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      Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement

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          Abstract

          Arjen Dondorp and colleagues investigate whether the plasma level of Plasmodium falciparum histidine-rich protein 2 can be used to distinguish between severe malaria and other severe febrile illness in African children with malaria.

          Abstract

          Background

          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.

          Methods and Findings

          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.

          Conclusions

          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.

          Please see later in the article for the Editors' Summary.

          Editors' Summary

          Background

          Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected mosquitoes. In 2010, malaria caused an estimated 655,000 deaths worldwide, mostly in Africa, where according to the World Health Organization, one African child dies every minute from the disease. There are four Plasmodium parasite species that cause malaria in humans, with one species, Plasmodium falciparum, causing the most severe disease. However, diagnosing severe falciparum malaria in children living in endemic areas is problematic, as many semi-immune children may have the malaria parasites in their blood (described as being parasitaemic) but do not have clinical disease. Therefore, a positive malaria blood smear may be coincidental and not be diagnostic of severe malaria, and unfortunately, neither are the clinical symptoms of severe malaria, such as shock, acidosis, or coma, which can also be caused by other childhood infections. For these reasons, the misdiagnosis of falciparum malaria in severely ill children is an important problem in sub-Saharan Africa, and may result in unnecessary child deaths.

          Why Was This Study Done?

          Previous studies have suggested that a parasite protein— P. falciparum histidine-rich protein -2 ( PfHRP2)—is a measure of the total number of parasites in the patient. Unlike the circulating parasites detected on a blood film, which do not represent the parasites that get stuck in vital organs, PfHRP2 is distributed equally through the total blood plasma volume, and so can be considered a measure of the total parasite burden in the previous 48 hours. So in this study, the researchers assessed the prognostic value of plasma PfHRP2 in African children with severe malaria and whether this protein could distinguish children who really do have severe malaria from those who have severe febrile illness but coincidental parasitaemia, who may have another infection.

          What Did the Researchers Do and Find?

          The researchers assessed levels of plasma PfHRP2 in 3,826 out of a possible 5,425 African children who participated in a large multinational trial (in Mozambique, The Gambia, Rwanda, Tanzania, Kenya, Uganda, and the Democratic Republic of Congo) that compared the anti-malarial drugs quinine and artesunate for the treatment of severe malaria. All children had a clinical diagnosis of severe malaria confirmed by a rapid diagnostic test, and the researchers used clinical signs to define the severity of malaria. The researchers assessed the relationship between plasma PfHRP2 concentrations and risk of death taking other well established predictors of death, such as coma, convulsions, hypoglycaemia, respiratory distress, and shock, into account.

          The researchers found that PfHRP2 was detectable in 3,800/3,826 (99%) children with severe malaria and that the average plasma PfHRP2 levels was significantly higher in the 381 children who died from malaria than in children who survived (1,611 ng/mL versus 1,046 ng/mL). Plasma PfHRP2 was also significantly higher in children with severe malaria signs and symptoms such as coma, acidosis, and severe anaemia. Importantly, the researchers found that high death rates were associated with either very low or very high values of plasma PfHRP2: the odds (chance) of death were 20% higher per unit increase in PfHRP2 above a specific threshold (174 ng/ml), but below this concentration, the risk of death increased with decreasing levels, probably because at lower levels disease was caused by a severe febrile disease other than malaria, like septicemia. Finally, the researchers found that in children within the highest PfHRP2 tertile, the chance of death when treated with the antimalarial drug artesunate versus quinine was 0.61 but that there was no difference in death rates in the lowest tertile, which supports that patients with very low plasma PfHRP2 have a different severe febrile illness than malaria. The researchers use mathematical modeling to provide cut-off values for plasma PfHRP2 denoting the proportion of patients with a diagnosis other than severe malaria.

          What Do These Findings Mean?

          These findings suggest that in areas of moderate or high malaria transmission where a high proportion of children are parasitaemic, plasma PfHRP2 levels taken on admission to hospital can differentiate children at highest risk of death from severe falciparum malaria from those likely to have alternative causes of severe febrile illness. Therefore, plasma PfHRP2 could be considered a valuable additional diagnostic tool and prognostic indicator in African children with severe falciparum malaria. This finding is important for clinicians treating children with severe febrile illnesses in malaria-endemic countries: while high levels of plasma PfHRP2 is indicative of severe malaria which needs urgent antimalarial treatment, low levels suggest that another severe infective disease should be considered, warranting additional investigations and urgent treatment with antibiotics.

          Additional Information

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001297.

          Related collections

          Most cited references 31

          • Record: found
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          Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.

          In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). Artesunate should become the treatment of choice for severe falciparum malaria in adults.
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            • Record: found
            • Abstract: found
            • Article: not found

            Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study.

