Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, Lewallen S, Liomba NG, Molyneux ME, 2004. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 10: 143–145.
Beare NA, Taylor TE, Harding SP, Lewallen S, Molyneux ME, 2006. Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am J Trop Med Hyg 75: 790–797.
Birbeck GL, Beare N, Lewallen S, Glover SJ, Molyneux ME, Kaplan PW, Taylor TE, 2010. Identification of malaria retinopathy improves the specificity of the clinical diagnosis of cerebral malaria: findings from a prospective cohort study. Am J Trop Med Hyg 82: 231–234.
Jakka SR, Veena S, Atmakuri RM, Eisenhut M, 2006. Characteristic abnormalities in cerebrospinal fluid biochemistry in children with cerebral malaria compared to viral encephalitis. Cerebrospinal Fluid Res 3: 8.
Medana IM, Idro R, Newton CR, 2007. Axonal and astrocyte injury markers in the cerebrospinal fluid of Kenyan children with severe malaria. J Neurol Sci 258: 93–98.
Mturi N, Keir G, Maclennan CA, Ross A, Willis AC, Elford BC, Berkley JA, Newton CR, 2008. Cerebrospinal fluid studies in Kenyan children with severe falciparum malaria. Open Trop Med J 1: 56–62.
Howard RJ, Uni S, Aikawa M, Aley SB, Leech JH, Lew AM, Wellems TE, Rener J, Taylor DW, 1986. Secretion of a malarial histidine-rich protein (Pf HRP II) from Plasmodium falciparum-infected erythrocytes. J Cell Biol 103: 1269–1277.
Desakorn V, Dondorp AM, Silamut K, Pongtavornpinyo W, Sahassananda D, Chotivanich K, Pitisuttithum P, Smithyman AM, Day NP, White NJ, 2005. Stage-dependent production and release of histidine-rich protein 2 by Plasmodium falciparum. Trans R Soc Trop Med Hyg 99: 517–524.
Moody A, 2002. Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev 15: 66–78.
Kifude CM, Rajasekariah HG, Sullivan DJ Jr, Stewart VA, Angov E, Martin SK, Diggs CL, Waitumbi JN, 2008. Enzyme-linked immunosorbent assay for detection of Plasmodium falciparum histidine-rich protein 2 in blood, plasma, and serum. Clin Vaccine Immunol 15: 1012–1018.
Mayor A, Moro L, Aguilar R, Bardaji A, Cistero P, Serra-Casas E, Sigauque B, Alonso PL, Ordi J, Menendez C, 2012. How hidden can malaria be in pregnant women? Diagnosis by microscopy, placental histology, polymerase chain reaction and detection of histidine-rich protein 2 in plasma. Clin Infect Dis 54: 1561–1568.
Sano T, Smith CL, Cantor CR, 1992. Immuno-PCR: very sensitive antigen detection by means of specific antibody-DNA conjugates. Science 258: 120–122.
Malou N, Raoult D, 2011. Immuno-PCR: a promising ultrasensitive diagnostic method to detect antigens and antibodies. Trends Microbiol 19: 295–302.
Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, Arnelle DR, Hollis D, McDonald MI, Granger DL, 1996. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med 184: 557–567.
WHO, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94: S1–S90.
WHO, 2012. Management of Severe Malaria: A Practical Handbook. Third edition. Geneva: WHO Press.
Rubach MP, Mukemba J, Florence S, John B, Crookston B, Lopansri BK, Yeo TW, Piera KA, Alder SC, Weinberg JB, Anstey NM, Granger DL, Mwaikambo ED, 2012. Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children. PLoS ONE 7: e35985.
van Dijk DP, Gillet P, Vlieghe E, Cnops L, van Esbroeck M, Jacobs J, 2009. Evaluation of the Palutop+4 malaria rapid diagnostic test in a non-endemic setting. Malar J 8: 293.
