Elevated brain derived neurotrophic factor in plasma and interleukin-6 levels in cerebrospinal fluid in meningitis compared to cerebral malaria.

Neurological infections, such as Cerebral malaria (CM) and meningitis are associated with high mortality and in survivors, particularly young children, persistent neurologic deficits often remain. As brain inflammation plays a role in the development of these neurological sequelae, multiplex assays were used to assess a select set of immune mediators in both plasma and cerebrospinal fluid (CSF) from Zambian children with neurological infections. Both CM and meningitis patients showed high levels of markers for vascular inflammation, such as soluble ICAM-1 and angiopoietins. Although high levels of angiopoietin 1 and angiopoietin 2 were found in the meningitis group, their levels in the CSF were low and did not differ. As expected, there were high levels of cytokines and notably a significantly elevated IL-6 level in the CSF of the meningitis group. Interestingly, although elevated levels BDNF were found, BDNF levels were significantly higher in plasma of the meningitis group but similar in the CSF. The striking differences in plasma BDNF and IL-6 levels in the CSF point to markedly different neuro-pathological processes. Therefore, further investigations in the role of both IL-6 and BDNF in the neurological outcomes are needed.

Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†.

BACKGROUND: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries. METHODS: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway. RESULTS: Participants were enrolled into RHDGen between December 2012 and March 2018. For GWAS, 2548 RHD cases and 2261 controls (3301 women [69%]; mean age [SD], 37 [16.3] years) were available. RHD cases were predominantly Black (66%), Admixed (24%), and other ethnicities (10%). Among RHD cases, 34% were asymptomatic, 26% had prior valve surgery, and 23% had atrial fibrillation. The trio family replication arm included 116 RHD trio probands and 232 parents. CONCLUSIONS: RHDGen presents a rare opportunity to identify relevant patterns of genetic factors and biomarkers in Africans that may be associated with differential RHD risk. Furthermore, the RHDGen Network provides a platform for further work on fully elucidating the causes and mechanisms associated with RHD susceptibility and development.

Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases.

BACKGROUND: Rheumatic heart disease (RHD) remains a major source of morbidity and mortality in developing countries. A deeper insight into the pathogenetic mechanisms underlying RHD could provide opportunities for drug repurposing, guide recommendations for secondary penicillin prophylaxis, and/or inform development of near-patient diagnostics. METHODS: We performed quantitative proteomics using Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectrometry (SWATH-MS) to screen protein expression in 215 African patients with severe RHD, and 230 controls. We applied a machine learning (ML) approach to feature selection among the 366 proteins quantifiable in at least 40% of samples, using the Boruta wrapper algorithm. The case-control differences and contribution to Area Under the Receiver Operating Curve (AUC) for each of the 56 proteins identified by the Boruta algorithm were calculated by Logistic Regression adjusted for age, sex and BMI. Biological pathways and functions enriched for proteins were identified using ClueGo pathway analyses. RESULTS: Adiponectin, complement component C7 and fibulin-1, a component of heart valve matrix, were significantly higher in cases when compared with controls. Ficolin-3, a protein with calcium-independent lectin activity that activates the complement pathway, was lower in cases than controls. The top six biomarkers from the Boruta analyses conferred an AUC of 0.90 indicating excellent discriminatory capacity between RHD cases and controls. CONCLUSIONS: These results support the presence of an ongoing inflammatory response in RHD, at a time when severe valve disease has developed, and distant from previous episodes of acute rheumatic fever. This biomarker signature could have potential utility in recognizing different degrees of ongoing inflammation in RHD patients, which may, in turn, be related to prognostic severity.

Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.

Importance: Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD. Objective: To identify common genetic loci associated with RHD susceptibility in Black African individuals. Design, Setting, and Participants: This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021. Main Outcomes and Measures: Genetic associations with RHD. Results: This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals. Conclusions and Relevance: This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.

Prevalence of rheumatic heart disease in Zambian school children.

BACKGROUND: The large global burden of rheumatic heart disease (RHD) has come to light in recent years following robust epidemiologic studies. As an operational research component of a broad program aimed at primary and secondary prevention of RHD, we sought to determine the current prevalence of RHD in the country's capital, Lusaka, using a modern imaging-based screening methodology. In addition, we wished to evaluate the practicality of training local radiographers in echocardiography screening methods. METHODS: Echocardiography was conducted on a random sample of students in 15 schools utilizing a previously validated, abbreviated screening protocol. Through a task-shifting scheme, and in the spirit of capacity-building to enhance local diagnostic and research skills, general radiographers based at Lusaka University Teaching Hospital (UTH) were newly trained to use portable echocardiography devices. Students deemed as screen-positive were referred for comprehensive echocardiography and clinical examination at UTH. Cardiac abnormalities were classified according to standard World Heart Federation criteria. RESULTS: Of 1102 students that were consented and screened, 53 students were referred for confirmatory echocardiography. Three students had definite RHD, 10 had borderline RHD, 29 were normal, and 11 students were lost to follow-up. The rates of definite, borderline, and total RHD were 2.7 per 1000, 9.1 per 1000, and 11.8 per 1000, respectively. Anterior mitral valve leaflet thickening and chordal thickening were the most common morphological defects. The pairwise kappa test showed fair agreement between the local radiographers and an echocardiographer quality assurance specialist. CONCLUSION: The prevalence of asymptomatic RHD in urban communities in Zambia is within the range of results reported in other sub-Saharan African countries using the WHF criteria. Task-shifting local radiographers to conduct echocardiography was feasible. The results of this study will be used to inform ongoing efforts in Zambia to control and eventually eliminate RHD. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov ( #NCT02661763 ).

Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué.

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a 'roadmap' of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organisations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime.