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An Immune Basis for Malaria Protection by the Sickle Cell Trait  [PDF]
Thomas N Williams ,Tabitha W Mwangi,David J Roberts,Neal D Alexander,David J Weatherall,Sammy Wambua,Moses Kortok,Robert W Snow,Kevin Marsh
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020128
Abstract: Background Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. Methods and Findings We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. Conclusions Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes.
Sickle cell protection from malaria: a review
Sandro Eridani
Hematology Reports , 2011, DOI: 10.4081/hr.2011.e24
Abstract: A linkage between presence of Sickle Haemoglobin (HbS) and protection from malaria infection and clinical manifestations in certain areas was suspected from early observations and progressively elucidated by more recent studies. Research has confirmed the abovementioned connection, but also clarified how such protection may be abolished by coexistence of sickle cell trait (HbS trait) and alpha thalassemia, which may explain the relatively low incidence of HbS trait in the Mediterranean. The mechanisms of such protective effect are now being investigated: factors of genetic, molecular and immunological nature are prominent. As for genetic factors attention is given to the role of the red blood cell (RBC) membrane complement regulatory proteins as polymorphisms of these components seem to be associated with resistance to severe malaria; genetic ligands like the Duffy group blood antigen, necessary for erythrocytic invasion, and human protein CD36, a major receptor for P. falciparum-infected RBC‘s, are also under scrutiny: attention is focused also on plasmodium erythrocyte-binding antigens, which bind to RBC surface components. Genome-wide linkage and association studies are now carried out too, in order to identify genes associated with malaria resistance. Only a minor role is attributed to intravascular sickling, phagocytosis and haemolysis, while specific molecular mechanisms are the object of intensive research: among these a decisive role is played by a biochemical sequence, involving activation of haeme oxygenase (HMO-1), whose effect appears mediated by carbon monoxide (CO). A central role in protection from malaria is also played by immunological factors, which may stimulate antibody production to plasmodium antigens in the early years of life; the role of agents like pathogenic CD8 T-cells has been suggested while the effects of molecular actions on the immunity mechanism are presently investigated. It thus appears that protection from malaria can be explained by interaction of different factors: the elucidation of such mechanisms may prove valuable for the prevention and treatment strategy of a disease which still affects large parts of the world.
SICKLE CELL ANAEMIA AND MALARIA  [cached]
Lucio Luzzatto
Mediterranean Journal of Hematology and Infectious Diseases , 2012, DOI: 10.4084/mjhid.2012.
Abstract: Sickle cell anaemia is a major chapter within haemolytic anaemias; at the same time, its epidemiology is a remarkable signature of the past and present world distribution of Plasmodium falciparum malaria. In this brief review, in keeping with the theme of this journal, we focus on the close and complex relationship betweeen this blood disease and this infectious disease. On one hand, heterozygotes for the sickle gene (AS) are relatively protected against the danger of dying of malaria, as now firmly established through a number of clinical field studies from different parts of Africa. In addition, experimental work is consistent with a plausibile mechanism: namely, that in AS heterozygotes P falciparum-infected red cells sickle preferentially and are then removed by macrophages. On the other hand, patients who are homozygous for the sickle gene and therefore suffer from sickle cell anaemia (SCA) are highly susceptible to the lethal effects of malaria. The simplest explanation of this fact is that malaria makes the anaemia of SCA more severe; in addition, in SCA there is often hyposplenism, which reduces clearance of parasites. From the point of view of public health it is important that in malaria-endemic countries patients with SCA, and
Long-term follow-up of kidney allografts in patients with sickle cell hemoglobinopathy
Friedrisch, Jo？o R.;Barros, Elvino J.;Manfro, Roberto C.;Bittar, Cristhina M.;Silla, Lúcia M. R.;
Revista Brasileira de Hematologia e Hemoterapia , 2003, DOI: 10.1590/S1516-84842003000200007
Abstract: although sickle cell anemia and sickle cell disease produce a variety of functional renal abnormalities they uncommonly cause end stage renal failure. renal transplantation has been a successful alternative for the treatment of the rare terminal chronic renal failure with outcomes comparable with non-sickle recipients. this approach, however, has not been often described on patients with renal failure associated with sc hemoglobinopathy. here we report the outcomes of two patients with chronic renal failure due to sc hemoglobinopathies who underwent renal transplantation. at the time of the transplantation they were both severely anemic and had frequent vasoocclosive pain crises. both patients evolved with good allograft function, near normal hematological parameters, and very rare pain crisis, thirteen and eight years after transplant. these cases illustrate that terminal renal failure due to sc hemoglobinopathy can be successfully managed by renal transplantation and satisfactory long-term results are achievable not only in terms of renal allograft function but also of their hematological condition.
