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Background Blackwater fever (BWF), one of the complications of severe malaria, has recently re-emerged as a cause of severe anemia (SA) in African children. However, postdischarge morbidity in children with BWF has previously not been described. Methods This was a descriptive cohort study in which children, aged 0–5 years, admitted to Jinja Regional Referral Hospital with acute episodes of SA (hemoglobin ≤5.0 g/dL) were followed up for 6 months after hospitalization. Incidence of readmissions or deaths during the follow-up period was compared between SA children with BWF and those without BWF. Results A total of 279 children with SA including those with BWF (n = 92) and no BWF (n = 187) were followed for the duration of the study. Overall, 128 (45.9%) of the study participants were readmitted at least once while 22 (7.9%) died during the follow-up period. After adjusting for age, sex, nutritional status, and parasitemia, SA children with BWF had higher risk of readmissions (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.1–2.5) and a greater risk of death (HR. 3.37; 95% CI, 1.3–8.5) compared with those without BWF. Malaria and recurrence of SA were the most common reasons for readmissions. Conclusions There is a high rate of readmissions and deaths in the immediate 6 months after initial hospitalization among SA children in the Jinja hospital. SA children with BWF had increased risk of readmissions and deaths in the postdischarge period. Postdischarge malaria chemoprophylaxis should be considered for SA children living in malaria endemic areas. [ABSTRACT FROM AUTHOR]

Background. In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF). Methods. We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of 3 malaria- protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. Results. Of 3170 trial participants, 394 (12.4%) had BWF. The majority (318 [81.0%]) presented in eastern Uganda and were the subjects of further analysis. BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level <5 g/dL) (238/310 [77%]). Plasmodium falciparum parasitemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum histidine rich protein 2 (192/246 [78.0%]) vs 811/1154 [70.3%]; P = .014), suggesting recent antimalarial treatment. Overall, 282 of 318 (88.7%) received transfusions, with 94 of 282 (33.3%) and 9 of 282 (3.4%) receiving 2 or 3 transfusions, respectively. By day 28, 39 of 318 (12.3%) BWF cases and 154 of 1554 (9.9%) non-BWF controls had died (P = .21), and 7 of 255 (3.0%) vs 13/1212 (1%), respectively, had severe anemia (P = .036). We found no association with G6PD deficiency. The prevalence of both the sickle cell trait (10/218 [4.6%]) and homozygous ɑ+thalassemia (8/216 [3.7%]) were significantly lower among cases than among population controls (334/2123 [15.7%] and 141/2114 [6.6%], respectively), providing further support for the role of malaria. Conclusions. We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required. [ABSTRACT FROM AUTHOR]

From about 1880 to 1920, a culture of medical experimentation promoted blood transfusion as a therapy for severe anemia in Europe, which was applied in German East Africa in 1892 for a case of blackwater fever, a complication of malaria afflicting mainly Europeans. This first case of blood transfusion in Africa, in which an African's blood was transfused into a German official, complicates the dominant narrative that blood transfusions in Africa came only after World War I. Medical researchers moreover experimented with blood serum therapies on human and animal subjects in Europe and Africa, injecting blood of different species, "races" and ethnicities into others to demonstrate parasite transmissibility and to discover vaccines for diseases such as malaria, sleeping sickness, and yellow fever. While research in German colonies is highlighted here, this was a transnational medical culture that crossed borders and oceans. This research is of interest as a possible early pathway for the epidemic spread of HIV and other zoonoses in Africa and the world, which biomedical researchers have identified as emerging in West-Central Africa sometime around the turn of the twentieth century. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Although the level of erythrocyte complement receptor type 1 (E-CR1) expression in patients with malaria has been extensively studied, whether the level of expression of E-CR1 is associated with severe malaria remains controversial. The present study examined a possible association of polymorphisms in the CR1 gene with the severity of malaria, and it evaluated the influence of the associated polymorphism on expression of E-CR1. Methods. Seventeen single-nucleotide polymorphisms in CR1 were genotyped in 477 Thai patients who had Plasmodium falciparum malaria (203 had mild malaria, 165 had noncerebral severe malaria, and 109 had cerebral malaria). The E-CR1 expression level was measured by flow cytometry in 24 healthy Thai subjects. Results. The T allele of the reference single-nucleotide polymorphism rs9429942 in the CR1 promoter region was strongly associated with protection against cerebral malaria (2.2% of patients with mild malaria vs. 7.8% of patients with cerebral malaria; P = .0009; Bonferroni-adjusted Pc = .0306). The E-CR1 expression level was significantly higher in individuals with the TT genotype of rs9429942 than in individuals with the TC genotype of rs9429942 (P = .0282). Conclusions. We identified a CR1 promoter allele, associated with higher E-CR1 expression, that conferred protection against cerebral malaria. Previous studies have shown that the rate of clearance of immune complexes (ICs) from the circulation is related to the E-CR1 level. These results lead to the hypothesis that the clearance of ICs regulated by E-CR1 therefore plays a crucial role in the pathogenesis of cerebral malaria. [ABSTRACT FROM AUTHOR]

