ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Newton CR , Taylor TE , Whitten RO , 1998. Pathophysiology of fatal falciparum malaria in African children. Am J Trop Med Hyg 58: 673–683.
-
2.
World Health Organization , 2022. WHO Guidelines for Malaria, 3 June 2022. Geneva, Switzerland: WHO.
-
3.
Roca-Feltrer A , Carneiro I , Armstrong Schellenberg JRM , 2008. Estimates of the burden of malaria morbidity in Africa in children under the age of 5 years. Trop Med Int Health 13: 771–783.
-
4.
World Health Organization , 2015. World Malaria Report 2015. Geneva, Switzerland: WHO.
-
5.
Taylor TE , Fu WJ , Carr RA , Whitten RO , Mueller JG , Fosiko NG , Lewallen S , Liomba NG , Molyneux ME , 2004. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 10: 143–145.
-
6.
Beare NAV , 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.
-
7.
O’Meara WP , Bejon P , Mwangi TW , Okiro EA , Peshu N , Snow RW , Newton CRJC , Marsh K , 2008. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet 372: 1555–1562.
-
8.
Watson JA et al., 2021. Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision. eLife 10: e69698.
-
9.
Watson JA et al., 2022. Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations. Sci Transl Med 14: eabn5040.
-
10.
Desakorn V , Dondorp AM , Silamut K , Pongtavornpinyo W , Sahassananda D , Chotivanich K , Pitisuttithum P , Smithyman AM , Day NPJ , 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.
-
11.
Dondorp AM et al., 2005. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2. PLoS Med 2: e204.
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12.
Lewallen S , Taylor TE , Molyneux ME , Wills BA , Courtright P , 1993. Ocular fundus findings in Malawian children with cerebral malaria. Ophthalmology 100: 857–861.
-
13.
MacCormick IJC , Beare NAV , Taylor TE , Barrera V , White VA , Hiscott P , Molyneux ME , Dhillon B , Harding SP , 2014. Cerebral malaria in children: using the retina to study the brain. Brain 137: 2119–2142.
-
14.
MacCormick IJC , Zhang B , Hill D , Cordeiro MF , Small DS , 2022. A proposed theoretical framework for retinal biomarkers. Alzheimers Dement (Amst) 14: e12327.
-
15.
Milner DA Jr. et al., 2015. Quantitative assessment of multiorgan sequestration of parasites in fatal pediatric cerebral malaria. J Infect Dis 212: 1317–1321.
-
16.
Barrera V et al., 2015. Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of Malawian children with fatal cerebral malaria. J Infect Dis 211: 1977–1986.
-
17.
Small DS , Taylor TE , Postels DG , Beare NAV , Cheng J , MacCormick IJC , Seydel KB , 2017. Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria. eLife 6: e23699.
-
18.
Hendriksen ICE et al., 2012. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med 9: e1001297.
-
19.
Hendriksen ICE et al., 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.
-
20.
Seydel KB , Milner DA , Kamiza SB , Molyneux ME , Taylor TE , 2006. The distribution and intensity of parasite sequestration in comatose Malawian children. J Infect Dis 194: 208–215.
-
21.
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.
-
22.
Dempster AP , Laird NM , Rubin DB , 1977. Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc B 39: 1–22.
-
23.
Scrucca L , Fop M , Murphy TB , Raftery AE , 2016. mclust 5: clustering, classification and density estimation using Gaussian finite mixture models. R J 8: 289.
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24.
R Core Team , 2018. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Available at: https://www.R-project.org/. Accessed December 2, 2022.
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25.
Braun H , 1980. A simple method for testing goodness of fit in the presence of nuisance parameters. J R Stat Soc B 42: 53–63.
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26.
DeLong ER , DeLong DM , Clarke-Pearson DL , 1988. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44: 837–845.
-
27.
Seydel KB et al., 2015. Brain swelling and death in children with cerebral malaria. N Engl J Med 372: 1126–1137.
-
28.