Long-term follow-up of kidney allografts in patients with sickle cell hemoglobinopathy
Friedrisch Jo？o R.,Barros Elvino J.,Manfro Roberto C.,Bittar Cristhina M.
Revista Brasileira de Hematologia e Hemoterapia , 2003,
Abstract: Although sickle cell anemia and sickle cell disease produce a variety of functional renal abnormalities they uncommonly cause end stage renal failure. Renal transplantation has been a successful alternative for the treatment of the rare terminal chronic renal failure with outcomes comparable with non-sickle recipients. This approach, however, has not been often described on patients with renal failure associated with SC hemoglobinopathy. Here we report the outcomes of two patients with chronic renal failure due to SC hemoglobinopathies who underwent renal transplantation. At the time of the transplantation they were both severely anemic and had frequent vasoocclosive pain crises. Both patients evolved with good allograft function, near normal hematological parameters, and very rare pain crisis, thirteen and eight years after transplant. These cases illustrate that terminal renal failure due to SC hemoglobinopathy can be successfully managed by renal transplantation and satisfactory long-term results are achievable not only in terms of renal allograft function but also of their hematological condition.
Micronutrients as therapeutic tools in the management of sickle cell disease, malaria and diabetes
VI Okochi, J Okpuzor
African Journal of Food, Agriculture, Nutrition and Development , 2004,
Abstract: The Global use of micronutrients in health care delivery has taken center stage due to the realization of their importance in disease management. Sickle cell disease, malaria and diabetes are among the diseases plaguing a good population of the developing world and the cost implication for their management is very high. Sickle cell disease and malari have anemia as a common factor and immunological disturbances are also prevalent in these disease conditions. Free radicals are generated in sickle cell disease, malaria and diabetes so a balance between minerals and antioxidants is imperative to maintain membrane integrity and function. Protection of red cell membranes from free radical-mediated oxidative stress is crucial to their management. Minerals such as copper, iron, chromium, magnesium, selenium and vanadium as well as vitamins like A, C, E, folate and the B group have been found to relieve oxidative stress associated with them. Micronutrients and their importance in the management of sickle cell disease, malaria and diabetes is reviewed here, with emphasis on the need to harness the natural resources abundant in our environment.
