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Thiranut Ramutton,
Ilse Ce Hendriksen,
Juliet Mwanga-Amumpaire,
George Mtove,
Rasaq Olaosebikan,
Antoinette K Tshefu,
Marie A Onyamboko,
Corine Karema,
Kathryn Maitland,
Ermelinda Gomes, [......],
Kamolrat Silamut,
Kesinee Chotivanich,
Kamoltip Promnares, Caterina I Fanello,
Lorenz von Seidlein,
Nicholas Pj Day,
Nicholas J White,
Arjen M Dondorp,
Mallika Imwong,
Charles J Woodrow
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ABSTRACT: Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements.
Studies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania.
There was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration.
These findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.
Malaria Journal 08/2012; 11:276. · 3.19 Impact Factor
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Ilse C E Hendriksen,
Juliet Mwanga-Amumpaire,
Lorenz von Seidlein,
George Mtove,
Lisa J White,
Rasaq Olaosebikan,
Sue J Lee,
Antoinette K Tshefu,
Charles Woodrow,
Ben Amos, [......],
Wirichada Pan-Ngum,
Samwel Gesase,
Kamolrat Silamut,
Hugh Reyburn,
Sarah Joseph,
Kesinee Chotivanich, Caterina I Fanello,
Nicholas P J Day,
Nicholas J White,
Arjen M Dondorp
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ABSTRACT: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.
Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.
Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
PLoS Medicine 08/2012; 9(8):e1001297. · 16.27 Impact Factor
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Ilse C E Hendriksen,
Josefo Ferro,
Pablo Montoya,
Kajal D Chhaganlal,
Amir Seni,
Ermelinda Gomes,
Kamolrat Silamut,
Sue J Lee,
Marcelino Lucas,
Kesinee Chotivanich, Caterina I Fanello,
Nicholas P J Day,
Nicholas J White,
Lorenz von Seidlein,
Arjen M Dondorp
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ABSTRACT: Background. Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria. Methods. HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status. Results. HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P < .001). In an age- and antimalarial treatment-adjusted logistic regression model, significant, independent predictors for death were renal impairment, acidosis, parasitemia, and plasma PfHRP2 concentration. Conclusions. Severe malaria in HIV-coinfected patients presents with higher parasite burden, more complications, and comorbidity, and carries a higher case fatality rate. Early identification of HIV coinfection is important for the clinical management of severe malaria.
Clinical Infectious Diseases 07/2012; 55(8):1144-53. · 9.15 Impact Factor
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Lorenz von Seidlein,
Rasaq Olaosebikan,
Ilse C E Hendriksen,
Sue J Lee,
Olanrewaju Timothy Adedoyin,
Tsiri Agbenyega,
Samuel Blay Nguah,
Kalifa Bojang,
Jacqueline L Deen,
Jennifer Evans, [......],
Marie A Onyamboko,
Hugh Reyburn,
Tharisara Sakulthaew,
Kamolrat Silamut,
Antoinette K Tshefu,
Noella Umulisa,
Samwel Gesase,
Nicholas P J Day,
Nicholas J White,
Arjen M Dondorp
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ABSTRACT: Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria.
African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model.
Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models.
Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.
Clinical Infectious Diseases 03/2012; 54(8):1080-90. · 9.15 Impact Factor
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Yoel Lubell,
Arthorn Riewpaiboon,
Arjen M Dondorp,
Lorenz von Seidlein,
Olugbenga A Mokuolu,
Margaret Nansumba,
Samwel Gesase,
Alison Kent,
George Mtove,
Rasaq Olaosebikan,
Wirichada Pan Ngum, Caterina I Fanello,
Ilse Hendriksen,
Nicholas P J Day,
Nicholas J White,
Shunmay Yeung
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ABSTRACT: To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets.
The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted.
The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively.
Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.
Bulletin of the World Health Organisation 07/2011; 89(7):504-12. · 4.64 Impact Factor
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Arjen M Dondorp, Caterina I Fanello,
Ilse C E Hendriksen,
Ermelinda Gomes,
Amir Seni,
Kajal D Chhaganlal,
Kalifa Bojang,
Rasaq Olaosebikan,
Nkechinyere Anunobi,
Kathryn Maitland, [......],
Kamolrat Silamut,
Kasia Stepniewska,
Charles J Woodrow,
Delia Bethell,
Bridget Wills,
Martina Oneko,
Tim E Peto,
Lorenz von Seidlein,
Nicholas P J Day,
Nicholas J White
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ABSTRACT: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.
This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054.
5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects.
Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.
The Wellcome Trust.
The Lancet 11/2010; 376(9753):1647-57. · 38.28 Impact Factor
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ABSTRACT: Antifolate drugs have an important role in the treatment of malaria. Polymorphisms in the genes encoding the dihydrofolate reductase and dihydropteroate synthetase enzymes cause resistance to the antifol and sulfa drugs, respectively. Rwanda has the highest levels of antimalarial drug resistance in Africa. We correlated the efficacy of chlorproguanil-dapsone plus artesunate (CPG-DDS+A) and amodiaquine plus sulfadoxine-pyrimethamine (AQ+SP) in children with uncomplicated malaria caused by Plasmodium falciparum parasites with pfdhfr and pfdhps mutations, which are known to confer reduced drug susceptibility, in two areas of Rwanda. In the eastern province, where the cure rates were low, over 75% of isolates had three or more pfdhfr mutations and two or three pfdhps mutations and 11% had the pfdhfr 164-Leu polymorphism. In the western province, where the cure rates were significantly higher (P < 0.001), the prevalence of multiple resistance mutations was lower and the pfdhfr I164L polymorphism was not found. The risk of treatment failure following the administration of AQ+SP more than doubled for each additional pfdhfr resistance mutation (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.01 to 5.55; P = 0.048) and each pfdhps mutation (OR = 2.1; 95% CI = 1.21 to 3.54; P = 0.008). The risk of failure following CPG-DDS+A treatment was 2.2 times higher (95% CI = 1.34 to 3.7) for each additional pfdhfr mutation, whereas there was no association with mutations in the pfdhps gene (P = 0.13). The pfdhfr 164-Leu polymorphism is prevalent in eastern Rwanda. Antimalarial treatments with currently available antifol-sulfa combinations are no longer effective in Rwanda because of high-level resistance.
Antimicrobial Agents and Chemotherapy 10/2009; 54(1):477-83. · 4.84 Impact Factor
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ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited human enzyme defect. This deficiency provides some protection from clinical malaria, but it can also cause haemolysis after administration of drugs with oxidant properties.
The safety of chlorproguanil-dapsone+artesunate (CD+A) and amodiaquine+sulphadoxine-pyrimethamine (AQ+SP) for the treatment of uncomplicated P. falciparum malaria was evaluated according to G6PD deficiency in a secondary analysis of an open-label, randomized clinical trial. 702 children, treated with CD+A or AQ+SP and followed for 28 days after treatment were genotyped for G6PD A- deficiency.
In the first 4 days following CD+A treatment, mean haematocrit declined on average 1.94% (95% CI 1.54 to 2.33) and 1.05% per day (95% CI 0.95 to 1.15) respectively in patients with G6PD deficiency and normal patients; a mean reduction of 1.3% per day was observed among patients who received AQ+SP regardless of G6PD status (95% CI 1.25 to 1.45). Patients with G6PD deficiency recipients of CD+A had significantly lower haematocrit than the other groups until day 7 (p = 0.04). In total, 10 patients had severe post-treatment haemolysis requiring blood transfusion. Patients with G6PD deficiency showed a higher risk of severe anaemia following treatment with CD+A (RR = 10.2; 95% CI 1.8 to 59.3) or AQ+SP (RR = 5.6; 95% CI 1.0 to 32.7).
CD+A showed a poor safety profile in individuals with G6PD deficiency most likely as a result of dapsone induced haemolysis. Screening for G6PD deficiency before drug administration of potentially pro-oxidants drugs, like dapsone-containing combinations, although seldom available, is necessary.
PLoS ONE 02/2008; 3(12):e4031. · 4.09 Impact Factor
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ABSTRACT: In Rwanda, amodiaquine+sulfadoxine/pyrimethamine (AQ+SP) is the current first-line treatment for malaria, introduced in 2001 as an interim strategy before the future deployment of an artemisinin-based combination treatment (ACT). Dihydroartemisinin/piperaquine (DHA-PQP) is a new co-formulated and well tolerated ACT increasingly used in Southeast Asia where it has proved to be highly effective against Plasmodium falciparum malaria. We tested the efficacy, safety and tolerability of DHA-PQP in children with uncomplicated P. falciparum malaria. A randomised, open trial was carried out in 2003-2004. Seven hundred and sixty-two children aged 12-59 months with uncomplicated P. falciparum malaria were randomly allocated to one of the following treatments: amodiaquine+artesunate; AQ+SP; or DHA-PQP. Patients were followed-up until Day 28 after treatment. Adverse events and clinical and parasitological outcomes were recorded. Children treated with DHA-PQP or AQ+AS had a significantly higher cure rate compared with those treated with amodiaquine+sulfadoxine/pyrimethamine (95.2% and 92.0% vs. 84.7%, respectively). Parasite clearance was significantly faster in children treated with DHA-PQP and AQ+AS compared with those treated with amodiaquine+sulfadoxine/pyrimethamine. The frequency of adverse events was significantly lower in patients treated with DHA-PQP than in those treated with combinations containing amodiaquine. A 3-day treatment with DHA-PQP proved to be efficacious with a good safety and tolerability profile and could be a good candidate for the next first-line treatment.
Transactions of the Royal Society of Tropical Medicine and Hygiene 01/2007; 100(12):1105-11. · 2.16 Impact Factor
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ABSTRACT: To assess the tolerability and efficacy of amodiaquine (AQ)+sulphadoxine-pyrimethamine (SP), the first-line malaria treatment in Rwanda.
Randomized, double-blind trial in 2003 in Kigali town. A total of 351 adult patients with uncomplicated Plasmodium falciparum malaria were randomly allocated to one of the following treatments: AQ+SP, AQ or SP. We followed patients until day 14 after treatment and recorded adverse events (AEs) and clinical and parasitological outcomes.
One hundred and eighteen patients reported at least one AE: 40% in the AQ, 39% in the AQ+SP and 21% in the SP groups. The AE was classified as possibly related to the antimalarial treatment for 86 patients. The Risk Ratio for at least one AE after treatment was significantly and about fourfold higher in patients receiving AQ or AQ+SP than in patients receiving SP. Pruritus and fatigue were significantly more frequent in patients treated with AQ or AQ+SP than in those receiving SP. Severe AEs, such as fatigue, nausea, dizziness and vomiting, were observed in four patients treated with AQ, in 10 treated with AQ+SP and in one patient treated with SP.
Amodiaquine+SP is not well tolerated and a substantial proportion of patients experienced pruritus and fatigue, thus decreasing their compliance and compromising the first line treatment implementation at national level. This renders AQ-containing regimens sub-optimal; better-tolerated treatments should be identified.