Xiaodong S, Tambo E, Chun W, Zhibin C, Yan D, Jian W, Jiazhi W, Xiaonong Z, 2013. Diagnostic performance of CareStart malaria HRP2/pLDH (Pf/pan) combo test versus standard microscopy on falciparum and vivax malaria between China-Myanmar endemic borders. Malar J 12: 6.
Lee N, Baker J, Andrews KT, Gatton ML, Bell D, Cheng Q, McCarthy J, 2006. Effect of sequence variation in Plasmodium falciparum histidine-rich protein 2 on binding of specific monoclonal antibodies: implications for rapid diagnostic tests for malaria. J Clin Microbiol 44: 2773–2778.
Jayshree RS, Dubey ML, Ganguly NK, Mahaj RC, 1989. Detection of malaria antigen in cerebrospinal fluid by counter-current immunoelectrophoresis. Lancet 2: 871.
Gitau EN, Kokwaro GO, Karanja H, Newton CR, Ward SA, 2013. Plasma and cerebrospinal proteomes from children with cerebral malaria differ from those of children with other encephalopathies. J Infect Dis 208: 1494–1503.
Pava Z, Echeverry DF, Diaz G, Murillo C, 2010. Large variation in detection of histidine-rich protein 2 in Plasmodium falciparum isolates from Colombia. Am J Trop Med Hyg 83: 834–837.
Hendriksen IC, White LJ, Veenemans J, Mtove G, Woodrow C, Amos B, Saiwaew S, Gesase S, Nadjm B, Silamut K, Joseph S, Chotivanich K, Day NP, von Seidlein L, Verhoef H, Reyburn H, White NJ, Dondorp AM, 2013. Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration. J Infect Dis 207: 351–361.
Tjitra E, Suprianto S, Dyer M, Currie BJ, Anstey NM, 1999. Field evaluation of the ICT malaria P.f/P.v immunochromatographic test for detection of Plasmodium falciparum and Plasmodium vivax in patients with a presumptive clinical diagnosis of malaria in eastern Indonesia. J Clin Microbiol 37: 2412–2417.
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ, 2010. Structure and function of the blood-brain barrier. Neurobiol Dis 37: 13–25.
Seydel KB, Fox LL, Glover SJ, Reeves MJ, Pensulo P, Muiruri A, Mpakiza A, Molyneux ME, Taylor TE, 2012. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis 206: 309–318.
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A cerebrospinal fluid (CSF) biomarker for cerebral malaria (CM) has not been validated. We examined the detection, semiquantification, and clinical use of the Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) as a parasite antigen biomarker for CM. The PfHRP-2 was detected in archival CSF samples from CM patients from Tanzania both by a newly developed sensitive and specific immuno-polymerase chain reaction (72 of 73) and by rapid diagnostic tests (62 of 73). The geometric mean PfHRP-2 CSF concentration was 8.76 ng/mL with no differences in those who survived (9.2 ng/mL), those who died (11.1 ng/mL), and those with neurologic sequelae (10.8 ng/mL). All aparasitemic endemic and nonendemic control samples had undetectable CSF PfHRP-2. In a separate group of 11 matched plasma and CSF cerebral malaria patient samples, the ratio of plasma to CSF PfHRP-2 was 175. The CSF PfHRP-2 reflects elevated plasma PfHRP-2 rather than elevated CM-specific CSF ratios, falling short of a validated biomarker.
Financial Support: The study was sponsored by a faculty JHBSPH Faculty Research Initiative Fund 1606510083. N. Anstey is supported by a Practitioner Fellowship from the Australian National Health and Medical Research Council. K. Mikita received partial support from a Japanese military grant. C. Pardo received support from the Bart McLean Fund for Neuroimmunology Research. Instrumentation for immuno-PCR was supported in part by the Bill and Melinda Gates Foundation (National Institute of Medical Research, Supplemental Project to Partnership for the Rapid Elimination of Trachoma, PRET+[48027]; Sheila West, principal investigator).
