Mannose-binding lectin variant associated with severe malaria in young African children

Mannose-binding lectin (MBL) is a serum protein which initiates innate immune responses to microbial pathogens by binding to non-self surface oligosaccharides. MBL deficiency is the most common congenital immunodeficiency of human and has been shown to predispose to infections, particularly in children and immune compromised. In a matched case-control study among 870 Ghanaian children, we examined the influence of six polymorphisms of the MBL2 gene on Plasmodium falciparum infection and severe malaria. A missense mutation resulting in low MBL activity (MBL2*C) was found in 35% of healthy controls, but in 42% of asymptomatically infected children (P=0.01), and in 46% of patients with severe malaria (P=0.007). Heterozygosity for MBL2*C was associated with increased odds of infection (odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.1), severe malaria (OR, 1.7; 95% CI, 1.2-2.4), and of severe anemia in particular (OR, 2.3; 95% CI, 1.4-3.8). The population attributable fraction of severe malaria cases attributable to MBL2*C heterozygosity was 17%. Our results suggest that the MBL pathway of the complement system is a critical determinant of both, susceptibility to P. falciparum infection and manifestation of severe malaria, particularly in young children in whom specific immune responses are weak or absent.     

Soil-transmitted helminthiasis: a critical but neglected factor influencing school participation of Aboriginal children in rural Malaysia

Soil-transmitted helminthiasis (STH), among the most common neglected tropical diseases, is a major public health problem in Malaysia with a possible impact on the nutritional status and school participation of rural children. This study was carried out among Aboriginal schoolchildren, living in an endemic area for STH in Malaysia, to determine the possible relationship between intestinal helminthiasis and school absenteeism. We also evaluated whether successful treatment of the infection will affect school attendance among the subjects. Stool analysis revealed that more than 90% of the subjects were infected with at least 1 helminth species, with Ascaris lumbricoides and Trichuris trichiura infections being most prevalent. Infection of moderate-to-heavy worm burdens, low level of fathers' education and anaemia were identified as the significant predictors of high absenteeism among the subjects (P<0·05). Following treatment of the infected children, it was found that school absenteeism was reduced significantly (P<0·01). In conclusion, STH continues to have significant impacts on public health, particularly in rural communities with a negatively significant effect on the school participation of Aboriginal children. A school-based de-worming programme should be introduced and incorporated in the current educational assistance targeted towards the Aboriginal communities, under the auspices of the government.     

Can morbidity associated with untreated asthma in primary school children be reduced?: a controlled intervention study.

OBJECTIVE--To determine whether an intervention programme based on existing school and community resources can reduce school absence and improve participation in games lessons and sport in children with unrecognised or undertreated asthma. DESIGN--Parallel group controlled intervention study. SETTING--102 primary schools in Nottingham: 49 were randomised to receive the intervention and 53 to be control schools. SUBJECTS--All children aged 5 to 10 years with parent reported absence from school because of wheezing in the previous year and taking no treatment or beta agonists only. INTERVENTIONS--Children with asthma were referred to their general practitioner for assessment of symptoms and treatment. Teachers were given education on asthma by the school nurse in 44 of the 49 intervention schools. MAIN OUTCOME MEASURES--Changes in school absence and missed games and swimming lessons because of wheezing, and schools'' policy towards management of asthma in school. RESULTS--Of 17,432 children screened, 451 met the entry criteria--228 in intervention schools and 223 in control schools. 152 (67%) children in intervention schools visited their general practitioner, of whom 39 (26%) were given a new diagnosis of asthma and 58 (38%) had treatment for asthma increased or changed. Over the next academic year mean (SE) parent reported school absence due to wheezing fell significantly, but to a similar extent, in both intervention and control schools (0.82 (0.11) and 1.09 (0.21) weeks respectively). There was little change in school recorded absence or participation in games lessons and swimming lessons in either group. At the end of the study intervention schools were more likely to have improved aspects of management of asthma in school. CONCLUSION--The intervention resulted in a majority of children being assessed by their general practitioner and improved teachers'' understanding and management of asthma, but it did not result in any appreciable reduction in morbidity.     

