The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations.

Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.

Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria.

Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.

Circulatory hepcidin is associated with the anti-inflammatory response but not with iron or anemic status in childhood malaria.

Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore, it is important to understand the pathology underlying the development of CM and SMA as opposed to uncomplicated malaria (UM). Increased levels of hepcidin have been associated with UM, but its level and role in severe malarial disease remains to be investigated. Plasma and clinical data were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, Nigeria. Here, we report that hepcidin levels are lower in children with SMA or CM than in those with milder outcome (UM). While different profiles of pro- and anti-inflammatory cytokines were observed between the malaria syndromes, circulatory hepcidin levels remained associated with the levels of its regulatory cytokine interleukin-6 and of the anti-inflammatory cytokine inerleukin-10, irrespective of iron status, anemic status, and general acute-phase response. We propose a role for hepcidin in anti-inflammatory processes in childhood malaria.

Impact of the 2017 AAP clinical guideline on the prevalence of high blood pressure among adolescents in Lagos, Nigeria.

Introduction: Adolescent high blood pressure (HBP) can lead to several end-organ complications if it continues into adulthood. The 2017 AAP Guideline has lower blood pressure cut-off points and consequently leads to the identification of more people with high blood pressure. This study evaluated the impact of the 2017 American Academy of Pediatrics (AAP) Clinical Guideline on the prevalence of high blood pressure among adolescents when compared to the 2004 Fourth Report. Methodology: A descriptive cross-sectional study was conducted from August 2020 to December 2020. The selection of 1,490 students, 10-19 years old, was by a two-stage sampling technique. Socio-demographic information and relevant clinical data were obtained using a structured questionnaire. Blood pressure was measured according to standard protocol. Categorical and numerical variables were summarized using frequency, percentages, mean, and standard deviation. The McNemar-Bowker test of symmetry was used to compare the blood pressure values in the 2004 Fourth Report and the 2017 AAP Clinical Guideline. The Kappa statistic was used to test for the degree of agreement between the 2004 Fourth Report and the 2017 AAP Clinical Guideline. Results: The prevalence rates of high blood pressure, elevated blood pressure, and hypertension among adolescents were 26.7%, 13.8%, and 12.9%, respectively, using the 2017 AAP Clinical Guideline, and 14.5%, 6.1%, and 8.4%, respectively, using the 2004 Fourth Report. The degree of agreement between the 2004 and 2017 guidelines with respect to the classification of blood pressure was 84.8%. The Kappa statistic was 0.71 (CI: 0.67-0.75). The impact of this was a 12.2%, 7.7%, and 4.5% increase in the prevalence of high blood pressure, elevated blood pressure, and hypertension, respectively, using the 2017 AAP Clinical Guideline. Conclusion: The 2017 AAP Clinical Guideline detects a greater proportion of high blood pressure among adolescents. The adoption of this new guideline in clinical practice and its use in the routine screening of high blood pressure among adolescents is recommended.

High blood pressure pattern amongst adolescents in Lagos, South West Nigeria.

Introduction: high blood pressure (HBP), once considered rare in adolescents is now a growing health problem. Usually asymptomatic in adolescents, if uncontrolled, can track into adulthood leading to various end-organ complications. In 2017, the American Academy of Pediatrics (AAP) published a new Clinical Practice Guideline (CPG) for screening and management of high blood pressure in children and adolescents to update the 2004 Fourth report. The objective of this study was to determine the prevalence of high blood pressure among adolescents in Mushin Local Government Area (LGA) using the 2017 AAP guidelines. Methods: a descriptive cross-sectional study, conducted from August 2020 to December 2020. A two-stage sampling technique was used to select 1490 students aged 10 to 19 years, from 14 secondary schools. Socio-demographic information and relevant clinical data were obtained using a structured questionnaire. The anthropometry and blood pressure measurements were taken according to standard protocol (elevated blood pressure is systolic and/or diastolic blood pressure ≥ 90th percentile but ≤ 95th percentile for age, gender and height). Socio-demographic and anthropometric characteristics were described with descriptive statistics. Categorical variables were summarized using frequency and percentages, while numerical variables were summarized using mean and standard deviation. The predictors of hypertension were determined using logistic regression analysis. Results: study participants were 1490, 49.9% (744) were male and 50.1% (746) females (male: female ratio was 1: 1). Subjects mean age was 14.39 ± 2.79 years. There were 8.9% overweight and 1.7% obese participants. Prevalence of high blood pressure, elevated blood pressure and hypertension were 26.7% (n = 398), 13.8% (n = 205), and 12.9% (n = 193). Middle and late adolescence, when compared to early adolescence, significantly predicted the likelihood of high blood pressure; aOR 1.78, 95%CI: 1.20 - 2.63, p=0.004 and 3.90 (2.69 - 5.67, p=0.001 respectively). Similarly, male sex had increased odds for raised blood pressure when compared to female sex aOR 1.49,95% CI: 1.1 - 2.0, p= 0.009. Conclusion: the prevalence of high blood pressure, elevated blood pressure and hypertension amongst adolescents was high. Early detection and treatment will forestall development of complications.

Haemoglobinuria among children with severe malaria attending tertiary care in Ibadan, Nigeria.

BACKGROUND: Haemoglobinuria is one of the manifestations of severe malaria and results from severe intravascular haemolysis. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been implicated in its aetiology. Haemoglobinuria may be associated with severe anaemia and, less frequently, acute renal failure. METHODS: A prospective case-control study was carried out to determine the incidence of haemoglobinuria as confirmed by dipstick urinalysis, microscopy and spectrophotometric measurement, among children with severe malaria. A total of 251 children presenting at the Children's Emergency Ward with severe malaria were recruited over a period of 21 months. The G6PD status and the outcomes of severe malaria in children with and without haemoglobinuria was studied with respect to renal failure, the recurrence of haemoglobinuria and blood pressure changes over a three-month follow-up period. RESULTS: It was found that the incidence of haemoglobinuria among children with severe malaria is 19.1%. Children <5 years constituted 76.8% of all the study patients. Patients with haemoglobinuria had median age of 52.5 months, which was significantly higher than 35 months in patients without haemoglobinuria (p=0.001). Although, haemaglobinuria was commoner among boys (54.2%) than girls (45.8%), the difference was not statistically significant. There were no significant differences between children with and without haemoglobinuria regarding their nutritional status or parasite densities. Among the clinical features of the study patients, only jaundice was significantly associated with haemoglobinuria (p=0.0001). Renal failure occurred in three out of 48 children with haemoglobinuria and in none of the 203 without. There was not recurrence of haemoglobinuria in the follow-up period. At discharge, blood pressure was elevated in six children (one previously haemoglobinuric), but all returned to normal within the follow-up period. CONCLUSIONS: Haemoglobinuria was a prominent feature of severe malaria and it was significantly associated with jaundice at presentation. Haemoglobinuria was commoner in older children than younger children but not related to sex. G6PD deficiency was not an independent predictor of the occurrence or outcome of haemoglobinuria. Blood pressure was not affected by haemoglobinuria on admission nor during follow-up.

The role of routine post-natal abdominal ultrasound for newborns in a resource-poor setting: a longitudinal study.

BACKGROUND: Neonatal abdominal ultrasound is usually performed in Nigeria to investigate neonatal symptoms rather than as a follow up to evaluate fetal abnormalities which were detected on prenatal ultrasound. The role of routine obstetric ultrasonography in the monitoring of pregnancy and identification of fetal malformations has partly contributed to lowering of fetal mortality rates. In Nigeria which has a high maternal and fetal mortality rate, many pregnant women do not have ante-natal care and not infrequently, women also deliver their babies at home and only bring the newborns to the clinics for immunization. Even when performed, most routine obstetric scans are not targeted towards the detection of fetal abnormalities.The aim of the present study is to evaluate the benefit of routinely performing abdominal scans on newborns with a view to detecting possible abnormalities which may have been missed ante-natally. METHODS: This was a longitudinal study of 202 consecutive, apparently normal newborns. Routine clinical examination and abdominal ultrasound scans were performed on the babies by their mother's bedside, before discharge. Neonates with abnormal initial scans had follow-up scans. RESULTS: There were 108 males and 94 females. There were 12 (5.9%) abnormal scans seen in five male and seven female neonates. Eleven of the twelve abnormalities were in the kidneys, six on the left and five on the right. Three of the four major renal anomalies- absent kidney, ectopic/pelvic kidney and two cases of severe hydronephrosis were however on the left side. There was one suprarenal abnormality on the right suspected to be a possible infected adrenal haemorrage. Nine of the abnormal cases reported for follow- up and of these, two cases had persistent severe abnormalities. CONCLUSIONS: This study demonstrated a 5.9% incidence of genito urinary anomalies on routine neonatal abdominal ultrasound in this small population. Routine obstetric USS is very useful but inadequate availability of skilled personnel and cost implications create great challenges in poor resource settings like Nigeria. However, awareness should be created so that parents who can afford such investigations can make informed decisions.

Data-driven malaria prevalence prediction in large densely populated urban holoendemic sub-Saharan West Africa.

Over 200 million malaria cases globally lead to half-million deaths annually. The development of malaria prevalence prediction systems to support malaria care pathways has been hindered by lack of data, a tendency towards universal "monolithic" models (one-size-fits-all-regions) and a focus on long lead time predictions. Current systems do not provide short-term local predictions at an accuracy suitable for deployment in clinical practice. Here we show a data-driven approach that reliably produces one-month-ahead prevalence prediction within a densely populated all-year-round malaria metropolis of over 3.5 million inhabitants situated in Nigeria which has one of the largest global burdens of P. falciparum malaria. We estimate one-month-ahead prevalence in a unique 22-years prospective regional dataset of > 9 × 104 participants attending our healthcare services. Our system agrees with both magnitude and direction of the prediction on validation data achieving MAE ≤ 6 × 10-2, MSE ≤ 7 × 10-3, PCC (median 0.63, IQR 0.3) and with more than 80% of estimates within a (+ 0.1 to - 0.05) error-tolerance range which is clinically relevant for decision-support in our holoendemic setting. Our data-driven approach could facilitate healthcare systems to harness their own data to support local malaria care pathways.

Low plasma haptoglobin is a risk factor for life-threatening childhood severe malarial anemia and not an exclusive consequence of hemolysis.

Severe Malarial Anemia (SMA), a life-threatening childhood Plasmodium falciparum malaria syndrome requiring urgent blood transfusion, exhibits inflammatory and hemolytic pathology. Differentiating between hypo-haptoglobinemia due to hemolysis or that of genetic origin is key to understand SMA pathogenesis. We hypothesized that while malaria-induced hypo-haptoglobinemia should reverse at recovery, that of genetic etiology should not. We carried-out a case-control study of children living under hyper-endemic holoendemic malaria burden in the sub-Saharan metropolis of Ibadan, Nigeria. We show that hypo-haptoglobinemia is a risk factor for childhood SMA and not solely due to intravascular hemolysis from underlying schizogony. In children presenting with SMA, hypo-haptoglobinemia remains through convalescence to recovery suggesting a genetic cause. We identified a haptoglobin gene variant, rs12162087 (g.-1203G > A, frequency = 0.67), to be associated with plasma haptoglobin levels (p = 8.5 × 10-6). The Homo-Var:(AA) is associated with high plasma haptoglobin while the reference Homo-Ref:(GG) is associated with hypo-haptoglobinemia (p = 2.3 × 10-6). The variant is associated with SMA, with the most support for a risk effect for Homo-Ref genotype. Our insights on regulatory haptoglobin genotypes and hypo-haptoglobinemia suggest that haptoglobin screening could be part of risk-assessment algorithms to prevent rapid disease progression towards SMA in regions with no-access to urgent blood transfusion where SMA accounts for high childhood mortality rates.

Children with transposition of the great arteries: Should they actually be born in Nigeria?

AIM: To describe the clinical and echocardiographic features of Nigerian children with transposition of the great arteries and emphasize the need for collaboration with cardiac centres in the developed countries to be able to salvage the children. METHODS: Prospective and cross sectional involving consecutive patients diagnosed with transposition of the great arteries using clinical evaluation and echocardiography at the Paediatric Department of Lagos State University Teaching Hospital, Lagos Nigeria as part of a large study between January 2007 and December 2015. RESULTS: There were 51 cases of transposition of the great arteries within the study period with a male to female ratio of 2:1 and a prevalence of 1.55 per 10000 among population of children who presented to centre during the study. Its proportion amongst children with congenital heart disease was 4.9%, while it was 15.4% among those with cyanotic congenital heart disease. The mean age ± SD of the subjects was 10.3 ± 21.8 mo. Up to 70% of the patients were less than 6 mo of age at initial presentation. The most common mode of presentation was cyanosis. The most common associated intracardiac anomaly was ventricular septal defect which occurred in 56% of the patients. CONCLUSION: Transposition of the great arteries is as common in Nigeria as in the other parts of the world. The most common mode of presentation was cyanosis. There is an urgent need to establish paediatric cardiac centres in Nigeria if these children are to be salvaged.

