Publications
107 results found
Andradi-Brown C, Wichers-Misterek JS, von Thien H, et al., 2023, A novel computational pipeline for var gene expression augments the discovery of changes in the Plasmodium falciparum transcriptome during transition from in vivo to short-term in vitro culture, eLife, Vol: 12
The pathogenesis of severe Plasmodium falciparum malaria involves cytoadhesive microvascular sequestration of infected erythrocytes, mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 variants are encoded by the highly polymorphic family of var genes, the sequences of which are largely unknown in clinical samples. Previously, we published new approaches for var gene profiling and classification of predicted binding phenotypes in clinical P. falciparum isolates (Wichers et al., 2021), which represented a major technical advance. Building on this, we report here a novel method for var gene assembly and multidimensional quantification from RNA-sequencing that even outperforms the earlier approach of (Wichers et al., 2021) on both laboratory and clinical isolates across a combination of metrics. It is a powerful tool to interrogate the var transcriptome in context with the rest of the transcriptome and can be applied to enhance our understanding of the role of var genes in malaria pathogenesis. We applied this new method to investigate changes in var gene expression through early transition to in vitro culture, using paired sets of ex vivo samples from our previous study, cultured for up to three generations. In parallel, changes in non-polymorphic core gene expression were investigated. Unpredictable var gene switching and convergence towards var2csa were observed in culture, along with differential expression of 19% of the core transcriptome between paired ex vivo and generation 1 samples. Our results cast doubt on the validity of the common practice of using short-term cultured parasites to make inferences about in vivo phenotype and behaviour.
Dewez JE, Pembrey L, Nijman RG, et al., 2022, Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians., PLoS One, Vol: 17, Pages: 1-22, ISSN: 1932-6203
BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicia
Hamilton F, Mitchell R, Cunnington A, et al., 2022, HMOX1 STR polymorphism and malaria: an analysis of a large clinical dataset, Malaria Journal, Vol: 21, Pages: 1-9, ISSN: 1475-2875
BackgroundInducible expression of heme oxygenase-1 (encoded by the gene HMOX1) may determine protection from heme released during malaria infections. A variable length, short tandem GT(n) repeat (STR) in HMOX1 that may influence gene expression has been associated with outcomes of human malaria in some studies. In this study, an analysis of the association between variation at the STR in HMOX1 on severe malaria and severe malaria subtypes is presented in a large, prospectively collected dataset (MalariaGEN).MethodsThe HMOX1 STR was imputed using a recently developed reference haplotype panel designed for STRs. The STR was classified by total length and split into three alleles based on an observed trimodal distribution of repeat lengths. Logistic regression was used to assess the association between this repeat on cases of severe malaria and severe malaria subtypes (cerebral malaria and severe malarial anaemia). Individual analyses were performed for each MalariaGEN collection site and combined for meta-analysis. One site (Kenya), had detailed clinical metadata, allowing the assessment of the effect of the STR on clinical variables (e.g. parasite count, platelet count) and regression analyses were performed to investigate whether the STR interacted with any clinical variables.ResultsData from 17,960 participants across 11 collection sites were analysed. In logistic regression, there was no strong evidence of association between STR length and severe malaria (Odds Ratio, OR: 0.96, 95% confidence intervals 0.91–1.02 per ten GT(n) repeats), although there did appear to be an association at some sites (e.g., Kenya, OR 0.90, 95% CI 0.82–0.99). There was no evidence of an interaction with any clinical variables.ConclusionsMeta-analysis suggested that increasing HMOX1 STR length is unlikely to be reliably associated with severe malaria. It cannot be ruled out that repeat length may alter risk in specific populations, although whether this is due to chance varia