Von Seidlein L et al., 2012. Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial. Clin Infect Dis 54: 1080–1090.
-
29.
Beare NAV , Glover SJ , Molyneux M , 2009. Malarial retinopathy in cerebral malaria. Am J Trop Med Hyg 80: 171.
-
30.
Joshi V , Wigdahl J , Nemeth S , Manda C , Lewallen S , Taylor T , MacCormick I , Harding S , Soliz P , 2018. Automated detection of malarial retinopathy in retinal fundus images obtained in clinical settings. Annu Int Conf IEEE Eng Med Biol Soc 2018: 5950–5953.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 1918 | 1119 | 54 |
| Full Text Views | 405 | 122 | 0 |
| PDF Downloads | 330 | 44 | 0 |
Using Malarial Retinopathy to Improve the Diagnosis of Pediatric Cerebral Malaria
Yuzhou Lin
Yuzhou Lin
Department of Statistics, Harvard University, Cambridge, Massachusetts;
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Andrew Tebulo
Andrew Tebulo
Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi;
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Dylan Small
Dylan Small
Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania;
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Karl Seydel
Karl Seydel
Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi;
Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan;
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Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan;
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Terrie Taylor
Terrie Taylor
Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi;
Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan;
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Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan;
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Bo Zhang
Bo Zhang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington
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ABSTRACT.
In malaria endemic areas, a high proportion of children have detectable parasitemia but show no clinical symptoms. When comatose from a cause other than malaria, this group confounds the cerebral malaria (CM) definition, making accurate diagnosis challenging. One important biomarker of CM is malarial retinopathy, a set of specific features visible in the ocular fundus. In this study, we quantified the contribution of malarial retinopathy in discriminating malaria-caused coma from non–malaria-caused coma. We estimated that 10% of our study cohort of N = 1,192 patients who met the WHO clinical definition of CM in Malawi had non-malarial coma based on a Gaussian mixture model using the parasite protein Plasmodium falciparum histidine-rich protein-2. A classification based on platelets, white blood cells, and retinopathy significantly improved the discriminative power of a previously established model including only platelets plus white blood cells (area under the receiver operating characteristic curve: 0.87 versus 0.75, P value < 0.001). We conclude that malarial retinopathy is highly predictive of malaria-caused versus non–malaria-caused coma and recommend that an ocular funduscopic examination to determine malarial retinopathy status be included in the assessment of parasitemic comatose African children.
- Supplemental Materials (PDF 160 KB)
Author Notes
Disclosure: T. T. sits on the Strategic Advisory Board for the Novartis Institute for Tropical Diseases and the Malaria Advisory Board for Novartis Pharma AG. Other authors declare no conflicts of interest.
Authors’ addresses: Yuzhou Lin, Department of Statistics, Harvard University, Cambridge, MA, E-mail: yuzhoulin@g.harvard.edu. Andrew Tebulo, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi, E-mail: abtebulo@gmail.com. Dylan Small, Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA, E-mail: dsmall@wharton.upenn.edu. Karl Seydel and Terrie Taylor, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi, and Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, MI, E-mails: seydel@msu.edu and ttmalawi@msu.edu. Bo Zhang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, E-mail: bzhang3@fredhutch.org.
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Newton CR , Taylor TE , Whitten RO , 1998. Pathophysiology of fatal falciparum malaria in African children. Am J Trop Med Hyg 58: 673–683.
-
2.
World Health Organization , 2022. WHO Guidelines for Malaria, 3 June 2022. Geneva, Switzerland: WHO.
-
3.
Roca-Feltrer A , Carneiro I , Armstrong Schellenberg JRM , 2008. Estimates of the burden of malaria morbidity in Africa in children under the age of 5 years. Trop Med Int Health 13: 771–783.
-
4.
World Health Organization , 2015. World Malaria Report 2015. Geneva, Switzerland: WHO.
-
5.