A Functional IL22 Polymorphism (rs2227473) Is Associated with Predisposition to Childhood Cerebral Malaria.

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection. This encephalopathy is characterized by coma and is thought to result from mechanical microvessel obstruction and an excessive activation of immune cells leading to pathological inflammation and blood-brain barrier alterations. IL-22 contributes to both chronic inflammatory and infectious diseases, and may have protective or pathogenic effects, depending on the tissue and disease state. We evaluated whether polymorphisms (n = 46) of IL22 and IL22RA2 were associated with CM in children from Nigeria and Mali. Two SNPs of IL22, rs1012356 (P = 0.016, OR = 2.12) and rs2227476 (P = 0.007, OR = 2.08) were independently associated with CM in a sample of 115 Nigerian children with CM and 160 controls. The association with rs2227476 (P = 0.01) was replicated in 240 nuclear families with one affected child from Mali. SNP rs2227473, in linkage disequilibrium with rs2227476, was also associated with CM in the combined cohort for these two populations, (P = 0.004, OR = 1.55). SNP rs2227473 is located within a putative binding site for the aryl hydrocarbon receptor, a master regulator of IL-22 production. Individuals carrying the aggravating T allele of rs2227473 produced significantly more IL-22 than those without this allele. Overall, these findings suggest that IL-22 is involved in the pathogenesis of CM.

Audit of availability and distribution of paediatric cardiology services and facilities in Nigeria.

BACKGROUND: Paediatric cardiac services in Nigeria have been perceived to be inadequate but no formal documentation of availability and distribution of facilities and services has been done. OBJECTIVE: To evaluate and document the currently available paediatric cardiac services in Nigeria. METHODS: In this questionnaire-based, cross-sectional descriptive study, an audit was undertaken from January 2010 to December 2014, of the personnel and infrastructure, with their distributions according to geopolitical zones of Nigeria. RESULTS: Forty-eight centres participated in the study, with 33 paediatric cardiologists and 31 cardiac surgeons. Echocardiography, electrocardiography and pulse oximetry were available in 45 (93.8%) centres while paediatric intensive care units were in 23 (47.9%). Open-heart surgery was performed in six (12.5%) centres. South-West zone had the majority of centres (20; 41.7%). CONCLUSIONS: Available paediatric cardiac services in Nigeria are grossly inadequate and poorly distributed. Efforts should be intensified to upgrade existing facilities, establish new and functional centres, and train personnel.

The burden of Fallot's tetralogy among Nigerian children.

BACKGROUND: There are only very few reports on Fallot's tetralogy in Africa especially from sub-Saharan Africa. At best tetralogy of Fallot (TOF) is only mentioned as part of reports of surveys of other congenital heart diseases or as case reports in the region. There has been no report on cohorts of children with TOF in West Africa. This article describes the pattern and presentation of children diagnosed with TOF patients in a tertiary hospital in sub-Saharan Africa over a 9-year period. METHODS: Prospective and consecutive review of all subjects with diagnosis of TOF confirmed with echocardiography at the Lagos State University Teaching Hospital (LASUTH) between January 2007 and December 2015. Data were analyzed using Statistical Package for Social Sciences (SPSS) version 20. Descriptive statistics were presented as percentages or means and standard deviation. Means of normally distributed variables were compared using the Students' t-test and proportions using Chi-square test. Skewed distributions were analyzed using appropriate non-parametric tests. Level of significance set at P<0.05. RESULTS: The prevalence of TOF among children presenting at LASUTH at the study period was 4.9 per 1,000 while its prevalence among those with congenital heart disease was 16.9%. There was a male predominance with a mean age of 50.9±45.9 (months) and median age of 36 months. Most children presented within 1-5 years of age. The most common indication for evaluation was cyanosis. One hundred and nineteen out of 165 (72.1%) children were clinically cyanosed on presentation. CONCLUSIONS: TOF is prevalent among Nigerian children. Cyanosis was the commonest presenting feature and indication for evaluation. Most of the subjects presented late hence were diagnosed after 1 year of age. There is a need to increase awareness of TOF in Nigeria to encourage early diagnosis and hence better outcomes in these subjects.

