Tumour necrosis factor allele variants and their association with the occurrence and severity of malaria in African children: a longitudinal study
Gichohi-Wainaina, W.N. ; Boonstra, A. ; Feskens, E.J.M. ; Demir, A.Y. ; Veenemans, J. ; Verhoef, H. - \ 2015
Malaria Journal 14 (2015). - ISSN 1475-2875 - 11 p.
plasmodium-falciparum malaria - tnf-alpha promoter - cerebral malaria - linkage disequilibrium - rheumatoid-arthritis - diabetes-mellitus - polymorphisms - gene - disease - hla
Background Tumour necrosis factor (TNF) is central to the immune response to Plasmodium infection. Its plasma concentration is influenced by allele variants in the promoter region of TNF. The study’s objectives were to assess TNF allele variants (TNF-1031 , TNF-308 ): (1) modulation of malaria rates in young Tanzanian children; (2) modulation of the severity of malaria as indicated by haemoglobin concentrations at the time of presentation with febrile episodes; and (3) the association between Plasmodium infection and haemoglobin concentration in symptomless parasite carriers. Methods Data from a placebo-controlled trial in which 612 Tanzanian children aged 6–60 months with height-for-age z-score in the range -3 SD to 1.5 SD was utilised. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. An episode of malaria was predefined as current Plasmodium infection with an inflammatory response (axillary temperature =37.5°C or whole blood C-reactive protein concentration =8 mg/L) in children reported sick. Linkage disequilibrium (LD) pattern assessment as well as haplotype analysis was conducted using HAPLOVIEW. Cox regression models used in the primary analysis accounted for multiple episodes per child. Results Genotyping of 94.9% (581/612) children for TNF-1031 (TNF-1031 T>C); allele frequency was 0.39. Corresponding values for rs1800629 (TNF-308 G>A) were 95.4% (584/612) and 0.17. Compared to the wild type genotype (TT), malaria rates were increased in the TNF-1031 CC genotype (hazard ratio, HR [95% CI]: 1.41 [1.01¿1.97] and 1.31 [0.97¿1.76] for crude analysis and adjusting for pre-specified baseline factors, respectively) but decreased in those with the TNF-308 AA genotype (corresponding HR: 0.13 [0.02¿0.63] and 0.16 [0.04¿0.67]). These associations were weaker when analysing first episodes of malaria (P value -0.59 and 0.38, respectively). No evidence that allele variants of TNF-1031 and TNF-308 affected haemoglobin concentration at first episode of malaria, or that they modified the association between Plasmodium infection and haemoglobin concentrations at baseline was observed.
Plasma concentration of parasite DNA as a measure of disease severity in falciparum malaria
Imwong, M. ; Woodrow, C. ; Hendriksen, I.C.E. ; Veenemans, J. ; Verhoef, J.C.M. - \ 2015
The Journal of Infectious Diseases 211 (2015)7. - ISSN 0022-1899 - p. 1128 - 1133.
real-time pcr - plasmodium-falciparum - pfhrp2 concentration - malawian children - cerebral malaria - blood - assay - retinopathy - clearance - diagnosis
In endemic areas malaria parasitemia is common in apparently healthy children and severe malaria is commonly misdiagnosed in patients with incidental parasitemia. We assessed the performance of plasma P. falciparum DNA concentration measurement in distinguishing uncomplicated from severe malaria in African children and Asian adults. P. falciparum DNA concentrations were measured by real-time PCR in 224 African children (111 uncomplicated, 113 severe) and 211 Asian adults (100 uncomplicated, 111 severe) presenting with acute falciparum malaria. The diagnostic accuracy of plasma PfDNA concentrations in identifying severe malaria was 0.834 in children and 0.788 in adults, similar to that of plasma PfHRP2, and substantially superior to parasite density (p
Defining falciparum malaria attributable sever febrile illness in moderate to high transmission settings based on plasma PfHRP2 concentration
Hendriksen, I.C.E. ; White, L.J. ; Veenemans, J. ; Verhoef, J.C.M. - \ 2013
The Journal of Infectious Diseases 207 (2013)2. - ISSN 0022-1899 - p. 351 - 361.
histidine-rich protein-2 - north-eastern tanzania - sub-saharan africa - plasmodium-falciparum - cerebral malaria - case definitions - systematic analysis - clinical-diagnosis - malawian children - endemic areas
Background. In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations. Methods. Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6-60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease. Results. The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%-100%), with a sensitivity of 74% (95% CI, 72%-77%), whereas a concentration of 10% (95% CI, 3%-27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles. Conclusions. The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.
Child hospitalization due to severe malaria is associated with the ICAM-1(Kilifi) allele but not adherence patterns of Plasmodium falciparum infected red blood cells to ICAM-1
Mwanziva, C. ; Mpina, M. ; Balthazary, S. ; Mkali, H. ; Mbugi, E.V. ; Mosha, F. ; Chilongola, J. - \ 2010
Acta Tropica 116 (2010)1. - ISSN 0001-706X - p. 45 - 50.
intercellular-adhesion molecule-1 - rhinovirus receptor - clinical severity - cerebral malaria - binding-sites - polymorphism - protein - domain - sequestration - cytoadherence
This study aimed at determining whether the predisposition of a mutation at position 179 of the ICAM-1 gene to child hospitalization due to malaria was mediated by changes in adherence properties of IRBCs to ICAM-1. ICAM-1 genotypes were determined by nested polymerase chain reaction of isolated DNA from filter blood spots followed by Restriction Fragment Length Polymorphism (RFLP). Plasmodium falciparum adherence assays were done on immobilized purified ICAM-1. Our data indicate that the homozygosity for the ICAM-1(Kilifi) mutation occurs at a frequency of 22.3% in Magugu-Babati, Northern Tanzania. Our results show that there are no differences in IRBC binding profiles across genotypes. We show in this study that homozygosity for the ICAM-1(Kilifi) is associated with child hospitalization (X-2 = 14.47, p <0.001). We have further shown that hospitalization was not associated with cytoadherence (X-2 = 0.17, p = 0.68). We conclude that the ICAM-1(Kilifi) allele occurs at a high frequency in Tanzania and that associations of this allele with higher child hospitalization frequencies is independent of cytoadherence patterns of IRBC isolated from ICAM-1 genotypes, implying that any associations reported to exist between the ICAM-1(Kilifi) mutation and severe malaria are unlikely to be mediated through altered IRBC cytoadherence properties.