Fatal pediatric cerebral malaria is associated with intravascular monocytes and platelets that are increased with HIV coinfection

Sarah E. Hochman, Theresa F. Madaline, Samuel C. Wassmer, Emmie Mbale, Namjong Choi, Karl B. Seydel, Richard O. Whitten, Julie Varughese, Georges E.R. Grau, Steve Kamiza, Malcolm E. Molyneux, Terrie E. Taylor, Sunhee Lee, Danny A. Milner, Kami Kima

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P<0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P=0.0178, chi-square test). HIV-infected (HIV+) children with autopsy-confirmed CM were older than HIVuninfected children (median age, 99 months versus 32 months, P=0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV+ and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV+ children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV+ children exacerbates the pathological features associated with CM.

Original languageEnglish (US)
Article numbere01390-15
JournalmBio
Volume6
Issue number5
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Microbiology
  • Virology

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    Hochman, S. E., Madaline, T. F., Wassmer, S. C., Mbale, E., Choi, N., Seydel, K. B., Whitten, R. O., Varughese, J., Grau, G. E. R., Kamiza, S., Molyneux, M. E., Taylor, T. E., Lee, S., Milner, D. A., & Kima, K. (2015). Fatal pediatric cerebral malaria is associated with intravascular monocytes and platelets that are increased with HIV coinfection. mBio, 6(5), [e01390-15]. https://doi.org/10.1128/mBio.01390-15