Effect of α+-thalassaemia on episodes of fever due to malaria and other causes: a community-based cohort study in Tanzania

Abstract

BackgroundIt is controversial to what degree α+-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium.MethodsIn Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α+-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child.ResultsThe overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α+-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α+-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes.ConclusionsIn this population, the association between α+-thalassaemia and malaria depends on age. Our data suggest that protection by α+-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.

World Distribution, Population Genetics, and Health Burden of the Hemoglobinopathies

“…Furthermore, unlike HbAS, there is little evidence that a thalassemia has any effect at the level of malaria parasite density (Allen et al 1997;Mockenhaupt et al 2004b;Migot-Nabias et al 2006;Wambua et al 2006;Enevold et al 2008;Veenemans et al 2008Veenemans et al , 2011. Such clinical observations suggest that the mechanisms by which a thalassemia protects against malaria might well be different from those involved in HbAS.…”

“…Whereas many more studies have recorded, the clinical relationship between a thalassemia and malaria, the results have not been entirely consistent. The incidence of uncomplicated clinical malaria has been lower in a thalassemic than normal subjects in some cohort studies (Wambua et al 2006;Enevold et al 2008), whereas in others the incidence has either been equal (Lin et al 2010;Veenemans et al 2011) or even higher (Williams et al 1996;Veenemans et al 2011). Conversely, studies focused on severe malaria have shown consistent evidence for a strongly protective effect that is generally more marked in homozygous than heterozygous subjects (Allen et al 1997;Mockenhaupt et al 2004b;Williams et al 2005d;Wambua et al 2006;May et al 2007).…”

“…Finally, it is also possible that immune factors might be involved. In two clinical studies, the incidence of uncomplicated clinical malaria has been paradoxically higher in the youngest a-thalassemic children (Williams et al 1996;Veenemans et al 2011), raising the possibility that a thalassemia might be acting like a natural vaccine, boosting exposure and immunity to malaria during early childhood. As for all the hemoglobin disorders, the story is more complicated than one might have thought at one point.…”

“…Recently, this relationship has been quantified statistically, an analysis that found strong geographical support for the malaria hypothesis in Africa but not in either the Americas or in Asia (Piel et al 2010). Hemoglobin S is absent from indigenous populations in the Americas, probably because malaria did not reach the continent until relatively recently, whereas in Asia it follows a rather Friedman 1978;Pasvol et al 1978;Friedman et al 1979 Enhanced removal of parasite-infected HbAS red blood cells Luzzatto et al 1970;Friedman 1978;Roth et al 1978;Shear et al 1993;Ayi et al 2004 Reduced pathogenicity of P. falciparum infected red blood cells because of reduced expression of PfEMP1 Cholera et al 2008;Cyrklaff et al 2011 Improved acquisition of malaria-specific immunity Edozien et al 1960;Cornille-Brogger et al 1979;Guggenmoos-Holzmann et al 1981;Marsh et al 1989;Bayoumi et al 1990;Abu-Zeid et al 1992 a thalassemia Specific protection against malaria-induced anaemia Allen et al 1997;Williams et al 2005d;Wambua et al 2006;May et al 2007;Fowkes et al 2008;Veenemans et al 2008 Reduced pathogenicity through reduced cytoadherence or rosetting Udomsangpetch et al 1993;Carlson et al 1994;Cockburn et al 2004 Immuological priming through crossspecies immunity between P. vivax and P. falciparum Williams et al 1996;Veenemans et al 2011 b thalassemia Enhanced removal of parasite-infected red blood cells Ayi et al 2004 Reduced invasion and growth of P. falciparum parasites Kaminsky et al 1986;Senok et al 1997 Reduced pathogenicity through reduced cytoadherence or rosetting restricted distribution, being confined to a small number of tribal populations in India …”

Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis

“…This protective effect may derive from the abnormal display of parasite virulence factors on the surface of parasitized HbC and HbS erythrocytes, 78,79 possibly owing to the disruption of the parasite’s remodeling of erythrocyte’s intracellular trafficking network by HbS and HbC. 80 Additionally, the age-dependent nature of malaria protection owing to HbAS 81,82 and α-thalassaemia 83 among children in recent reports support a protective mechanism based upon an enhanced acquisition of malaria immunity. Though HbS does not generally enhance IgG responses to a diverse array of P. falciparum proteins, 84 HbS may yet enhance IgG responses specifically to the parasite’s major cytoadherence ligand and virulence factor Plasmodium falciparum erythrocyte membrane protein (PfEMP1).…”