Combinations of Host Biomarkers Predict Mortality among Ugandan Children with Severe Malaria: A Retrospective Case-Control Study

Background: Severe malaria is a leading cause of childhood mortality in Africa. However, at presentation, it is difficult to predict which children with severe malaria are at greatest risk of death. Dysregulated host inflammatory responses and endothelial activation play central roles in severe malaria pathogenesis. We hypothesized that biomarkers of these processes would accurately predict outcome among children with severe malaria. Methodology/Findings: Plasma was obtained from children with uncomplicated malaria (n = 53), cerebral malaria (n = 44) and severe malarial anemia (n = 59) at time of presentation to hospital in Kampala, Uganda. Levels of angiopoietin-2, von Willebrand Factor (vWF), vWF propeptide, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble endoglin, soluble FMS-like tyrosine kinase-1 (Flt-1), soluble Tie-2, C-reactive protein, procalcitonin, 10 kDa interferon gamma-induced protein (IP-10), and soluble triggering receptor expressed on myeloid cells-1 (TREM-1) were determined by ELISA. Receiver operating characteristic (ROC) curve analysis was used to assess predictive accuracy of individual biomarkers. Six biomarkers (angiopoietin-2, soluble ICAM-1, soluble Flt-1, procalcitonin, IP-10, soluble TREM-1) discriminated well between children who survived severe malaria infection and those who subsequently died (area under ROC curve>0.7). Combinational approaches were applied in an attempt to improve accuracy. A biomarker score was developed based on dichotomization and summation of the six biomarkers, resulting in 95.7% (95% CI: 78.1-99.9) sensitivity and 88.8% (79.7-94.7) specificity for predicting death. Similar predictive accuracy was achieved with models comprised of 3 biomarkers. Classification tree analysis generated a 3-marker model with 100% sensitivity and 92.5% specificity (cross-validated misclassification rate: 15.4%, standard error 4.9%). Conclusions: We identified novel host biomarkers of pediatric severe and fatal malaria (soluble TREM-1 and soluble Flt-1) and generated simple biomarker combinations that accurately predicted death in an African pediatric population. While requiring validation in further studies, these results suggest the utility of combinatorial biomarker strategies as prognostic tests for severe malaria

Transfusion in sub-Saharan Africa: Blood products, clinical care and community perceptions

Blood transfusion in sub-Saharan Africa (SSA) is a life-saving therapy for patients with severe anemia and acute hemorrhage. Access to transfusion is a national healthcare priority. Gaps in blood supply are related to several factors including the high prevalence of transfusion-transmissible infections (TTIs), insufficient inventory, and community participation as blood donors. This thesis documents blood utilization in SSA, explores ways to improve blood safety, highlights transfusion monitoring, and describes community perceptions regarding transfusion. Transfusion in SSA is primarily used for pediatric malaria, sickle cell anemia, and obstetric hemorrhage. Most transfusion is either packed red cells (RBC, 58.5%) or whole blood (31.7%). Current blood safety strategies focus on TTIs, but hemovigilance programs with increased attention to proper blood utilization are also needed. Our research found that RBC storage duration did not influence the efficacy of oxygen delivery by transfusion as measured by lactate clearance and by cerebral tissue oxygenation. For SSA where blood is in short supply, our findings validate use of full expiry dates to improve inventory management. Recurrent severe anemia (RSA) is a major cause of morbidity and mortality for children after hospital discharge. Strategies to reduce RSA should address its risk factors, such as un-diagnosed sickle cell anemia and malaria. Community perceptions of transfusion are important because they influence healthcare seeking. In Uganda, community members hold blood transfusion in high regard but addressing perceived risks may further improve acceptance of transfusion services. In summary, this thesis investigates the principal routes for improving access to safe transfusion in SSA

Estimating the burden of severe malarial anaemia and access to hospital care in East Africa

Severe malarial anaemia can be fatal if not promptly treated. Hospital studies may under-represent the true burden because cases often occur in settings with poor access to healthcare. We estimate the relationship of community prevalence of malaria infection and severe malarial anaemia with the incidence of severe malarial anaemia cases in hospital, using survey data from 21 countries and hospital data from Kenya, Tanzania and Uganda. The estimated percentage of severe malarial anaemia cases that were hospitalised is low and consistent for Kenya (21% (95% CrI: 7%, 47%)), Tanzania (18% (95% CrI: 5%, 52%)) and Uganda (23% (95% CrI: 9%, 48%)). The majority of severe malarial anaemia cases remain in the community, with the consequent public health burden being contingent upon the severity of these cases. Alongside health system strengthening, research to better understand the spectrum of disease associated with severe malarial anaemia cases in the community is a priority

Tuberculosis in human immunodeficiency virus infected Ugandan children starting on antiretroviral therapy

OBJECTIVE: To identify the incidence of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children in a resource-limited setting before and after initiation of antiretroviral therapy (ART), and to assess the impact of TB screening by tuberculin skin testing and clinical history. METHODS: A retrospective cohort study of 1806 HIV-infected children and adolescents (age <18 years) initiating ART from 2003 to 1 July 2006 in Kampala, Uganda. A TB screening program was instituted clinic-wide in January 2006. RESULTS: Of 311 (17.2%) HIV-infected children, 171 had been diagnosed with TB before and 140 after ART initiation. During the first 100 days of ART, risk of a new TB diagnosis was 2.7-fold higher compared to the pre-ART period (RR 2.7, 95%CI 2.1-3.5, P < 0.001). After 100 days of ART, the TB incidence rate decreased to below pre-ART levels (RR 0.41, 95%CI 0.30-0.54, P = 0.002). After TB screening was instituted in 2006, the proportion of new TB cases diagnosed after starting ART decreased by 70% (95%CI 51-82, P < 0.001), abating the early excess risk. CONCLUSIONS: TB is common among African children and adolescents initiating ART in sub-Saharan Africa. More aggressive screening for active TB before starting ART can diminish the rate of TB during immune reconstitution. Future studies are needed to determine optimal screening practices for HIV-infected children

Tuberculosis in human immunodeficiency virus infected Ugandan children starting on antiretroviral therapy

This article argues that in the first verse of Catullus’ epigram 85, the commonly found translation of quare as ‘why’ in English versions since the 17th century, but particularly in translations produced in the last fifty years, cannot be accepted. In the context of Catullus’s poetry, with poems 72 and 75 offering an explicit background to and rationale for the contradiction in the poet’s feelings between love and hate, and in the light of the incontrovertible connotation of quare (or qua re) as ‘how’ in a passage of Terence’s Eunuchus, the correct translation of the word can only be ‘how’. Some suggestions are made to account for the origins and the persistence of the mistranslation. The translation as ‘why’ in the prose version in the 1912 Loeb edition edited by F.W.Cornish is suggested to have influenced a generation of English-speaking students, and Martial’s epigram 1.32 is invoked as a cause. But it is further argued that in taking Catullus’s epigram as a model for his own, Martial may have expressly intended to suggest that the meaning of quare as ‘why’ that was current in his time was different in that very respect from the connotation ‘how’ clearly intended by his predecessor