Selection pressure exerted by pathogens contributes to the persistence of polymorphisms in GM and KM allotypes, which are antigenic determinants of immunoglobulins. This study investigated the impact of GM and KM allotypes on the clinical response to Plasmodium falciparum infection among Beninese children, including 65 with severe malaria, 37 with uncomplicated malaria, and 53 with asymptomatic carriage. An inverse relationship was found between the GM 5,6,13,14; 1,17 phenotype and uncomplicated malaria. Genetic markers implicated in the composition and activity of immunoglobulins may be associated with the genetic control of both malaria infection and morbidity. [ABSTRACT FROM AUTHOR]

Background. Multidrug-resistant strains of Plasmodium vivax are emerging in Southeast Asia. Methods. In vitro drug susceptibility and pvmdr1 genotype were determined in P. vivax field isolates from Indonesia and Thailand. Results. Increased pvmdr1 copy number was present in 21% of isolates from Thailand (15/71) and none from Indonesia (0/114; P < .001). Compared with Indonesian isolates, the median IC50 of Thai isolates was lower for chloroquine (36 vs. 114 nmol/L; P < .001) but higher for amodiaquine (34 vs. 13.7 nmol/L; P = .032), artesunate (8.33 vs. 1.58 nmol/L; P < .001), and mefloquine (111 vs. 9.87 nmol/L; P < .001). In 11 cryopreserved Thai isolates, those with increased pvmdr1 copy number had a higher IC50 for mefloquine (78.6 vs. 38 nmol/L for single-copy isolates; P = .006). Compared with isolates with the wild-type allele, the Y976F mutation of pvmdr1 was associated with reduced susceptibility to chloroquine (154 nmol/L [range, 4.6 -3505] vs. 34 nmol/L [range, 6.7-149]; P < .001) but greater susceptibility to artesunate (1.8 vs. 9.5 nmol/L; P = .009) and mefloquine (14 vs. 121 nmol/L; P < .001). Conclusions. Amplification of pvmdr1 and single-nucleotide polymorphisms are correlated with susceptibility of P. vivax to multiple antimalarial drugs. Chloroquine and mefloquine appear to exert competitive evolutionary pressure on pvmdr1, similar to that observed with pfmdr1 in Plasmodium falciparum. [ABSTRACT FROM AUTHOR]

We cultured Plasmodium falciparum parasites from 98 Ugandan children with malaria and determined the complexity of infection (COI) on the basis of msp-2 polymorphisms daily for 9 days. The mean COI decreased during culture from 1.73 to 1.56. New strains appeared after day 0 in 20 cultures. Strains disappeared after day 0 in56%of 45 cultures that were initially mixed; persisting strains more commonly had wild-type dhfr (C59) and dhps (K540) sequences and mutant pfmdr1 (86Y) sequences. Thus, initial genotypes offer an imperfect representation of clinical COI. Loss of strains in culture may be due to diminished fitness of some drug-resistant strains. [ABSTRACT FROM AUTHOR]

