title: Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection.
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 HIV-uninfected 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. IMPORTANCE : There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV(+)) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV(+) than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV(+) children. Our findings raise the possibility that HIV(+) children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hochman
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Theresa F
authors.initials: TF
authors.lastname: Madaline
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA Department of Pathology, Sydney Medical School, University of Sydney, Camperdown, Australia.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wassmer
authors.affiliation: Department of Paediatrics and Child Health, University of Malawi College of Medicine, Blantyre, Malawi Malawi-Liverpool-Wellcome Trust Clinical Research Program, Blantyre, Malawi.
authors.forename: Emmie
authors.initials: E
authors.lastname: Mbale
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Namjong
authors.initials: N
authors.lastname: Choi
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Seydel
authors.affiliation: CellNetix Pathology and Laboratories, Olympia, Washington, USA.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Whitten
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Varughese
authors.affiliation: Department of Pathology, Sydney Medical School, University of Sydney, Camperdown, Australia.
authors.forename: Georges E R
authors.initials: GE
authors.lastname: Grau
authors.affiliation: Department of Histopathology, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Steve
authors.initials: S
authors.lastname: Kamiza
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Program, Blantyre, Malawi Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA kami.kim@einstein.yu.edu.
authors.forename: Kami
authors.initials: K
authors.lastname: Kim
mesh_terms: D001792:Blood Platelets; D001921:Brain / Q000473:pathology*; D060085:Coinfection / Q000401:mortality / Q000473:pathology; D015658:HIV Infections / Q000150:complications* / Q000473:pathology*; D006801:Humans; D016779:Malaria, Cerebral / Q000453:epidemiology* / Q000401:mortality / Q000473:pathology*; D008295:Malawi / Q000453:epidemiology; D009000:Monocytes; D016019:Survival Analysis