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  • Journal article
    Georgiadou A, Naidu P, Walsh S, Kamiza S, Barrera V, Harding SP, Moxon CA, Cunnington AJet al., 2021,

    Localized release of matrix metallopeptidase 8 in fatal cerebral malaria

    , Clinical & Translational Immunology, Vol: 10, Pages: 1-7, ISSN: 2050-0068

    ObjectiveCerebral malaria (CM) is a complication of Plasmodium falciparum malaria, in which progressive brain swelling is associated with sequestration of parasites and impaired barrier function of the cerebral microvascular endothelium. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in CM, we examined its expression and association with extravascular fibrinogen leak in a case–control study of post‐mortem retinal samples from 13 Malawian children who met the clinical case definition of CM during life. Cases were seven children who were found on post‐mortem examination to have ‘true‐CM’ (parasite sequestration in brain blood vessels), whilst controls were six children who had alternative causes of death (‘faux‐CM’, no parasite sequestration in blood vessels).MethodsWe used immunofluorescence microscopy and independent scoring, by two assessors blinded to the CM status, to assess MMP8 expression, extravascular fibrinogen as an indicator of vascular leak and their co‐localisation in the retinal microvasculature.ResultsIn ‘true‐CM’ subjects, MMP8 staining was invariably associated with sequestered parasites and a median of 88% (IQR = 74–91%) of capillaries showed MMP8 staining, compared with 14% (IQR = 3.8–24%) in ‘faux‐CM’ (P‐value = 0.001). 41% (IQR = 28–49%) of capillaries in ‘true‐CM’ subjects showed co‐localisation of extravascular fibrinogen leak and MMP8 staining, compared with 1.8% of capillaries in ‘faux‐CM’ (IQR = 0–3.9%, P‐value = 0.01). Vascular leak was rare in the absence of MMP8 staining.ConclusionMatrix metallopeptidase 8 was extensively expressed in retinal capillaries of Malawian children with malarial retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 as a cause of the vascular endothelial barrier disruption in CM, which may precip

  • Journal article
    Morang'a CM, Amenga-Etego L, Bah SY, Appiah V, Amuzu DSY, Amoako N, Abugri J, Oduro AR, Cunnington AJ, Awandare GA, Otto TDet al., 2020,

    Machine learning approaches classify clinical malaria outcomes based on haematological parameters

    , BMC Medicine, Vol: 18, ISSN: 1741-7015

    BACKGROUND: Malaria is still a major global health burden, with more than 3.2 billion people in 91 countries remaining at risk of the disease. Accurately distinguishing malaria from other diseases, especially uncomplicated malaria (UM) from non-malarial infections (nMI), remains a challenge. Furthermore, the success of rapid diagnostic tests (RDTs) is threatened by Pfhrp2/3 deletions and decreased sensitivity at low parasitaemia. Analysis of haematological indices can be used to support the identification of possible malaria cases for further diagnosis, especially in travellers returning from endemic areas. As a new application for precision medicine, we aimed to evaluate machine learning (ML) approaches that can accurately classify nMI, UM, and severe malaria (SM) using haematological parameters. METHODS: We obtained haematological data from 2,207 participants collected in Ghana: nMI (n = 978), SM (n = 526), and UM (n = 703). Six different ML approaches were tested, to select the best approach. An artificial neural network (ANN) with three hidden layers was used for multi-classification of UM, SM, and uMI. Binary classifiers were developed to further identify the parameters that can distinguish UM or SM from nMI. Local interpretable model-agnostic explanations (LIME) were used to explain the binary classifiers. RESULTS: The multi-classification model had greater than 85% training and testing accuracy to distinguish clinical malaria from nMI. To distinguish UM from nMI, our approach identified platelet counts, red blood cell (RBC) counts, lymphocyte counts, and percentages as the top classifiers of UM with 0.801 test accuracy (AUC = 0.866 and F1 score = 0.747). To distinguish SM from nMI, the classifier had a test accuracy of 0.96 (AUC = 0.983 and F1 score = 0.944) with mean platelet volume and mean cell volume being the unique classifiers of SM. Random forest was used

  • Journal article
    Thompson H, Hogan A, Walker P, White M, Cunnington A, Ockenhouse C, Ghani Aet al., 2020,

    Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination

    , Vaccine, Vol: 38, Pages: 7498-7507, ISSN: 0264-410X

    Anti-circumsporozoite antibody titres have been established as an essential indicator for evaluating the immunogenicity and protective capacity of the RTS,S/AS01 malaria vaccine. However, a new delayed-fractional dose regime of the vaccine was recently shown to increase vaccine efficacy, from 62.5% (95% CI 29.4–80.1%) under the original dosing schedule to 86.7% (95% CI, 66.8–94.6%) without a corresponding increase in antibody titres. Here we reanalyse the antibody data from this challenge trial to determine whether IgG avidity may help to explain efficacy better than IgG titre alone by adapting a within-host mathematical model of sporozoite inoculation. We demonstrate that a model incorporating titre and avidity provides a substantially better fit to the data than titre alone. These results also suggest that in individuals with a high antibody titre response that also show high avidity (both metrics in the top tercile of observed values) delayed-fractional vaccination provided near perfect protection upon first challenge (98.2% [95% Credible Interval 91.6–99.7%]). This finding suggests that the quality of the vaccine induced antibody response is likely to be an important determinant in the development of highly efficacious pre-erythrocytic vaccines against malaria.

  • Journal article
    Mousa A, Al-Taiar A, Anstey NM, Badaut C, Barber BE, Bassat Q, Challenger J, Cunnington AJ, Datta D, Drakeley C, Ghani AC, Gordeuk VR, Grigg MJ, Hugo P, John CC, Mayor A, Migot-Nabias F, Opoka RO, Pasvol G, Rees C, Reyburn H, Riley EM, Shah BN, Sitoe A, Sutherland CJ, Thuma PE, Unger SA, Viwami F, Walther M, Whitty CJM, William T, Okell LCet al., 2020,

    The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: a systematic review and a pooled multicentre individual-patient meta-analysis

    , PLoS Medicine, Vol: 17, Pages: 1-28, ISSN: 1549-1277

    Background: Delay in receiving treatment for uncomplicated malaria is often reported to increase the risk of developing severe malaria, but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as “test-and-treat” policies administered by community health workers. We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with severe malaria.Methods and Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe P. falciparum malaria which included information on treatment delay, such as fever duration 12(inceptions to 22nd September 2017). Studies identified included five case-control and eight other observational clinical studies of severe and uncomplicated malaria cases. Risk of bias was assessed using the Newcastle–Ottawa scale and all studies were ranked as “Good”, scoring ≥7/10. Individual-patient data were pooled from thirteen studies of 3,989(94.1% aged <15 years)severe malaria patients and 5,780(79.6% aged <15 years)uncomplicated malaria cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen and Zambia. Definitions of severe malaria were standardised across studies to compare treatment delay in patients with uncomplicated malaria and different severe malaria phenotypes using age-adjusted mixed-effects regression. The odds of any severe malaria phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (OR=1.33, 95%CI:1.07-1.64 for a delay of >24 hours vs. ≤24 hours;p=0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children

  • Journal article
    Prah DA, Amoah LE, Gibbins MP, Bediako Y, Cunnington AJ, Awandare GA, Hafalla JCRet al., 2020,

    Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections.

    , Malaria Journal, Vol: 19, Pages: 364-364, ISSN: 1475-2875

    BACKGROUND: The immune mechanisms that determine whether a Plasmodium falciparum infection would be symptomatic or asymptomatic are not fully understood. Several studies have been carried out to characterize the associations between disease outcomes and leucocyte numbers. However, the majority of these studies have been conducted in adults with acute uncomplicated malaria, despite children being the most vulnerable group. METHODS: Peripheral blood leucocyte subpopulations were characterized in children with acute uncomplicated (symptomatic; n = 25) or asymptomatic (n = 67) P. falciparum malaria, as well as malaria-free (uninfected) children (n = 16) from Obom, a sub-district of Accra, Ghana. Leucocyte subpopulations were enumerated by flow cytometry and correlated with two measures of parasite load: (a) plasma levels of P. falciparum histidine-rich protein 2 (PfHRP2) as a proxy for parasite biomass and (b) peripheral blood parasite densities determined by microscopy. RESULTS: In children with symptomatic P. falciparum infections, the proportions and absolute cell counts of total (CD3 +) T cells, CD4 + T cells, CD8 + T cells, CD19 + B cells and CD11c + dendritic cells (DCs) were significantly lower as compared to asymptomatic P. falciparum-infected and uninfected children. Notably, CD15 + neutrophil proportions and cell counts were significantly increased in symptomatic children. There was no significant difference in the proportions and absolute counts of CD14 + monocytes amongst the three study groups. As expected, measures of parasite load were significantly higher in symptomatic cases. Remarkably, PfHRP2 levels and parasite densities negatively correlated with both the proportions and absolute numbers of peripheral leucocyte subsets: CD3 + T, CD4 + T, CD8 + T, CD19 + B, CD56&th

  • 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.

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