Children With Tetralogy of Fallot in an Urban Centre in Africa.

INTRODUCTION: There is a dearth of literature on tetralogy of fallot (TOF) in children in Sub-Saharan Africa. This study up aims to describe the prevalence, clinical profile and associated cardiac anomaly of children diagnosed with TOF documented over an eight year period in a tertiary hospital in South Western Nigeria. METHODS: A prospective review of all consecutive cases of TOF diagnosed with echocardiography at the Lagos State University Teaching Hospital (LASUTH) between January 2007 and December 2014. Data were analyzed using SPSS version 20. Tables and charts were used to depict those variables. Descriptive statistic are presented as percentages or means and standard deviation. Means of normally distributed variables were compared using the student t test and proportions using chi-square test. Skewed distribution were analyzed using appropriate non-parametric tests. Level of significance set at P < 0.05. RESULT: The prevalence of TOF among children presenting at LASUTH at the study period was 4.9 per 10 000 while its prevalence among those with congenital heart disease was 16.9%. There was a male predominance and most children presented within 1-5 years of age. Chromosomal abnormalities such as Down syndrome, Turners syndrome and CATCH 22 syndrome were documented in some subjects. Some of the subjects had atypical presentation. CONCLUSION: TOF is as common in Nigeria as other parts of the world, there is a need to established cardiac centers to salvage these children. Collaboration from developed countries will be helpful in this resource limited region.

Severe childhood malaria syndromes defined by plasma proteome profiles.

BACKGROUND: Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore it is important to understand the pathology underlying the development of CM and SMA, as opposed to uncomplicated malaria (UM). Different host responses to infection are likely to be reflected in plasma proteome-patterns that associate with clinical status and therefore provide indicators of the pathogenesis of these syndromes. METHODS AND FINDINGS: Plasma and comprehensive clinical data for discovery and validation cohorts were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, an urban and densely populated holoendemic malaria area in Nigeria. A total of 946 children participated in this study. Plasma was subjected to high-throughput proteomic profiling. Statistical pattern-recognition methods were used to find proteome-patterns that defined disease groups. Plasma proteome-patterns accurately distinguished children with CM and with SMA from those with UM, and from healthy or severely ill malaria-negative children. CONCLUSIONS: We report that an accurate definition of the major childhood malaria syndromes can be achieved using plasma proteome-patterns. Our proteomic data can be exploited to understand the pathogenesis of the different childhood severe malaria syndromes.

The history of the Pan-African Society of Cardiology (PASCAR): the first 30 years, 1981-2011.

The year 2011 marks the 30th anniversary of the founding of the Pan-African Society of Cardiology (PASCAR). Throughout its brief history, PASCAR has been integral to improving the cardiovascular health of the people of Africa. During the past three decades, many African countries have been vulnerable to political and social turmoil, and PASCAR itself has been repeatedly challenged to press on with its mission, in spite of innumerable practical obstacles. This article celebrates the hard work and dedication of PASCAR's founders and subsequent leaders, and challenges the present and future generations to carry on the charge of furthering the health of Africans.

Health status of working and non-working school children in Ibadan, Nigeria.

Child labour continues to pose a challenge to national and international agencies. This study compares the health status of working and non-working school children in Ibadan, Nigeria. Altogether, 223 working and 230 non-working children were interviewed. Their ages ranged between 8 and 15 years. Fifty-nine (13%) reported fever, 36 (8%) visual problems, 28 (6%) skin lesions, 17 (4%) muscular and joint pains and 5 (1%) diarrhoea. Schistosoma ova were observed in 25 (6%) children. There was no difference in the occurrence of diseases between working and non-working children. Twenty-seven per cent of the children were underweight and 30% were stunted. Malnutrition was more prevalent among working children as 74 (33%) were underweight (p =0.001) and 76 (34%) were stunted. Public enlightenment about the effect of child labour might discourage parents from engaging their school-age children in work. Governments should address the socio-economic factors that promote child labour.