Sulfadoxine-pyrimethamine (SP) inhibits folate metabolism by the malaria parasite. We investigated the association between folate levels and SP failure in pregnant women. Data from a trial to assess the effect that folate supplementation has on SP failure in 467 pregnant women were analyzed. Plasma folate levels were determined at enrollment and at day 7. High baseline folate levels, high parasite densities, and age <20 years were risk factors for SP failure. High-dose (5 mg daily) folate supplementation or high folate levels at day 7 were independent risk factors. Therefore, pregnant women receiving SP should receive low-/moderate-dose folate supplementation. [ABSTRACT FROM AUTHOR]

Summary: The Anti Malaria Campaign distributed approximately 300000 long-lasting impregnated nets (LLINs) to malaria-endemic areas in Sri Lanka during the years 2005 to 2007. We conducted a community-based cross-sectional survey among 2467 households distributed among the three major ethnic groups of Sri Lanka to study the perceptions and practices with regard to the use of LLINs in order to improve their use. In a majority of households the number of LLINs available was not sufficient for the number of people, although there was a small percentage of households that had excess nets. The information and advice given at the time of distribution regarding use of the nets differed amongst the three groups and was not consistent. Dissemination of this knowledge within the family was not observed. A relationship between knowledge regarding LLINs and reported practices on washing and drying of LLINs was found. It was noted that net shape may influence net use, with cone shaped nets being more popular. Efforts to increase knowledge on LLINs using behaviour change communication techniques would have more effectively contributed to achieve planned outcomes. Proper use of LLINs will undoubtedly contribute to further reduction of malaria in Sri Lanka. [Copyright &y& Elsevier]

Summary: Tafenoquine is being developed for radical cure and post-exposure prophylaxis of Plasmodium vivax malaria. In an open-label study, 1512 Australian Defence Force personnel received one of three tafenoquine 3 d regimens [400mg once daily (od), 200mg twice daily (bid), 200mg od] or daily primaquine (22.5mg) plus doxycycline (100mg) over 14 d in Bougainville and in Timor-Leste for post-exposure prophylaxis. The relapse rate of subjects treated in Bougainville with tafenoquine (n =173) was 1.2% (200mg bid×3 d) and 2.3% (400mg od×3 d), while primaquine plus doxycycline (n =175) was 3.4%. For subjects treated in Timor-Leste with tafenoquine (n =636), the relapse rate was 4.9% (200mg od×3 d), 5.3% (200mg bid×3 d) and 11.0% (400mg od×3d), while primaquine plus doxycycline (n =289) was 10.0%. The most frequent adverse events reported across all groups were nausea, abdominal distress and diarrhoea. There was a dose-dependent reduction in adverse events with a reduced dose of tafenoquine, with the lowest dose (total 600mg over 3 d) producing rates of adverse events equivalent to that of primaquine plus doxycycline. The much shorter dosing regimen of tafenoquine should increase compliance, which is often suboptimal with primaquine after leaving an endemic area. [Australian New Zealand Clinical Trials Registry Number 12607000588493]. [Copyright &y& Elsevier]

Summary: Chloroquine (CQ) is an effective treatment of choice for vivax malaria in most settings, but with the spread of CQ-resistant Plasmodium falciparum, many countries now use artemisinin-based combination therapy for treatment of falciparum malaria. In areas co-endemic for falciparum and vivax malaria incorrect differential diagnosis is always a risk. In Afghanistan the adoption of sulfadoxine–pyrimethamine plus artesunate (SP+AS) as first-line falciparum treatment raises the prospect of a significant proportion of vivax malaria being misdiagnosed and treated with the combination. SP is considered to have limited efficacy against vivax malaria, and the efficacy of SP+AS against Plasmodium vivax has not been established in areas that are using SP+AS. A randomised, non-inferiority trial comparing SP+AS with CQ monotherapy was undertaken on 190 vivax malaria patients in eastern Afghanistan. Standard WHO procedures for in vivo evaluation of antimalarial drugs were followed. A total of 180 individuals completed the trial to day 42. Using a per protocol analysis, both regimens resulted in ≥96% treatment success at 28 d, but significantly more cases failed in the CQ arm (46%) than in the SP+AS arm (24%) by day 42. In areas where vivax infections might be misdiagnosed as falciparum infections and treated with SP+AS, patient management would be as good, or better than, with the standard CQ treatment [ClinicalTrials.gov Registration No. NCT00486694]. [Copyright &y& Elsevier]