Tan CD, van der Walle EEPL, Vermont CL, et al., 2022, Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4199-4209, ISSN: 0340-6199
Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0-18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0-2.3). Management per ED varied as follows: use of diagnostic tests 14-83%, antibiotic treatment 23-54%, admission 34-86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0-38%), partial adherence occurred in 56% (484/868, range 35-77%). CONCLUSION: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. WHAT IS KNOWN: • Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. • There is practice variation in management of young febrile children due to differences in guideline
Najer A, Blight J, Ducker CB, et al., 2022, Potent virustatic polymer-lipid nanomimics block viral entry and inhibit malaria parasites in vivo, ACS Central Science, Vol: 8, Pages: 1238-1257, ISSN: 2374-7943
Infectious diseases continue to pose a substantial burden on global populations, requiring innovative broad-spectrum prophylactic and treatment alternatives. Here, we have designed modular synthetic polymer nanoparticles that mimic functional components of host cell membranes, yielding multivalent nanomimics that act by directly binding to varied pathogens. Nanomimic blood circulation time was prolonged by reformulating polymer–lipid hybrids. Femtomolar concentrations of the polymer nanomimics were sufficient to inhibit herpes simplex virus type 2 (HSV-2) entry into epithelial cells, while higher doses were needed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given their observed virustatic mode of action, the nanomimics were also tested with malaria parasite blood-stage merozoites, which lose their invasive capacity after a few minutes. Efficient inhibition of merozoite invasion of red blood cells was demonstrated both in vitro and in vivo using a preclinical rodent malaria model. We envision these nanomimics forming an adaptable platform for developing pathogen entry inhibitors and as immunomodulators, wherein nanomimic-inhibited pathogens can be secondarily targeted to sites of immune recognition.
Malpartida-Cardenas K, Baum J, Cunnington A, et al., 2022, Electricity-free nucleic acid extraction method from dried blood spots on filter paper for point-of-care diagnostics
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Nucleic acid extraction is a crucial step for molecular biology applications, being a determinant for any diagnostic test procedure. Dried blood spots (DBS) have been used for decades for serology, drug monitoring, environmental investigations, and molecular studies. Nevertheless, nucleic acid extraction from DBS remains one of the main challenges to translate them to the point-of-care (POC).</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We have developed a fast nucleic acid extraction (NAE) method from DBS which is electricity-free and relies on cellulose filter papers (DBSFP). The performance of NAE was assessed with loop-mediated isothermal amplification (LAMP), targeting the human reference gene beta-actin. The developed method was evaluated against FTA cards and magnetic bead-based purification, using time-to-positive (min) for comparative analysis. We optimised and validated the developed method for elution (<jats:italic>eluted disk</jats:italic>) and disk directly in the reaction (<jats:italic>in-situ disk)</jats:italic>, RNA and DNA detection, and whole blood stored in anticoagulants (K<jats:sub>2</jats:sub>EDTA and lithium heparin). Furthermore, the compatibility of DBSFP with colourimetric detection was studied to show the transferability to the POC.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The proposed DBSFP is based on grade 3 filter paper pre-treated with 8% (v/v) igepal surfactant, 1 min washing step with PBS 1X and elution in TE 1X buffer after 5 min incubation at room temperature, enabling NAE under 7 min. Obtained results were comparable to gold standard methods across tested matrices, targets and experimental conditions, demonstrating the versatility of the methodology. Las
Jackson H, Calle IR, Broderick C, et al., 2022, Characterisation of the blood RNA host response underpinning severity in COVID-19 patients, Scientific Reports, Vol: 12, ISSN: 2045-2322
Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.