Taylor TE , Fu WJ , Carr RA , Whitten RO , Mueller JG , Fosiko NG , Lewallen S , Liomba NG , Molyneux ME , 2004. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 10: 143–145.
-
6.
Beare NAV , 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.
-
7.
O’Meara WP , Bejon P , Mwangi TW , Okiro EA , Peshu N , Snow RW , Newton CRJC , Marsh K , 2008. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet 372: 1555–1562.
-
8.
Watson JA et al., 2021. Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision. eLife 10: e69698.
-
9.
Watson JA et al., 2022. Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations. Sci Transl Med 14: eabn5040.
-
10.
Desakorn V , Dondorp AM , Silamut K , Pongtavornpinyo W , Sahassananda D , Chotivanich K , Pitisuttithum P , Smithyman AM , Day NPJ , 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.
-
11.
Dondorp AM et al., 2005. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2. PLoS Med 2: e204.
-
12.
Lewallen S , Taylor TE , Molyneux ME , Wills BA , Courtright P , 1993. Ocular fundus findings in Malawian children with cerebral malaria. Ophthalmology 100: 857–861.
-
13.
MacCormick IJC , Beare NAV , Taylor TE , Barrera V , White VA , Hiscott P , Molyneux ME , Dhillon B , Harding SP , 2014. Cerebral malaria in children: using the retina to study the brain. Brain 137: 2119–2142.
-
14.
MacCormick IJC , Zhang B , Hill D , Cordeiro MF , Small DS , 2022. A proposed theoretical framework for retinal biomarkers. Alzheimers Dement (Amst) 14: e12327.
-
15.
Milner DA Jr. et al., 2015. Quantitative assessment of multiorgan sequestration of parasites in fatal pediatric cerebral malaria. J Infect Dis 212: 1317–1321.
-
16.
Barrera V et al., 2015. Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of Malawian children with fatal cerebral malaria. J Infect Dis 211: 1977–1986.
-
17.
Small DS , Taylor TE , Postels DG , Beare NAV , Cheng J , MacCormick IJC , Seydel KB , 2017. Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria. eLife 6: e23699.
-
18.
Hendriksen ICE et al., 2012. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med 9: e1001297.
-
19.
Hendriksen ICE et al., 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.
-
20.
Seydel KB , Milner DA , Kamiza SB , Molyneux ME , Taylor TE , 2006. The distribution and intensity of parasite sequestration in comatose Malawian children. J Infect Dis 194: 208–215.
-
21.
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.
-
22.
Dempster AP , Laird NM , Rubin DB , 1977. Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc B 39: 1–22.
-
23.
Scrucca L , Fop M , Murphy TB , Raftery AE , 2016. mclust 5: clustering, classification and density estimation using Gaussian finite mixture models. R J 8: 289.
-
24.
R Core Team , 2018. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Available at: https://www.R-project.org/. Accessed December 2, 2022.
-
25.
Braun H , 1980. A simple method for testing goodness of fit in the presence of nuisance parameters. J R Stat Soc B 42: 53–63.
-
26.
DeLong ER , DeLong DM , Clarke-Pearson DL , 1988. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44: 837–845.
-
27.
Seydel KB et al., 2015. Brain swelling and death in children with cerebral malaria. N Engl J Med 372: 1126–1137.
-
28.
Von Seidlein L et al., 2012. Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial. Clin Infect Dis 54: 1080–1090.
-
29.
Beare NAV , Glover SJ , Molyneux M , 2009. Malarial retinopathy in cerebral malaria. Am J Trop Med Hyg 80: 171.
-
30.
Joshi V , Wigdahl J , Nemeth S , Manda C , Lewallen S , Taylor T , MacCormick I , Harding S , Soliz P , 2018. Automated detection of malarial retinopathy in retinal fundus images obtained in clinical settings. Annu Int Conf IEEE Eng Med Biol Soc 2018: 5950–5953.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 1918 | 1119 | 54 |
| Full Text Views | 405 | 122 | 0 |
| PDF Downloads | 330 | 44 | 0 |