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  • Journal article
    Patel H, Dunican C, Cunnington A, 2020,

    Predictors of outcome in childhood Plasmodium falciparum malaria

    , Virulence, Vol: 11, Pages: 199-221, ISSN: 2150-5594

    Plasmodium falciparum malaria is classified as either uncomplicated or severe, determining clinical management and providing a framework for understanding pathogenesis. Severe malaria in children is defined by the presence of one or more features associated with adverse outcome, but there is wide variation in the predictive value of these features. Here we review the evidence for the usefulness of these features, alone and in combination, to predict death and other adverse outcomes, and we consider the role that molecular biomarkers may play in augmenting this prediction. We also examine whether a more personalized approach to predicting outcome for specific presenting syndromes of severe malaria, particularly cerebral malaria, has the potential to be more accurate. We note a general need for better external validation in studies of outcome predictors and for the demonstration that predictors can be used to guide clinical management in a way that improves survival and long-term health.

  • Journal article
    Georgiadou A, Cunnington AJ, 2019,

    Shedding of the vascular endothelial glycocalyx - a common pathway to severe malaria?

    , Clinical Infectious Diseases, Vol: 69, Pages: 1721-1723, ISSN: 1058-4838
  • Journal article
    Charani E, Cunnington AJ, Yousif AHA, Ahmed MS, Ahmed AEM, Babiker S, Bedri S, Buytaert W, Crawford MA, Elbashir MI, Elhag K, Elsiddig KE, Hakim N, Johnson MR, Miras AD, Swar MO, Templeton MR, Taylor-Robinson SDet al., 2019,

    In transition: current health challenges and priorities in Sudan

    , BMJ Global Health, Vol: 4:e001723, ISSN: 2059-7908

    A recent symposium and workshop in Khartoum, the capital of the Republic of Sudan, brought together broad expertise from three universities to address the current burden of communicable and non-communicable diseases facing the Sudanese healthcare system. These meetings identified common challenges that impact the burden of diseases in the country, most notably gaps in data and infrastructure which are essential to inform and deliver effective interventions. Non-communicable diseases, including obesity, type 2 diabetes, renal disease and cancer are increasing dramatically, contributing to multimorbidity. At the same time, progress against communicable diseases has been slow, and the burden of chronic and endemic infections remains considerable, with parasitic diseases (such as malaria, leishmaniasis and schistosomiasis) causing substantial morbidity and mortality. Antimicrobial resistance has become a major threat throughout the healthcare system, with an emerging impact on maternal, neonatal, and paediatric populations. Meanwhile, malnutrition, micronutrient deficiency, and poor perinatal outcomes remain common and contribute to a lifelong burden of disease. These challenges echo the UN sustainable development goals and concentrating on them in a unified strategy will be necessary to address the national burden of disease. At a time when the country is going through societal and political transition, we draw focus on the country and the need for resolution of its healthcare needs.

  • Journal article
    Georgiadou A, Lee HJ, Walther M, van Beek A, Fitriani F, Wouters D, Kuijpers T, Nwakanma D, D'Alessandro U, Riley E, Otto T, Ghani A, Levin M, Coin L, Conway D, Bretscher M, Cunnington Aet al., 2019,

    Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions

    , Nature Microbiology, Vol: 4, Pages: 1592-1602, ISSN: 2058-5276

    During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of mechanisms of disease and protection. We sought to model the contributions of parasite multiplication rate and host response to observed parasite load in individual subjects with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in severe malaria cases, with severe anemia being more insidious than cerebral malaria. We predicted that parasite growth-inhibition was associated with platelet consumption, lower expression of CXCL10 and type-1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. Parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.

  • Journal article
    van Beek AE, Sarr I, Correa S, Nwakanma D, Brouwer MC, Wouters D, Secka F, Anderson STB, Conway DJ, Walther M, Levin M, Kuijpers TW, Cunnington AJet al., 2018,

    Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity.

    , Open Forum Infect Dis, Vol: 5, ISSN: 2328-8957

    Background: Plasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity. Methods: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity. Results: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load. Conclusions: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.

  • Journal article
    Lee HJ, Georgiadou A, Walther M, Nwakanma D, Stewart L, Levin M, Otto T, Conway D, Coin L, Cunnington Aet al., 2018,

    Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria

    , Science Translational Medicine, Vol: 10, ISSN: 1946-6234

    The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here we performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule-related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Co-expression analyses revealed interactions between human and P. falciparum, with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ related genes, together with inadequate suppression of type-1 interferon signalling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying targets for adjunctive therapy.

  • Journal article
    Grimes JET, Tadesse G, Mekete K, Wuletaw Y, Gebretsadik A, French MD, Harrison WE, Drake LJ, Gardiner IA, Yard E, Templeton MRet al., 2016,

    School water, sanitation, and hygiene, soil-transmitted helminths, and schistosomes: national mapping in Ethiopia

    , PLOS Neglected Tropical Diseases, Vol: 10:e0004515, ISSN: 1935-2735
  • Journal article
    Opi DH, Uyoga S, Orori EN, Williams TN, Rowe JAet al., 2016,

    Red blood cell complement receptor one level varies with Knops blood group, α+thalassaemia and age among Kenyan children

    , Genes and Immunity, Vol: 17, Pages: 171-178, ISSN: 1476-5470

    Both the invasion of red blood cells (RBCs) by Plasmodium falciparum parasites and the sequestration of parasite-infected RBCs in the microvasculature are mediated in part by complement receptor one (CR1). RBC surface CR1 level can vary between individuals by more than 20-fold and may be associated with the risk of severe malaria. The factors that influence RBC CR1 level variation are poorly understood, particularly in African populations. We studied 3535 child residents of a malaria-endemic region of coastal Kenya and report, for the first time, that the CR1 Knops blood group alleles Sl2 and McCb, and homozygous HbSS are positively associated with RBC CR1 level. Sickle cell trait and ABO blood group did not influence RBC CR1 level. We also confirm the previous observation that α+thalassaemia is associated with reduced RBC CR1 level, possibly due to small RBC volume, and that age-related changes in RBC CR1 expression occur throughout childhood. RBC CR1 level in malaria-endemic African populations is a complex phenotype influenced by multiple factors that should be taken into account in the design and interpretation of future studies on CR1 and malaria susceptibility.

  • Journal article
    Seale AC, Davies MR, Anampiu K, Morpeth SC, Nyongesa S, Mwarumba S, Smeesters PR, Efstratiou A, Karugutu R, Mturi N, Williams TN, Scott JAG, Kariuki S, Dougan G, Berkley JAet al., 2016,

    Invasive group A Streptococcus amongst children in rural Kenya

    , Emerging Infectious Diseases, Vol: 22, Pages: 224-232, ISSN: 1080-6059

    There are minimal data on the burden of Streptococcus pyogenes (group A Streptococcus; GAS) in sub-Saharan Africa and none on serotypes causing disease. We analyzed systematically collected clinical and microbiological surveillance data from 64,741 hospital admissions in Kilifi, Kenya (1998-2011), to describe incidence, clinical presentations and emm-types of invasive GAS (iGAS). There were 370 cases; commonly skin and soft tissue infections (258/369,70%), severe pneumonia (86/369,23%), and primary bacteremia (53/369,14%); overall case fatality risk was 45/369 (12%). Incidence of iGAS was, in neonates 0.6/1000 live-births; <1 year 101/100,000, and <5 years 35/100,000. Using genome sequencing, 88 different emm-types were observed, highlighting extensive circulating GAS heterogeneity. GAS is an important cause of serious bacterial disease in this setting, especially in neonates, with considerable genotypic diversity. There may be limited benefit from the most advanced GAS type-specific vaccines and efforts must be directed to protect against disease in high burden regions.

  • Journal article
    Williams TN, 2016,

    Sickle cell disease in Sub-Saharan Africa

    , Hematology/Oncology Clinics of North America, Vol: 30, Pages: 343-358, ISSN: 1558-1977

    In Africa, at least 240,000 children are born each year with sickle cell disease. Historically, in the absence of newborn screening and appropriate treatment, most such children died undiagnosed in early childhood. However, with increasing awareness of the condition and economic and epidemiologic transition, increasing numbers are surviving. Greater investments in basic and applied research in the African context, and increased sensitization or African ministries of health regarding the importance of this condition, could make a substantial difference to the lives and livelihoods of millions of people living with sickle cell disease on the continent and their families.

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