Cunnington AJ, Digital Diagnostics for Africa Network, 2022, The potential of digital molecular diagnostics for infectious diseases in sub-Saharan Africa, PLOS Digital Health, Vol: 1, ISSN: 2767-3170
There is a large gap between diagnostic needs and diagnostic access across much of sub-Saharan Africa, particularly for infectious diseases which inflict a substantial burden of morbidity and mortality. Accurate diagnostics are essential for the correct treatment of individuals and provide vital information underpinning disease surveillance, prevention, and control strategies. Digital molecular diagnostics combine the high sensitivity and specificity of molecular detection with point-of-care format and mobile connectivity. Recent developments in these technologies create an opportunity for a radical transformation of the diagnostic ecosystem. Rather than trying to emulate diagnostic laboratory models in resource-rich settings, African countries have the potential to pioneer new models of healthcare designed around digital diagnostics. This article describes the need for new diagnostic approaches, highlights advances in digital molecular diagnostic technology, and outlines their potential for tackling infectious diseases in sub-Saharan Africa. It then addresses the steps which will be necessary for development and implementation of digital molecular diagnostics. Although the focus is on infectious diseases in sub-Saharan Africa, many of the principles apply to other resource limited settings and to non-communicable diseases.
Mooney JP, DonVito SM, Jahateh M, et al., 2022, ‘Bouncing Back’ from subclinical malaria: inflammation and erythrocytosis after resolution of P. falciparum infection in Gambian children, Frontiers in Immunology, Vol: 13, Pages: 1-12, ISSN: 1664-3224
Recent malaria is associated with an increased risk of systemic bacterial infection. The aetiology of this association is unclear but malaria-related haemolysis may be one contributory factor. To characterise the physiological consequences of persistent and recently resolved malaria infections and associated haemolysis, 1650 healthy Gambian children aged 8–15 years were screened for P. falciparum infection (by 18sRNA PCR) and/or anaemia (by haematocrit) at the end of the annual malaria transmission season (t1). P. falciparum-infected children and children with moderate or severe anaemia (haemoglobin concentration < 11g/dl) were age matched to healthy, uninfected, non-anaemic controls and screened again 2 months later (t2). Persistently infected children (PCR positive at t1 and t2) had stable parasite burdens and did not differ significantly haematologically or in terms of proinflammatory markers from healthy, uninfected children. However, among persistently infected children, IL-10 concentrations were positively correlated with parasite density suggesting a tolerogenic response to persistent infection. By contrast, children who naturally resolved their infections (positive at t1 and negative at t2) exhibited mild erythrocytosis and concentrations of pro-inflammatory markers were raised compared to other groups of children. These findings shed light on a ‘resetting’ and potential overshoot of the homeostatic haematological response following resolution of malaria infection. Interestingly, the majority of parameters tested were highly heterogeneous in uninfected children, suggesting that some may be harbouring cryptic malaria or other infections.
Mongru R, Rose D, Costelloe C, et al., 2022, Retrospective analysis of North-West London Healthcare Utilisation by children during the COVID-19 pandemic, BMJ Paediatrics Open, Vol: 6, ISSN: 2399-9772
Objective:To explore the impact of the measures taken to combat COVID-19 on the patterns of acute illness in children presenting to primary and secondary care for North-West London.Design / Setting / Participants:Retrospective analysis of 8,309,358 primary and secondary healthcare episodes of children <16 years registered with a North-West London primary care practice between 2015 and 2021.Main outcome measures: Numbers of primary care consultations, emergency department attendances (ED) and emergency admissions during the pandemic were compared with those in the preceding five years. Trends were examined by age and for ICD10-coded diagnoses of: infectious diseases, and injuries and poisonings for admitted children.Results:Comparing 2020 to the 2015-19 mean, primary care consultations were 22% lower, ED attendances were 38% lower and admissions 35% lower. Following the first national lockdown in April 2020, primary care consultations were 39% lower compared to the April 2015-19 mean, ED attendances were 72% lower, and unscheduled hospital admissions were 63% lower. Admissions >48 hours were on average 13% lower overall during 2020, and 36% lower during April 2020. The reduction in admissions for infections (61% lower than 2015-19 mean) between April-August 2020 was greater than for injuries (31% lower).Conclusion:The COVID-19 pandemic was associated with an overall reduction in childhood illness presentations to health services in North-West London, most prominent during periods of national lockdown, and with a greater impact on infections than injuries. These reductions demonstrate the impact on children of measures taken to combat COVID-19 across the health system.
Challenger J, Foo C, Wu Y, et al., 2022, Modelling upper respiratory viral load dynamics of SARS-CoV-2, BMC Medicine, Vol: 20, ISSN: 1741-7015
Relationships between viral load, severity of illness, and transmissibility of virus, are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of viral load dynamics observed in the upper respiratory tract (URT), drawing upon 2172 serial measurements from 605 subjects, collected from 17 different studies. We developed a mechanistic model to describe viral load dynamics and host response, and contrast this with simpler mixed-effects regression analysis of peak viral load and its subsequent decline. We observed wide variation in URT viral load between individuals, over 5 orders of magnitude, at any given point in time since symptom onset. This variation was not explained by age, sex, or severity of illness, and these variables were not associated with the modelled early or late phases of immune-mediated control of viral load. We explored the application of the mechanistic model to identify measured immune responses associated with control of viral load. Neutralizing antibody correlated strongly with modelled immune-mediated control of viral load amongst subjects who produced neutralizing antibody. Our models can be used to identify host and viral factors which control URT viral load dynamics, informing future treatment and transmission blocking interventions.
Georgiadou A, Dunican C, Sorro-Barrio P, et al., 2022, Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria, eLife, Vol: 11, ISSN: 2050-084X
Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.
Mousa A, Challenger JD, Griffin J, et al., 2021, THE RELATIONSHIP BETWEEN SEVERE MALARIA PHENOTYPES AND AGE AND ESTIMATES OF BURDEN ACROSS SUB-SAHARAN AFRICA., Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 142-142, ISSN: 0002-9637
Johnson H, Piggin M, Cunnington A, 2021, Online survey insight report: Involving children, young people, and families in our research, Online survey insight report: Involving children, young people, and families in our research
Insight report summarising the findings from an online public involvement survey to help shape child, young persons, and family research in North West London.
McArdle AJ, Cunnington AJ, Levin M, 2021, Therapy for Multisystem Inflammatory Syndrome in Children REPLY, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 385, ISSN: 0028-4793
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Nijman R, Oostenbrink R, Moll HA, et al., 2021, A novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies, Frontiers in Pediatrics, Vol: 9, Pages: 1-18, ISSN: 2296-2360
Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI.Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination.Results: Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis (“definite bacterial” category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis (“definite viral” category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of “definite bacterial” vs. “definite viral” following the PERFORM algorithm than using the “SBI” vs. “non-SBI” c
McArdle AJ, Vito O, Patel H, et al., 2021, Treatment of multisystem inflammatory syndrome in children, New England Journal of Medicine, Vol: 385, Pages: 11-22, ISSN: 0028-4793
BACKGROUNDEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.METHODSWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.RESULTSData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.CONCLUSIONSWe found n
Georgiadou A, Dunican C, Soro-Barrio P, et al., 2021, Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria
<jats:title>Abstract</jats:title><jats:p>Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. <jats:italic>Plasmodium yoelii</jats:italic> 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. Our data will aid selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.</jats:p>
Georgiadou A, Naidu P, Walsh S, et 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
Katsoulis O, Georgiadou A, Cunnington A, 2021, Immunopathology of acute kidney injury in severe malaria, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224
Acute kidney injury (AKI) is a common feature of severe malaria, and an independent risk factor for death. Previous research has suggested that an overactivation of the host inflammatory response is at least partly involved in mediating the kidney damage observed in P. falciparum patients with AKI, however the exact pathophysiology of AKI in severe malaria remains unknown. The purpose of this mini-review is to describe how different aspects of malaria pathology, including parasite sequestration, microvascular obstruction and extensive intravascular hemolysis, may interact with each other and contribute to the development of AKI in severe malaria, by amplifying the damaging effects of the host inflammatory response. Here, we highlight the importance of considering how the systemic effects and multi-organ involvement of malaria are intertwined with the localized effects on the kidney.
