Severe childhood malaria syndromes defined by plasma proteome profiles

BACKGROUND Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore it is important to understand the pathology underlying the development of CM and SMA, as opposed to uncomplicated malaria (UM). Different host responses to infection are likely to be reflected in plasma proteome-patterns that associate with clinical status and therefore provide indicators of the pathogenesis of these syndromes. METHODS AND FINDINGS Plasma and comprehensive clinical data for discovery and validation cohorts were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, an urban and densely populated holoendemic malaria area in Nigeria. A total of 946 children participated in this study. Plasma was subjected to high-throughput proteomic profiling. Statistical pattern-recognition methods were used to find proteome-patterns that defined disease groups. Plasma proteome-patterns accurately distinguished children with CM and with SMA from those with UM, and from healthy or severely ill malaria-negative children. CONCLUSIONS We report that an accurate definition of the major childhood malaria syndromes can be achieved using plasma proteome-patterns. Our proteomic data can be exploited to understand the pathogenesis of the different childhood severe malaria syndromes

Prevalence and clinical pattern of paediatric HIV infection at the University College Hospital, Ibadan, Nigeria: a prospective cross-sectional study

Abstract Background The prevalence of Paediatric HIV infection is largely unknown in many countries in sub-Saharan Africa. This study was aimed at determining the prevalence, clinical pattern of HIV infection and outcome among new patients aged Methods A prospective cross sectional study was carried out using the provider initiated HIV testing and counselling (PITC) model. HIV rapid test in parallel was used for screening and confirmation was with HIV DNA PCR in children Results A total of 600 children were enrolled with ages ranging between one day and 179 months. Male: female ratio was 1.2:1. HIV seroprevalence was 12.3% and after confirmatory tests, the prevalence was 10%. Fourteen (37.8%) of the children aged less 18 months were exposed but not infected. Mother-to-child transmission accounted for 93.3% of cases. Features predictive of HIV infection were diarrhoea, cough, weight loss, ear discharge generalized lymphadenopathy, presence of skin lesions, parotid swelling and oral thrush. About 75% presented in advanced or severe clinical stages of the disease, 56.8% had severe immunodeficiency while 50% had viral loads more than 100,000 copies/ml. Mortality rate was 14.3% among HIV positive compared with 11.3% in HIV negative children but was not significant. Among the HIV positive children, 26.7% were orphans. Conclusions The prevalence rate of HIV infection among new patients screened using the PITC model was high, majority resulting from mother-to-child transmission. Most children presented in advanced stages of the disease and mortality rate among them was high. Though, the study site being a referral centre might have contributed to the high prevalence observed in this study, there is a need to expand access to PMTCT services, ensure implementation of PITC in paediatric settings and expand support services for HIV infected children.</p

Blood Transfusion–Associated HIV Infection in Children in Ibadan, Nigeria

Introduction: This study describes the epidemiologic features and clinical course of children with blood transfusion-associated HIV infection (TAHI) in Ibadan, Nigeria. Methodology: All children diagnosed to have TAHI at the University College Hospital, Ibadan, were studied and compared with children who acquired HIV vertically using the pediatric HIV database in the hospital. Results: Transfusion-associated HIV infection accounted for 14 (2.3%) of the 597 children diagnosed to have HIV infection between January 2004 and December 2011. The mean age at diagnosis of TAHI was 10.2 years and that of vertically acquired HIV infection was 3.9 years ( P < .001). In 9 cases, blood transfusion took place in private hospitals and in 5 cases in public hospitals. Median interval between infection and diagnosis of AIDS was 84 months in cases with TAHI and 48 months in vertically acquired cases ( P = .542). Conclusion: Optimal blood safety practices are advocated for prevention of TAHI in Nigeria

Circulatory hepcidin is associated with the anti-inflammatory response but not with iron or anemic status in childhood malaria

Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore, it is important to understand the pathology underlying the development of CM and SMA as opposed to uncomplicated malaria (UM). Increased levels of hepcidin have been associated with UM, but its level and role in severe malarial disease remains to be investigated. Plasma and clinical data were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, Nigeria. Here, we report that hepcidin levels are lower in children with SMA or CM than in those with milder outcome (UM). While different profiles of pro- and anti-inflammatory cytokines were observed between the malaria syndromes, circulatory hepcidin levels remained associated with the levels of its regulatory cytokine interleukin-6 and of the anti-inflammatory cytokine inerleukin-10, irrespective of iron status, anemic status, and general acute-phase response. We propose a role for hepcidin in anti-inflammatory processes in childhood malaria

Discriminatory performance of proteome profiles across study groups in ROC space.

<p>CM = Cerebral Malaria; SMA = Severe Malarial Anemia; UM = Uncomplicated Malaria; DC = Disease Controls; CC = Community Controls. (a.) Discriminatory performance in ROC space of predictive models built with relevant m/z clusters using the discovery cohort data. Error bars indicate +/− standard deviations obtained by 100 train/test randomizations of the data. (b.) Discriminatory performance in ROC space of the best predictive model from (a.) when applied to the validation cohort data.</p

Visualization of (a-c) disease control (DC, non-parasitemic) children <i>versus</i> parasitemic children groups; (d-f) among CM, SMA and UM parasitaemic children groups.

<p>Each sphere represents an individual child proteome profile plotted in 3D space defined by the first three principal components. CM = Cerebral Malaria (red); SMA = Severe Malarial Anemia (purple); UM = Uncomplicated Malaria (yellow); DC = Disease Controls (blue). (a.) DC vs. CM; (b.) DC vs. SMA; (c.) DC vs. UM; (d.) CM vs. SMA; (e.) CM vs. UM and (f.) SMA vs. UM.</p

Discriminatory accuracy of proteome profiles across six anionic plasma fractions (f1 to f6) among CM, SMA and UM (all parasitemic) groups of children.

<p>CM = Cerebral Malaria; SMA = Severe Malarial Anemia; UM = Uncomplicated Malaria. f1 to f6 represent anionic plasma fractions at pH 9.0 (f1), pH 7.0 (f2), pH 5.0 (f3), pH 4.0 (f4), pH 3.0 (f5) and organic phase (f6). In brackets are shown the number of relevant m/z clusters that make up the discriminatory proteome profile. (a.) CM vs. SMA; (b.) CM vs. UM; (c.) SMA vs. UM.</p