Tropical Medicine & International Health 06/2006; 11(5):589-96. · 2.80 Impact Factor
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Amir Attaran,
Karen I Barnes,
Christopher Curtis,
Umberto d'Alessandro, Caterina I Fanello,
Mary R Galinski,
Gilbert Kokwaro,
Sornchai Looareesuwan,
Michael Makanga,
Theonest K Mutabingwa,
Ambrose Talisuna,
Jean François Trape,
William M Watkins
The Lancet 02/2004; 363(9404):237-40. · 38.28 Impact Factor
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Amir Attaran,
Karen I Barnes,
Roger Bate,
Fred Binka,
Alessandro, Caterina I Fanello,
Laurie Garrett,
Theonest K Mutabingwa,
Donald Roberts,
Carol Hopkins,
Ambrose Talisuna,
Jean-Pierre Van,
William M Watkins
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ABSTRACT: The World Bank has an annual budget of US$20 billion, and is the largest organisation operating with a mission to reduce poverty worldwide. Malaria destroys about 1 million lives a year; the disease is the leading parasitic cause of death for Africa's children and impoverishment for their families. Here we examine how these factors meet in the new Global Strategy & Booster Program, which is the Bank's plan for controlling that disease in 2005–10. 1 We believe this plan is inadequate to reverse the Bank's troubling history of neglect for malaria. In the past 5 years, the Bank has failed to uphold a pledge to increase funding for malaria control in Africa, has claimed success in its malaria programmes by promulgating false epi-demiological statistics, and has approved clinically obs-olete treatments for a potentially deadly form of malaria. Crucially, the Bank also downsized its malaria staff , so that it cannot swiftly execute the restoration it plans under the Global Strategy & Booster Program. We summarise the evidence, show that the Bank possesses demonstrably little expertise in malaria, and argue that the Bank should relinquish its funding to other agencies better placed to control the disease. Historical antecedents 8 years ago, the World Bank launched the Roll Back Malaria campaign, promising to halve malaria deaths this decade. After studying its options, the Bank made an unprecedented pledge before Africa's heads of state in 2000: it would spend (or rather, loan) $300–500 million to fi ght malaria in Africa. 2 This promise of funding was warmly welcomed, because contemporary economic arguments held that malaria cost Africa dearly—perhaps even tens of billions of dollars a year. But the Bank failed to lend Africa the funds for malaria control that it said it would, and rather than admit this with candor, the Bank concealed the fact by using untransparent and contradictory accounting. In 2001, the year after its pledge to Africa's heads of state, the Bank made the impressive claim that it had "about $450 million out in various forms of anti-malaria programs". 3 But by 2002, it appeared to backtrack, writing that "Bank direct fi nancing for malaria control activities is over US$200 million". 4 The Bank also cut the number of countries where it supported antimalaria programmes, from 46 to about 25. 3,4 Although the Bank's statements lack complete precision, they do give the appearance that in just 1 year, the Bank slashed a quarter of a billion dollars of malaria-control funding, and nearly halved the number of countries it assisted. For this reason, we and others started to question the Bank's commitment to increasing malaria funding for Africa. 5 In oral and written inquiries dating back to 2003, we asked the Bank to disclose precisely its malaria-related disbursements by country and amount. 6,7 Without excep-tion, the Bank refused to do so. We informed the Bank that its lack of public transparency was inappropriate, given that it had an "obligation of transparency to the public" when spending public money. 8 The Bank again refused, characterising our inquiries as "overly-hortatory", and "constant threats…going back many months". 9 Finally, the Bank confi rmed our suspicions. Instead of increasing malaria funding as promised for Africa, the Bank furnished further evidence that it had cut malaria funding worldwide. Its most recent accounting, published in April, 2005, reads that from 2000 to 2005, the Bank com mitted "about US$100–150 million in earmarked funds for malaria control" worldwide, plus an unspecifi ed amount of non-earmarked funds that it says are "diffi cult to quantify". 1,10 No one knows how much money the Bank actually disbursed, but even if it disbursed every dollar that it earmarked, the total is still very much less than the pledge of $300–500 million for Africa alone. The most disturbing fact, however, is that the Bank actually does not know, and at best guesses, how much money it spends or loans for malaria. In stating that it earmarked $100–150 million, plus other "diffi cult to quantify" funds, the implication is that the Bank operates with a 50% or more margin of inaccuracy. No commercial high-street bank could keep such imprecise accounts for its clients, without running a serious risk of civil or criminal illegality. That the Bank's management tolerates such vague accounting when serving its clients, the African states to whom it pledged an increase of malaria-control funds, is extraordinary.