Genetic factors associated with development of cerebral malaria and fibrotic schistosomiasis

Collaborative studies have identified some genetic factors contributing to the development of severe forms of malaria and schistosomiasis. In Thailand, the TNF-alpha 5'-flanking region shows biallelic polymorphic sites at nucleotides -238, -308, -857, -863, and -1031, and seven alleles have been identified in patients from Myanmar. We found that the TNF promoter (TNFP)-D allele was significantly associated with cerebral malaria in populations from Karen (P < 0.0001, OR = 124.86) and ethnic Burma (P < 0.0001, OR = 34.50). In China, we have identified two major genes related to the severity of liver fibrosis, one an HLA class II gene, and the other the IL-13 gene. The frequency of the HLA-DRB5*0101 allele and that of the IL-13 promoter A/A (IL-13P- A/A) genotype were elevated in fibrotic patients, although the two genes are located on different chromosomes, chromosomes 6p and 5q, respectively. Subjects with both genotypes had odds ratios (OR = 24.5) much higher than the sum of the ratios for each individual genotype (OR = 5.1, 95% Confidence Interval 1.3-24.7 for HLA-DRB5*0101, OR = 3.1 95% CI 1.5 - 6.5 for IL-13P- A/A). That the effects of the two susceptibility markers are synergistic rather than additive, strongly suggests that the pathogenic Th2 response directly influences the prognosis of post-schistosomal liver fibrosis.     

Low malaria morbidity in a cohort of Senegalese children with free access to health structures

We report the impact of the free access to health facilities on malaria morbidity in children from two to 15 years old, during a malaria transmission season in Niakhar, Senegal. Between July and December 2002, 227 malaria attacks occured in 566 children. Only one case of severe malaria was observed and no death has been reported. Our results demonstrate furthermore that easier access to health facilities and to early treatment is playing a key role in malaria control.     

Genes,nitric oxide and malaria in African children

The unresolved and complex relationship between nitric oxide and falciparum malaria is reflected in recent genetic and immunohistochemical studies in African children. Different genetic associations, perhaps geographically distinctive, are seen between genetic variants of the inducible nitric oxide gene and various disease manifestations in African populations. The picture might not be complete without considering the emerging roles of carbon monoxide, another endogenous gaseous mediator with similar effects to those of nitric oxide. Only when genetic comparisons from across tropical Africa are examined, in conjunction with the newly recognized complexities in the events of systemic inflammation, will this relationship be understood.     

Sickle cell disease and malaria morbidity: a tale with two tails

More than 230,000 children are born in Africa with sickle cell disease (SCD) each year: approximately 85% of all affected births worldwide. Although malaria is commonly viewed as a major problem for African patients with this condition, questions still remain about its relative importance as a cause of ill heath and death. In the absence of definitive studies investigating the contribution of malaria to morbidity and mortality in African children with SCD, policy makers will continue to lack the evidence on which to base appropriate management guidelines.     

Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study

Background

Differentiating cerebral malaria (CM) from other causes of serious illness in African children is problematic, owing to the non-specific nature of the clinical presentation and the high prevalence of incidental parasitaemia. CM is associated with endothelial activation. In this study we tested the hypothesis that endothelium-derived biomarkers are associated with the pathophysiology of severe malaria and may help identify children with CM.

Methods and Findings

Plasma samples were tested from children recruited with uncomplicated malaria (UM; n = 32), cerebral malaria with retinopathy (CM-R; n = 38), clinically defined CM without retinopathy (CM-N; n = 29), or non-malaria febrile illness with decreased consciousness (CNS; n = 24). Admission levels of angiopoietin-2 (Ang-2), Ang-1, soluble Tie-2 (sTie-2), von Willebrand factor (VWF), its propeptide (VWFpp), vascular endothelial growth factor (VEGF), soluble ICAM-1 (sICAM-1) and interferon-inducible protein 10 (IP-10) were measured by ELISA. Children with CM-R had significantly higher median levels of Ang-2, Ang-2:Ang-1, sTie-2, VWFpp and sICAM-1 compared to children with CM-N. Children with CM-R had significantly lower median levels of Ang-1 and higher median concentrations of Ang-2:Ang-1, sTie-2, VWF, VWFpp, VEGF and sICAM-1 compared to UM, and significantly lower median levels of Ang-1 and higher median levels of Ang-2, Ang-2:Ang-1, VWF and VWFpp compared to children with fever and altered consciousness due to other causes. Ang-1 was the best discriminator between UM and CM-R and between CNS and CM-R (areas under the ROC curve of 0.96 and 0.93, respectively). A comparison of biomarker levels in CM-R between admission and recovery showed uniform increases in Ang-1 levels, suggesting this biomarker may have utility in monitoring clinical response.