Disclosure: David Sullivan receives royalties from Alere for provision of positive control antigens for the Binax malaria rapid diagnostic test and is a named inventor and consultant for Fyodor biotechnologies who licensed a urine malaria test from Johns Hopkins University. This statement is made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.
Authors' addresses: Kei Mikita and David J. Sullivan, The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, E-mails: kmikita@jhsph.edu and dsulliv7@jhmi.edu. Kiran Thakur and Carlos A. Pardo, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, E-mails: kthakur1@jhmi.edu and cpardov1@jhmi.edu. Nicholas M. Anstey, Global Health Division, Menzies School of Health Research, Charles Darwin University, Casuarina, Australia, and the Royal Darwin Hospital, Darwin, Queensland, Australia, E-mail: Nicholas.Anstey@menzies.edu.au. Kim A. Piera, Global Health Division, Menzies School of Health Research, Charles Darwin University, Casuarina, Australia, E-mail: Kim.Piera@menzies.edu.au. J. Brice Weinberg, Duke University and Veterans Administration Medical Centers, Durham, North Carolina. E-mail: Weinberg-brice@duke.edu. Jackson Mukemba, Salvatore Florence, and Esther D. Mwaikambo, Hubert Kairuki Memorial University, Dar es Salaam, Tanzania, E-mails: jackmukemba@yahoo.fr, mukalabamu@yahoo.com, and esther.mwaikambo@gmail.com. Donald L. Granger, University of Utah School of Medicine and Veterans Administration Medical Center, Salt Lake City, Utah, E-mail: Granger-don.granger@hsc.utah.edu.
Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, Lewallen S, Liomba NG, Molyneux ME, 2004. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 10: 143–145.
Beare NA, Taylor TE, Harding SP, Lewallen S, Molyneux ME, 2006. Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am J Trop Med Hyg 75: 790–797.
Birbeck GL, Beare N, Lewallen S, Glover SJ, Molyneux ME, Kaplan PW, Taylor TE, 2010. Identification of malaria retinopathy improves the specificity of the clinical diagnosis of cerebral malaria: findings from a prospective cohort study. Am J Trop Med Hyg 82: 231–234.
Jakka SR, Veena S, Atmakuri RM, Eisenhut M, 2006. Characteristic abnormalities in cerebrospinal fluid biochemistry in children with cerebral malaria compared to viral encephalitis. Cerebrospinal Fluid Res 3: 8.
Medana IM, Idro R, Newton CR, 2007. Axonal and astrocyte injury markers in the cerebrospinal fluid of Kenyan children with severe malaria. J Neurol Sci 258: 93–98.
Mturi N, Keir G, Maclennan CA, Ross A, Willis AC, Elford BC, Berkley JA, Newton CR, 2008. Cerebrospinal fluid studies in Kenyan children with severe falciparum malaria. Open Trop Med J 1: 56–62.
Howard RJ, Uni S, Aikawa M, Aley SB, Leech JH, Lew AM, Wellems TE, Rener J, Taylor DW, 1986. Secretion of a malarial histidine-rich protein (Pf HRP II) from Plasmodium falciparum-infected erythrocytes. J Cell Biol 103: 1269–1277.
Desakorn V, Dondorp AM, Silamut K, Pongtavornpinyo W, Sahassananda D, Chotivanich K, Pitisuttithum P, Smithyman AM, Day NP, White NJ, 2005. Stage-dependent production and release of histidine-rich protein 2 by Plasmodium falciparum. Trans R Soc Trop Med Hyg 99: 517–524.
Moody A, 2002. Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev 15: 66–78.
Kifude CM, Rajasekariah HG, Sullivan DJ Jr, Stewart VA, Angov E, Martin SK, Diggs CL, Waitumbi JN, 2008. Enzyme-linked immunosorbent assay for detection of Plasmodium falciparum histidine-rich protein 2 in blood, plasma, and serum. Clin Vaccine Immunol 15: 1012–1018.