            To study the diagnosis and outcomes in people admitted to hospital with a diagnosis of severe malaria in areas with differing intensities of malaria transmission. Prospective observational study of children and adults over the course a year. 10 hospitals in north east Tanzania. 17,313 patients were admitted to hospital; of these 4474 (2851 children aged under 5 years) fulfilled criteria for severe disease. Details of the treatment given and outcome. Altitudes of residence (a proxy for transmission intensity) measured with a global positioning system. Blood film microscopy showed that 2062 (46.1%) of people treated for malaria had Plasmodium falciparum (slide positive). The proportion of slide positive cases fell with increasing age and increasing altitude of residence. Among 1086 patients aged > or = 5 years who lived above 600 metres, only 338 (31.1%) were slide positive, while in children < 5 years living in areas of intense transmission (< 600 metres) most (958/1392, 68.8%) were slide positive. Among 2375 people who were slide negative, 1571 (66.1%) were not treated with antibiotics and of those, 120 (7.6%) died. The case fatality in slide negative patients was higher (292/2412, 12.1%) than for slide positive patients (142/2062, 6.9%) (P < 0.001). Respiratory distress and altered consciousness were the strongest predictors of mortality in slide positive and slide negative patients and in adults as well as children. In Tanzania, malaria is commonly overdiagnosed in people presenting with severe febrile illness, especially in those living in areas with low to moderate transmission and in adults. This is associated with a failure to treat alternative causes of severe infection. Diagnosis needs to be improved and syndromic treatment considered. Routine hospital data may overestimate mortality from malaria by over twofold.
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              • Abstract: found
              • Article: not found

              Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration.

              For investigation of the pathogenesis of cerebral malaria, immediate postmortem samples from brain and other tissues of patients dying with Plasmodium falciparum malaria, with (CM) or without (NCM) cerebral malaria, were processed for electron microscopy. Counts of parasitized erythrocytes (PRBCs) in cerebral and other vessels showed that the proportion of PRBCs was higher in CM than in NCM, and also that the proportion of PRBCs was higher in the brain than in other organs examined in both CM and NCM. Cerebral vessels from CM patients were more tightly packed with RBCs than those from NCM patients, but there was no significant difference in the amount or degree of endothelial damage or numbers of vessels with endothelial pseudopodia. Fibrillar (fibrin) deposits were present in a small proportion of vessels, but no thrombosis was present. There was neither acute nor chronic inflammation, and leukocytes were absent within or outside cerebral vessels. There was no immune complex deposition in cerebral vessels. Parasites in cerebral vessels were mainly trophozoites or schizonts. Occasional RBC remnants following parasite release were seen. Some parasites were degenerate, resembling crisis forms. PRBCs adhered to endothelium via surface knobs. It is concluded that there is no evidence for an inflammatory or immune pathogenesis for human cerebral malaria and that the clinical effects probably relate to anoxia and the metabolic activities of the parasites.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science ( San Francisco, USA )
                1549-1277
                1549-1676
                August 2012
                August 2012
                21 August 2012
                : 9
                : 8
                Affiliations
                [1 ]Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [2 ]Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom
                [3 ]Mbarara University of Science and Technology and Epicentre Research Base, Mbarara, Uganda
                [4 ]Menzies School of Health Research, Casuarina, NT, Australia
                [5 ]National Institute for Medical Research, Amani Centre, Tanga, Tanzania
                [6 ]Medical Research Council Laboratories, Banjul, The Gambia
                [7 ]Kinshasa School of Public Health, Kingasani Research Centre, Kinshasa, Democratic Republic of the Congo
                [8 ]Teule Hospital, Muheza, Tanzania
                [9 ]Malaria Control Program, Ministry of Health, Kigali, Rwanda
                [10 ]Kenya Medical Research Institute (KEMRI)–Wellcome Trust Research Programme, Kilifi, Kenya
                [11 ]Hospital Central da Beira, Beira, Mozambique
                [12 ]National Institute for Medical Research, Tanga Medical Research Centre, Tanga, Tanzania
                [13 ]London School of Tropical Medicine & Hygiene, London, United Kingdom
                [14 ]Medical Research Council, London, United Kingdom
                University of Melbourne, Australia
                Author notes

                Lorenz von Seidlein and Nicholas J. White are on the Editorial Board of PLOS Medicine. The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CIF AMD ICEH NPJD LVS NJW. Performed the experiments: SS ICEH CW SJ KS KC BA. Analyzed the data: ICEH LJW SJL CW AMD. Contributed reagents/materials/analysis tools: LJW SJL WPN HR. Wrote the first draft of the manuscript: ICEH. Contributed to the writing of the manuscript: AMD CW LVS HR NPJD NJW. ICMJE criteria for authorship read and met: ICEH JMA LVS GM LJW RO SJL AKT CW BA CK SS KM EG WPN SG KS HR SJ KC CIF NPJD NJW AMD. Agree with manuscript results and conclusions: ICEH JMA LVS GM LJW RO SJL AKT CW BA CK SS KM EG WPN SG KS HR SJ KC CIF NPJD NJW AMD. Enrolled patients: JMA GM SG RO AKT CK KM EG ICEH LVS.

                Article
                PMEDICINE-D-12-00100
                10.1371/journal.pmed.1001297
                3424256
                22927801

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 1
                Funding
                This trial was supported by grants 076908 and 082541 from the Wellcome Trust, and was coordinated as part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain ( http://www.wellcome.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Infectious Diseases
                Parasitic Diseases
                Malaria
                Plasmodium Falciparum

                Medicine

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