Conclusions

These results suggest that endothelial proteins are informative biomarkers of malarial disease severity. These results require validation in prospective studies to confirm that this group of biomarkers improves the diagnostic accuracy of CM from similar conditions causing fever and altered consciousness.     

Puerperal morbidity: a neglected area of maternal health in Sri Lanka

Pregnancy is the period during which a mother prepares herself physically and psychologically for the delivery and care of the offspring. However, during this period the central concern is the welfare of the baby, but not the mother. When the mother and the child subsequently become two separate beings, the mother's health care is totally neglected unless she develops obvious symptoms of gross physiological and psychological abnormalities. This study, which was carried out in three MOH areas of the Kalutara District on maternal morbidity, had two main objectives. The first was to determine the prevalence of puerperal morbidity and the second was to identify characteristics of those with high levels of morbidity. Of the mothers who are registered by the PHM of the study area 600 were selected for this study. Data were collected using structured interviews conducted within the first week after puerperium (43-50 days after delivery). The morbidity rate revealed by the study is much higher than expected. Excessive bleeding from the vagina was reported by 40 per cent of mothers, while minor symptoms like breast engorgement and chills were reported by many mothers. Only 11 per cent of the mothers in the study did not have any symptoms or signs of ill health, and the rest reported one or more illnesses. Primae gravidae and those who experienced pregnancy wastage during an early pregnancy had a higher morbidity.     

Mosquitocidal vaccines: a neglected addition to malaria and dengue control strategies

The transmission of vector-borne diseases is dependent upon the ability of the vector to survive for longer than the period of development of the pathogen within the vector. One means of reducing mosquito lifespan, and thereby reducing their capacity to transmit diseases, is to target mosquitoes with vaccines. Here, the principle behind mosquitocidal vaccines is described, their potential impact in malaria and dengue control is modeled and the current research that could make these vaccines a reality is reviewed. Mosquito genome data, combined with modern molecular techniques, can be exploited to overcome the limited advances in this field. Given the large potential benefit to vector-borne disease control, research into the development of mosquitocidal vaccines deserves a high profile.     

Prevalence of urogenital and intestinal schistosomiasis among school children in South-west Nigeria

BackgroundThe risk of co-infection with Schistosoma haematobium and S. mansoni and the potential harmful effect on morbidity and control is enhanced by the overlapping distribution of both species in sub-Saharan Africa. Despite the reported high endemicity of both species in Nigeria, studies on the spread and effect of their mixed infection are limited. Therefore, a cross-sectional survey was conducted among school children in two communities in South-west Nigeria to investigate the prevalence of mixed human schistosome infection, intensity, and possible ectopic egg elimination.MethodsUrine and stool samples were collected from consenting school children in Ilie and Ore communities of Osun State, Nigeria. Schistosoma haematobium eggs were detected in urine using the urine filtration technique, while S. mansoni eggs were detected in stool using the Kato–Katz thick smear technique.ResultsThe study enrolled 466 primary and secondary school children (211; 45.3% males vs. 255; 54.7% females; mean age 11.6 ± 3.16 years). The overall prevalence of schistosomiasis was 40% (185/466), with 19% (89/466) recording single S. haematobium infection while 9% (41/465) had a single S. mansoni infection. The geometric mean egg count for S. haematobium was 189.4 egg/10ml urine; 95% CI: range 115.9–262.9, while for S. mansoni, it was 115.7 epg; 95% CI: range 78.4–152.9. The prevalence of ectopic S mansoni (S. mansoni eggs in urine) was 4.7%, while no ectopic S. haematobium (S. haematobium eggs in stool) was recorded. Mixed infection of S. haematobium/S. mansoni had a prevalence of 9.5% (44/466). More females (54.5%) presented with S. haematobium/S. mansoni co-infection. For both parasites, males had higher infection intensity, with a significant difference observed with S. haematobium (p = 0.0004). Hematuria was significant in individuals with single S. haematobium infection (p = 0.002), mixed ectopic S. haematobium/S. mansoni (p = 0.009) and mixed S. haematobium/S. mansoni/ectopic S. mansoni (p = 0.0003).ConclusionsThese findings suggest the probability of interspecific interactions between S. haematobium and S. mansoni. Scaling up of mass administration of praziquantel and control measures in the study areas is highly desirable.     