Mayor A, Moro L, Aguilar R, Bardaji A, Cistero P, Serra-Casas E, Sigauque B, Alonso PL, Ordi J, Menendez C, 2012. How hidden can malaria be in pregnant women? Diagnosis by microscopy, placental histology, polymerase chain reaction and detection of histidine-rich protein 2 in plasma. Clin Infect Dis 54: 1561–1568.
Sano T, Smith CL, Cantor CR, 1992. Immuno-PCR: very sensitive antigen detection by means of specific antibody-DNA conjugates. Science 258: 120–122.
Malou N, Raoult D, 2011. Immuno-PCR: a promising ultrasensitive diagnostic method to detect antigens and antibodies. Trends Microbiol 19: 295–302.
Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, Arnelle DR, Hollis D, McDonald MI, Granger DL, 1996. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med 184: 557–567.
WHO, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94: S1–S90.
WHO, 2012. Management of Severe Malaria: A Practical Handbook. Third edition. Geneva: WHO Press.
Rubach MP, Mukemba J, Florence S, John B, Crookston B, Lopansri BK, Yeo TW, Piera KA, Alder SC, Weinberg JB, Anstey NM, Granger DL, Mwaikambo ED, 2012. Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children. PLoS ONE 7: e35985.
van Dijk DP, Gillet P, Vlieghe E, Cnops L, van Esbroeck M, Jacobs J, 2009. Evaluation of the Palutop+4 malaria rapid diagnostic test in a non-endemic setting. Malar J 8: 293.
Xiaodong S, Tambo E, Chun W, Zhibin C, Yan D, Jian W, Jiazhi W, Xiaonong Z, 2013. Diagnostic performance of CareStart malaria HRP2/pLDH (Pf/pan) combo test versus standard microscopy on falciparum and vivax malaria between China-Myanmar endemic borders. Malar J 12: 6.
Lee N, Baker J, Andrews KT, Gatton ML, Bell D, Cheng Q, McCarthy J, 2006. Effect of sequence variation in Plasmodium falciparum histidine-rich protein 2 on binding of specific monoclonal antibodies: implications for rapid diagnostic tests for malaria. J Clin Microbiol 44: 2773–2778.
Jayshree RS, Dubey ML, Ganguly NK, Mahaj RC, 1989. Detection of malaria antigen in cerebrospinal fluid by counter-current immunoelectrophoresis. Lancet 2: 871.
Gitau EN, Kokwaro GO, Karanja H, Newton CR, Ward SA, 2013. Plasma and cerebrospinal proteomes from children with cerebral malaria differ from those of children with other encephalopathies. J Infect Dis 208: 1494–1503.
Pava Z, Echeverry DF, Diaz G, Murillo C, 2010. Large variation in detection of histidine-rich protein 2 in Plasmodium falciparum isolates from Colombia. Am J Trop Med Hyg 83: 834–837.
Hendriksen IC, White LJ, Veenemans J, Mtove G, Woodrow C, Amos B, Saiwaew S, Gesase S, Nadjm B, Silamut K, Joseph S, Chotivanich K, Day NP, von Seidlein L, Verhoef H, Reyburn H, White NJ, Dondorp AM, 2013. Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration. J Infect Dis 207: 351–361.
Tjitra E, Suprianto S, Dyer M, Currie BJ, Anstey NM, 1999. Field evaluation of the ICT malaria P.f/P.v immunochromatographic test for detection of Plasmodium falciparum and Plasmodium vivax in patients with a presumptive clinical diagnosis of malaria in eastern Indonesia. J Clin Microbiol 37: 2412–2417.
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ, 2010. Structure and function of the blood-brain barrier. Neurobiol Dis 37: 13–25.
Seydel KB, Fox LL, Glover SJ, Reeves MJ, Pensulo P, Muiruri A, Mpakiza A, Molyneux ME, Taylor TE, 2012. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis 206: 309–318.
Past two years | Past Year | Past 30 Days | |
---|---|---|---|
Abstract Views | 364 | 333 | 20 |
Full Text Views | 399 | 24 | 1 |
PDF Downloads | 98 | 24 | 1 |