therapeutic procedure. There were no objections or concerns regarding use of stored biological samples for future research purposes. There is thus, a need to improve understanding of caregivers on the information provided during the informed consent process. Context-specific studies on the age of assent in specific populations are needed. [ABSTRACT FROM AUTHOR]

Abstract Background Artesunate-amodiaquine (AS+AQ) and artemether-lumefantrine (AM-L) are efficacious artemisinin combination therapy (ACT) regimens that have been widely adopted in sub-Saharan Africa. However, there is little information on the efficacy of these regimens on subsequent episodes beyond 28 days, or on the safety of repeated treatments. Methods Children aged six months to 14 years with uncomplicated malaria were randomly assigned to treatment with AS+AQ (n = 116), or AM-L (n = 111). Recruited subjects were followed-up, initially for 28 days, and then monthly for up to one year. All subsequent attacks of uncomplicated malaria after 28 days were treated with the same regimen as at randomization. Investigations aimed at determining efficacy and side effects were conducted. Results Adequate clinical and parasitological response in subjects with evaluable end-points were, 97.1% (100/103) and 98.2% (107/109) on day 14, and 94.2% (97/103) and 95.3% (102/107) on day 28 in the AM-L and AS+AQ groups, respectively. Similar results were obtained after PCR correction. The incidence of malaria attacks in the year following recruitment was similar between the two treatment groups (p = 0.93). There was a high incidence of potentially AQ-resistant parasites in the study area. The incidence of adverse events, such as pruritus, fatigue and neutropaenia were similar in the two treatment groups. No patient showed signs of hearing impairment, and no abnormal neurological signs were observed during one year of follow-up. Other adverse events were mild in intensity and overlapped with known malaria symptomatology. No adverse event exacerbation was observed in any of the subjects who received multiple treatment courses with these ACT regimens during one year follow-up. Conclusion AS+AQ and AM-L were efficacious for treatment of children with uncomplicated malaria in Ghana and drug-related adverse events were rare in treated subjects during one year of follow-up. The high prevalence of potentially AQ resistant parasites raises questions about the utility of AQ as a partner drug for ACT in Ghana. The efficacy of AS+AQ in Ghana requires, therefore, continuous monitoring and evaluation. Trial registration NCT 00406146 http://www.clinicaltrials.gov

Abstract Background Severe anaemia (SA), intravascular haemolysis (IVH) and respiratory distress (RD) are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism leading to excess anaemia in acute P. falciparum infection. Methods The direct Coombs test (DCT) and flow cytometry were used to investigate the mean levels of RBC-bound complement fragments (C3d and C3bαβ) and the regulatory proteins [complement receptor 1 (CD35) and decay accelerating factor (CD55)] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb) levels and RD were investigated. Results Of the 484 samples tested, 131(27%) were positive in DCT, out of which 115/131 (87.8%) were positive for C3d alone while 16/131 (12.2%) were positive for either IgG alone or both. 67.4% of the study population were below 5 years of age and DCT positivity was more common in this age group relative to children who were 5 years or older (Odds ratio, OR = 3.8; 95%CI, 2.2–6.7, p < 0.001). DCT correlated significantly with RD (β = -304, p = 0.006), but multiple regression analysis revealed that, Hb (β = -0.341, p = 0.012) and coma (β = -0.256, p = 0.034) were stronger predictors of RD than DCT (β = 0.228, p = 0.061). DCT was also not associated with IVH, p = 0.19, while spleen size was inversely correlated with Hb (r = -402, p = 0.001). Flow cytometry showed similar mean fluorescent intensity (MFI) values of CD35, CD55 and C3bαβ levels on the surfaces of RBC in patients and asymptomatic controls (AC). However, binding of C3bαβ correlated significantly with CD35 or CD55 (p < 0.001). Conclusion These results suggest that complement activation contributed to anaemia in acute childhood P. falciparum malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement regulatory proteins, CD35 and CD55 and malarial anaemia. These findings suggest that complement activation could also be involved in the pathogenesis of RD but larger studies are needed to confirm this finding.

