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 hos...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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 Kim
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5189f1d3b89541a3baa1c8eae4df4826
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5189f1d3b89541a3baa1c8eae4df4826
record_format	dspace
spelling	oai:doaj.org-article:5189f1d3b89541a3baa1c8eae4df48262021-11-15T15:41:31ZFatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection10.1128/mBio.01390-152150-7511https://doaj.org/article/5189f1d3b89541a3baa1c8eae4df48262015-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01390-15https://doaj.org/toc/2150-7511ABSTRACT 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.Sarah E. HochmanTheresa F. MadalineSamuel C. WassmerEmmie MbaleNamjong ChoiKarl B. SeydelRichard O. WhittenJulie VarugheseGeorges E. R. GrauSteve KamizaMalcolm E. MolyneuxTerrie E. TaylorSunhee LeeDanny A. MilnerKami KimAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 5 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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 Kim Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection
description	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.
format	article
author	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 Kim
author_facet	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 Kim
author_sort	Sarah E. Hochman
title	Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection
title_short	Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection
title_full	Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection
title_fullStr	Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection
title_full_unstemmed	Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection
title_sort	fatal pediatric cerebral malaria is associated with intravascular monocytes and platelets that are increased with hiv coinfection
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/5189f1d3b89541a3baa1c8eae4df4826
work_keys_str_mv	AT sarahehochman fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT theresafmadaline fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT samuelcwassmer fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT emmiembale fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT namjongchoi fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT karlbseydel fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT richardowhitten fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT julievarughese fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT georgesergrau fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT stevekamiza fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT malcolmemolyneux fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT terrieetaylor fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT sunheelee fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT dannyamilner fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection AT kamikim fatalpediatriccerebralmalariaisassociatedwithintravascularmonocytesandplateletsthatareincreasedwithhivcoinfection
_version_	1718427703116300288

Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection

Ejemplares similares