Morang'a CM, Amenga-Etego L, Bah SY, et 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
Thompson H, Hogan A, Walker P, et 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.
Mousa A, Al-Taiar A, Anstey NM, et 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
Prah DA, Amoah LE, Gibbins MP, et 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
Moranga CM, AmengaEtego L, Bah SY, et al., 2020, Machine learning approaches classify clinical malaria outcomes based on haematological parameters
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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 (RDT) is threatened by<jats:italic>Pfhrp2/3</jats:italic>deletions and decreased sensitivity at low parasitemia. Analysis of haematological indices can be used to support identification of possible malaria cases for further diagnosis, especially in travelers 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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We obtained haematological data from 2,207 participants collected in Ghana; nMI (n=978), UM (n=526), and SM (n=703). Six different machine learning 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-agonistic explanations (LIME) were used to explain the binary classifiers.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 =
Montaldo P, Cunnington A, Oliveira V, et al., 2020, Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy, Scientific Reports, Vol: 10, Pages: 1-7, ISSN: 2045-2322
A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth,predicts adverse neurodevelopmental outcomeeighteenmonths after neonatal encephalopathy.We performed next generation sequencing on whole blood ribonucleic acid obtained within sixhours of birth from the first 47encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX)trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1and SMC4 werethe most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatoninand polo-like kinase in babieswith adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanismsand identify novel therapeutic targetsfor neuroprotection.
Amulic B, Moxon C, Cunnington A, 2020, A more granular view of neutrophils in malaria, Trends in Parasitology, Vol: 36, Pages: 501-503, ISSN: 0169-4758
Neutrophils are abundant innate immune cells with crucial roles in immunity and vascular inflammation. Recent evidence indicates that neutrophils have a dual role in malaria, contributing to both pathogenesis and control of Plasmodium. We discuss emerging mechanisms behind these opposing functions and identify key outstanding questions.
Ebmeier S, Cunnington AJ, 2020, Correspondence regarding recently published editorial: ‘Will children reveal their secret? The coronavirus dilemma’, European Respiratory Journal, Vol: 56, Pages: 1-3, ISSN: 0903-1936
Suen HM, Pasvol G, Cunnington A, 2020, Clinical and laboratory features associated with serum phosphate concentrations in malaria and other febrile illnesses, Malaria Journal, Vol: 19, ISSN: 1475-2875
BackgroundHypophosphatemia is common in severe infections including malaria. Previous studies suggested that serum phosphate concentrations correlate with temperature, but it is unclear whether the type of infection and other factors occurring during infection influence this association. Here relationships were investigated between serum phosphate levels, cause of fever, demographic, clinical and laboratory parameters.MethodsAnonymized data were analysed from 633 adults with malaria or other febrile illness admitted to Northwick Park Hospital, London, UK. Univariable and multivariable generalized linear model analyses were performed to examine associations with serum phosphate levels. Interaction terms were included to investigate whether cause of fever (malaria vs other illness), malaria parasite species, or malaria severity influenced the association of other variables with phosphate.ResultsHypophosphatemia was common in subjects with malaria (211/542 (39%)), and in other febrile illnesses (24/91 (26%)), however median phosphate levels did not differ significantly by diagnostic group, parasite species or severity of malaria. In all analyses, there were highly significant negative associations between serum phosphate and axillary temperature, and positive associations between serum phosphate and platelet count. There were no significant interactions between these variables and cause of fever, parasite species or severity of illness. Sodium and potassium concentrations were associated with serum phosphate in subjects with malaria and when data from all subjects was combined.ConclusionSerum phosphate is consistently associated with temperature and platelet count in adults with diverse causes of fever. This may be a consequence of phosphate shifts from plasma into cells to support ATP generation for thermogenesis and platelet activation.
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.
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