Background: Individuals with sickle cell disease (SCD) are susceptible to infective conditions that predispose them to hemolysis and anemia. Folic acid is recommended as a preventative measure against anemia in SCD patients; however, there is scarce literature on the implications of this practice. Patients and Methods: Plasma concentrations of folate were measured in acutely ill pediatric SCD patients presenting with malaria or bacteremia and compared with those of SCD patients in steady state, or acutely ill non-SCD patients with confirmed malaria. Results: The proportion of individuals with high (> 45.3 nmol/L) folate concentrations was 29.5% (13/44), 18.2% (8/44), 33.3% (6/18), and 0% in the SCD-malaria, SCD steady state, SCD bacteremia, and the non-SCD malaria groups, respectively. The proportion of SCD patients with high folate levels did not vary significantly at steady state and during confirmed malaria (p = 0.216), and during acute bacteremia (p = 0.20). The median (interquartile range) plasma folate levels were 34.50 (24.40– 52.00 nmol/L), 33.40 (15.83– 60.85 nmol/L), 30.85 (24.68– 39.65 nmol/L), and 13.30 (10.03– 17.18 nmol/L), respectively, in the SCD malaria, SCD bacteremia, SCD steady state, and the non-SCD malaria sub-groups. The median folate levels of SCD steady state, SCD malaria, and SCD bacteremia sub-groups differed significantly (p < 0.0001) when compared with non-SCD patients, but the levels in the SCD bacteremia and malaria groups were not significantly different from the SCD steady state group. Conclusion: Elevated levels of plasma folate were found in a high proportion of pediatric SCD patients. The implications of such elevated folate levels in pediatric SCD patients are unknown but may suggest a need for review of current recommendations for prophylactic doses of folic acid in SCD patients. [ABSTRACT FROM AUTHOR]

Abstract Background Severe anaemia can develop in the aftermath of Plasmodium falciparum malaria because of protracted bone marrow suppression, possibly due to residual subpatent parasites. Materials and methods Blood was collected from patients with recent malaria and negative malaria microscopy. Detection of the Plasmodium antigens, lactate dehydrogenase (Optimal®), aldolase and histidine rich protein 2 (Now malaria®) were used to differentiate between patients with (1) no malaria, (2) recent cleared malaria, (3) persistent P. falciparum infection. Red cell distribution width (RDW), plasma levels of soluble transferrin receptor (sTfR) and erythropoietin (EPO) were measured as markers of erythropoiesis. Interleukin (IL) 10 and tumour necrosis factor (TNF)α were used as inflammation markers. Results EPO was correlated with haemoglobin, irrespective of malaria (R = -0.36, P < 0.001). Persistent P. falciparum infection, but not recent malaria without residual parasites, was associated with bone marrow suppression i.e., low RDW (P < 0.001 vs. P = 0.56) and sTfR (P = 0.02 vs. P = 0.36). TNF-α and IL-10 levels were not associated with bone marrow suppression. Conclusion In the treatment of malaria, complete eradication of parasites may prevent subsequent development of anaemia. Severely anaemic children may benefit from antimalarial treatment if antigen tests are positive, even when no parasites can be demonstrated by microscopy.

SUMMARY P. falciparum malaria is associated with increased activation among peripheral lymphocytes. In the present study, we investigated markers of susceptibility to apoptosis and expression of IFN-γ and IL-4 by CD28 - and CD28 + T cells in West African children with acute P. falciparum malaria. The study showed increased susceptibility to apoptosis and cytokine production among T lymphocytes during acute malaria but also that T cells, in particular IFN-γ producing CD28 - T cells, were substantially reduced. These results are in line with previous studies suggesting that certain T cell subsets are sequestered away from the peripheral blood during P. falciparum malaria. [ABSTRACT FROM AUTHOR]