Plasmodium falciparum-specific interleukin-2 and tumor necrosis factor-alpha expressing-T cells are associated with resistance to reinfection and severe malaria in healthy African children

The frequency of P. falciparum-specific interleukin (IL)-2-, interferon (IFN)-gamma-, tumor necrosis factor (TNF)-alpha- and IL-10-expressing CD3+ cells was studied in healthy Gabonese children segregated according to their clinical presentation at admission to a longitudinal study of severe and mild malaria. The percentage of IL-2- and TNF-alpha- expressing P. falciparum-specific CD3+ cells was significantly higher in the children with prior mild malaria and less frequent reinfections compared to the children with prior severe malaria and more frequent reinfections. No differences were shown for P. falciparum-specific IFN-gamma and IL-10 expression within CD3+ cells and parasite-non-specific expression of IL-2, IL-4, IL-6, IL-10, IL-13, TNF-alpha, and IFN-gamma within the CD4+, CD8+, TCRgamma\delta+ CD3+ and CD94+ CD3- cell populations, indicating that immunological determinants regulating the susceptibility to malaria in age-matched children are parasite-specific. The ability of P. falciparum-specific T cells to mount a rapid IL-2 and TNF-alpha response might be of significance in preventing severe disease and reinfection.     

Association of common health symptoms with bullying in primary school children.

OBJECTIVE--To estimate the prevalence of bullying in primary school children and to examine its association with common symptoms in childhood. DESIGN--Semistructured health interview conducted by school nurses as part of a school medical. SETTING--Newham, east London. SUBJECTS--All children in year 4 of school during the academic year 1992-93. MAIN OUTCOME MEASURES--Reported bullying and common health symptoms. RESULTS--2962 children (93.1% of those on the school roll) were interviewed (ages 7.6 to 10.0 years). Information about bullying was not recorded for 114 children, 22.4% (95% confidence interval 20.9 to 24.0) of children for whom information was available reported that they had been bullied. There was an association between children reporting being bullied sometimes or more often and reporting not sleeping well (odds ratio 3.6, 2.5 to 5.2), bed wetting (1.7, 1.3 to 2.4), feeling sad (3.6, 1.9 to 6.8), and experiencing more than occasional headaches (2.4, 1.8 to 3.4) and tummy aches (2.4, 1.8 to 3.3). A significant trend for increasing risk of symptoms with increased frequency of bullying was shown for all reported health symptoms (P < 0.001). CONCLUSIONS--Health professionals seeing primary schoolchildren who present with headaches, tummy ache, feeling sad or very sad, bed wetting, and sleeping difficulties should consider bullying as a possible contributory factor.     

V beta profiles in African children with acute cerebral or uncomplicated malaria: very focused changes among a remarkable global stability

T cells are thought to play a critical role in cerebral malaria pathogenesis. However, available evidences are restricted to rodent models in which V beta specific T cell expansion has been associated with neurological syndrome suggesting involvement of superantigens or dominant antigens. Using flow cytometry, we studied the peripheral V beta T cell repertoire of Ghanaian children with cerebral malaria, uncomplicated malaria and asymptomatic control children, to look for either expansion or deletion of specific V beta associated with cerebral malaria. At admission, the general pattern of the repertoire of the patients was very similar, with no major distortion compared to the control group a part a significant increase of the frequency of the V beta 21.3 subset correlating with disease severity and attributed to the CD4 subset. During convalescence very limited fluctuations were observed including a significant decrease of the V beta 21.3 subset and increase of the V beta 20 subset, a subset not detected at admission. The remarkable stability of the V beta repertoire observed in acute malaria either cerebral or uncomplicated argues against the idea that cerebral malaria would result from a T cell-mediated inflammatory shock syndrome driven by some dominant super-antigenic activity(ies). The significance of the reproducible increase of the CD4+V beta 21.3T cell subset deserves further investigations.     

A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial

Background

Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.

Methods and Findings

Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6–59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37–0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41–1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28–0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21–0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30–0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26–0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.

Conclusions

This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00393679","term_id":"NCT00393679"}}NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750 Please see later in the article for the Editors'' Summary