Summary: This collaborative cross-border study was performed to determine the therapeutic efficacy of antimalarial drugs used by the National Programmes for falciparum malaria along the eastern Indo-Nepal border where there is unregulated population movement across the border. The study was conducted at sites in Jhapa District, Nepal and Darjeeling District, India. The study was conducted from August 2003 to February 2004, following the WHO 28 day treatment protocol. The efficacy of chloroquine was tested in India among 91 subjects and of sulfadoxine–pyrimethamine in Nepal among 107 subjects with laboratory-confirmed Plasmodium falciparum malaria. Of the 102 subjects who completed the study in Nepal, there were 21 (20.6%) treatment failures comprising 7 (6.9%) early treatment failures (ETF) and 14 (14.7%) late treatment failures (LTF) (5 late clinical failures [LCF] and 9 late parasitological failures [LPF]). Of the 89 subjects who completed the study in India, there were 46 (51.7%) treatment failures comprising 7 (7.9%) ETFs and 39 (43.8%) LTFs (13 LCFs and 26 LPFs). Based on WHO guidelines both countries need to review their drug policy urgently and make appropriate changes, taking into account aspects of cross-border collaboration in the control of drug-resistant malaria. [Copyright &y& Elsevier]

Blackwater fever (BWF), one of the commonest causes of death of Europeans living in Africa at the beginning of the twentieth century, but rarely diagnosed since the 1950s, is related to Plasmodium falciparum malaria but there is considerable debate and controversy about its aetiology. From 1990 to 2000, the whole population of Dielmo, a village in Senegal, was involved in a prospective study of malaria. Three cases of BWF occurred in 3 children aged 4, 7 and 10 years, belonging to a subgroup of children who suffered malaria attacks every 4 to 6 weeks over many years, who had received repeated quinine treatment. The spread of chloroquine resistance, by increasing the use of more toxic alternative drugs, may expose endemic populations to a high incidence of severe side effects of antimalarials. [Copyright &y& Elsevier]

Presents information on a study which examined the cases of blackwater fever among European expatriates who lived in sub-Sahara Africa from 1990 to 1999. Methodology; Results of the study; Discussion.

Summary: We describe here the results of an analysis of Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene copy number from 440 field isolates from Papua New Guinea. No multiple copies of the gene were found, which corresponds to the lack of usage of mefloquine. These data extend regional knowledge about the distribution of multidrug-resistant P. falciparum. [Copyright &y& Elsevier]

Summary: Malaria rapid diagnostic tests (RDT) are being procured and used in increasing numbers. However, the resultant effect of RDT-based diagnosis on fever management has been limited by lack of confidence in RDT results or the inability to act on results appropriately. If the utilisation of malaria RDTs is going to achieve the significant public health and financial benefits anticipated, they must be introduced in a carefully structured way and viewed as a tool for the management of febrile illness, not just malaria. If this is to occur, a re-think is required of the way many malaria programmes are funded and run. [Copyright &y& Elsevier]

Blackwater fever was typically reported after quinine administration, although it is poor recognized in patients receiving artesunate. This case describes a blackwater fever in a non-immune patient after artesunate for severe malaria. It highlights the importance of monitoring haemolytic parameters in severe malaria to avoid renal impairment or severe anaemia. [ABSTRACT FROM AUTHOR]

A case of a patient who was admitted to hospital in Paris, France, in February 2001 with autoimmune haemolytic anaemia, probably due to artemether-lumefantrine therapy, is presented. Such a complication has previously been observed in patients receiving drugs containing aryl-amino-alcohols but never before in a patient receiving lumefantrine and may be associated with the increase in episodes of blackwater fever seen in recent years. [Copyright &y& Elsevier]