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Role of HIV-1 and Bacteremia Co-infection in Promoting Inflammatory Mediator production in Kenyan Children with Severe Malarial Anemia

Davenport, Gregory Charles (2010) Role of HIV-1 and Bacteremia Co-infection in Promoting Inflammatory Mediator production in Kenyan Children with Severe Malarial Anemia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Severe anemia is the primary outcome of childhood malaria in holoendemic malaria transmission regions such as western Kenya. HIV-1 and bacteremia are equally important diseases in Kenyan children. Anemia is also the hallmark trait of pediatric HIV-1 infection, and despite our previous reports of exacerbated anemia in malaria/HIV-1 co-infected childrena, we also observed significantly lower parasitemias without worsening anemia in malaria/bacteremia co-infected children. Abundant production of pro-inflammatory cytokines is known to adversely affect erythropoiesis and is common to malaria, HIV-1, and bacteremia. As such, we performed a comprehensive bead-based 25-plex Multiplex assay to identify cytokines patterns and profiles associated with negative and positive hematolgic outcomes in co-infected children. Children in Aims 1 and 2 infected with P. falciparum malaria (Pf[+], aged 3-36 mos., n=542) were stratified into three groups: HIV-1 negative (HIV-1[-]/Pf[+]); HIV-1 exposed (HIV-1[exp]/Pf[+]); and HIV-1 infected (HIV-1[+]/Pf[+]). In Aim 3, malaria and bacteremia co-infected children (n=192) were divided into three categories: malaria alone, Pf[+]; Gram negative bacteremia/malaria co-infected, G[-]/Pf[+]; and Gram positive bacteremia/malaria co-infected, G[+]/Pf[+]. Univariate, correlational, and hierarchical regression analyses were used to determine differences among the groups and to define predictors of worsening anemia. Aim 1 analyses revealed HIV-1[+]/Pf[+] children had significantly more malarial pigment-containing neutrophils (PCN), monocytosis, increased severe anemia (Hb<6.0g/dL), and ~10-fold greater mortality. Hierarchical multiple regression revealed that worsening anemia was associated with elevated pigment-containing monocytes, younger age, and increasing HIV-1 status (HIV-1[-]→HIV-1[exp]→HIV-1[+]). Aim 2, addressing the inflammatory milieu, demonstrated that exacerbated anemia was associated with inflammatory mediator (IM) dysregulation, but not parasitemic or erythropoietic indices. A principal component analysis revealed that IL-12 was the most influential variable on Hb levels in HIV-1[+]/Pf[+] children, while the IL-1β:IL-10 ratio was most influenced by PCN. In Aim 3, both bacteremia co-infected groups had lower parasitemia compared to the Pf[+] group. A multiple mediation model examining IMs responsible for decreased parasitemia in the bacteremia co-infected groups identified IL-4, IL-10, IL-12, and IFN-γ as the key molecules in decreasing parasitemia. Thus, malaria/HIV-1 co-infection is defined by significantly enhanced anemia that is associated with unique IM profiles known to exacerbate anemia, while enhanced immune activation in malaria/bacteremia co-infected children appears to promote reduced parasitemia without adversely affecting anemia outcomes. By defining the inflammatory milieu associated with severe anemia, therapies can be developed to mitigate detrimental immune responses, thereby lessening the pediatric public health burden in western Kenya.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Davenport, Gregory Charlesgreg.davenport@yahoo.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReinhart, Todd Areinhar@pitt.eduREINHAR
Committee CoChairPerkins, Douglas Jdperkins@salud.unm.edu
Committee MemberNorris, Karen Akan1@pitt.eduKAN1
Committee MemberWadowsky, Robert WRobert.Wadowsky@chp.edu
Committee MemberWang, Tianyitywang@pitt.eduTYWANG
Date: 28 September 2010
Date Type: Completion
Defense Date: 19 April 2010
Approval Date: 28 September 2010
Submission Date: 26 July 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: anemia; bacteremia; cytokines; inflammatory mediators; malaria; chemokines; sepsis; HIV
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07262010-170719/, etd-07262010-170719
Date Deposited: 10 Nov 2011 19:54
Last Modified: 15 Nov 2016 13:47
URI: http://d-scholarship.pitt.edu/id/eprint/8630

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