Value of Plasmodium falciparum histidine-rich protein 2 level and malaria retinopathy in distinguishing cerebral malaria from other acute encephalopathies in Kenyan children

Abstract

Background: The diagnosis of cerebral malaria is problematic in malaria-endemic areas because encephalopathy in patients with parasitemia may have another cause. Abnormal retinal findings are thought to increase the specificity of the diagnosis, and the level of histidine-rich protein 2 (HRP2) may reflect the parasite biomass.

Methods: We examined the retina and measured plasma HRP2 levels in children with acute nontraumatic encephalopathy in Kenya. Logistic regression, with HRP2 level as an independent variable and World Health Organization-defined cerebral malaria and/or retinopathy as the outcome, was used to calculate malaria-attributable fractions (MAFs) and retinopathy-attributable fractions (RAFs).

Results: Of 270 children, 140 (52%) had peripheral parasitemia, 80 (30%) had malaria retinopathy, and 164 (61%) had an HRP2 level of >0 U/mL. During 2006-2011, the incidence of HRP2 positivity among admitted children declined by 49 cases per 100 000 per year (a 78% reduction). An HRP2 level of >0 U/mL had a MAF of 93% for cerebral malaria, with a MAF of 97% observed for HRP2 levels of ≥ 10 U/mL (the level of the best combined sensitivity and specificity). HRP2 levels of >0 U/mL had a RAF of 77% for features of retinopathy combined, with the highest RAFs for macular whitening (99%), peripheral whitening (98%), and hemorrhages (90%).

Conclusion: HRP2 has a high attributable fraction for features of malarial retinopathy, supporting its use in the diagnosis of cerebral malaria. HRP2 thresholds improve the specificity of the definition.

Keywords: attributable fractions; cerebral malaria; children; histidine-rich protein-2; malaria retinopathy.

Figure 1.

Flowchart of slide-positive, histidine-rich protein 2 (HRP2) positivity and retinopathy positivity among children admitted with encephalopathy. Parasitemia and malaria retinopathy were examined on the day of admission, whereas assays of HRP2 were done in the last year of the study.

Figure 2.

The median and distribution of histidine-rich protein 2 (HRP2) levels among admitted children with acute encephalopathy, by malaria and/or retinopathy status, and the sensitivities and specificities associated with HRP2 levels among admitted children with World Health Organization–defined cerebral malaria. The median levels of HRP2 were significantly higher among children with than among those without a slide positive for malaria parasites, and levels were higher among children with than among those without retinopathy. Sensitivities worsened with higher levels of HRP2, whereas specificities improved.

Figure 3.

Sensitivity and specificity of malaria-attributable fractions for children admitted with encephalopathy, by histidine-rich protein 2 (HRP2) level. MAFs were first determined at HRP2 levels of >0 U/mL and then at HRP2 levels with the best combined sensitivity and specificity.

Figure 4.

The declining incidence of histidine-rich protein 2 (HRP2) positivity among children admitted with coma during a period when the malaria incidence had declined. The incidence was calculated for children who lived in the Kilifi Health Demographic Surveillance System, using the annual midyear populations of children as the denominators.