Sickle cell trait (HbAS) and stunting in children below two years of age in an area of high malaria transmission
Benno Kreuels, Stephan Ehrhardt, Christina Kreuzberg, Samuel Adjei, Robin Kobbe, Gerd D Burchard, Christa Ehmen, Matilda Ayim, Ohene Adjei, Jürgen May
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-16
Abstract: 1,070 children were recruited at three months of age and followed-up for 21 months with anthropometric measurements performed every three months. Incidence rate ratios with 95% confidence intervals were calculated by Poisson regression to estimate the association of β-globin genotypes with the number of malaria episodes. Odds ratios (OR) were calculated for the association between the occurrence of β-globin genotypes and/or malaria episodes and stunting. The age-dependent between-group and within-group effects for the β-globin genotypes were assessed by population-averaged models estimated by generalized estimation equation with autoregressive correlation structure.Analyses showed a significantly lower age-dependent risk of stunting (OR 0.56; 95% CI 0.33–0.96) in carriers of the HbAS genotype (n = 102) in comparison to those with HbAA (n = 692). This effect was restricted to children who experienced malaria episodes during the observation period suggesting that the beneficial effect of the β-globin HbS variant on the incidence of stunting is closely linked to its protection from mild malaria episodes.The lower risk of chronic malnutrition in early childhood, mediated by protection against mild malaria episodes, may contribute to the survival advantage of HbAS carriers in areas of high malaria transmission.There is much epidemiological evidence that sickle cell trait decreases the risk for all manifestations of severe malaria and that this protective effect has caused a balanced polymorphism of the sickle cell mutation (HbS) in malaria endemic regions [1]. In addition to protection against severe malaria, HbS has also been shown to exhibit some level of protection against mild malaria [2]. The importance of this observation for the survival advantage of individuals with HbAS remains unclear [3]. Repeated malaria episodes in early childhood can impair a child's development and induce malnutrition [4-6]. Stunting (length/height-for-age z-score < -2) in early childhood,
Prevalence of Deletional Alpha Thalassemia and Sickle Gene in a Tribal Dominated Malaria Endemic Area of Eastern India  [PDF]
Prasanta Purohit,Snehadhini Dehury,Siris Patel,Dilip Kumar Patel
ISRN Hematology , 2014, DOI: 10.1155/2014/745245
Abstract: Inherited hemoglobin disorders like alpha thalassemia and sickle gene are common in the Indian subcontinent. These disorders in the heterozygous state act as malaria resistance genes and influence the susceptibility to Plasmodium falciparum malaria. There is inadequate knowledge about the epidemiology of these malaria resistance genes in the tribal dominated malaria endemic region of the state of Odisha in eastern India. A cross sectional prevalence study was undertaken in 594 subjects in five tribal populations in this region, namely, Sahara (42.4%), Kutia Kandha (30.0%), Kuda (15.8%), Gond (9.8%), and Oraon (2.0%). Sickling test, Hb electrophoresis, HPLC, and molecular studies were undertaken to diagnose the prevalence of sickle allele, β-thalassemia allele, and deletional alpha thalassemia. Sickle and β thalassemia alleles were found in 13.1% and 3.4% of subjects, respectively. Sickle allele was found both in heterozygous (10.1%) and homozygous state (3.03%). The prevalence of alpha thalassemia was 50.84% with an allelic frequency of 0.37. Both α？3.7 and α？4.2 alpha thalassemia were detected with an allele frequency of 0.33 and 0.04, respectively. The high prevalence of alpha thalassemia and sickle gene in this population is probably due to selection pressure of endemic malaria in this part of India. 1. Introduction Inherited hemoglobin disorders are the commonest monogenic diseases in humans [1]. Between 3,00,000 and 4,00,000 babies are born each year with serious hemoglobin disorders and up to 90% of these births occur in low and middle income countries [2]. Many of these inherited hemoglobin disorders are malaria resistance genes and in the heterozygous state influence the susceptibility to P. falciparum malaria [3, 4]. However our knowledge regarding their epidemiology and the pathophysiological basis of malaria protection is inadequate [3]. Alpha thalassemia, a commonly encountered inherited hemoglobin disorder presents in one of four clinical phenotypes (a) clinically asymptomatic (occurring in silent carrier state) due to a single alpha gene deletion (– / ) with no or little hematological changes [5], (b) alpha thalassemia minor due to deletion of two genes (– /– ; –？–/ ), (c) hemoglobin H disease due to deletion of three of the four alpha genes (–？–/– ), and (d) Barts hydrops fetalis, a fatal hemoglobin produced due to deletion of all four alpha genes (–？–/–？–) [5]. Both alpha thalassemia minor and hemoglobin H lead to a phenotype resembling thalassemia intermedia [4]. Alpha thalassemia is especially frequent in Mediterranean countries, South
Malaria Prevention in Children with Sickle Cell Disease: A Review of Options
A.A. Abdulkarim
International Journal of Tropical Medicine , 2012,
Abstract: Malaria remains a major source of morbidity and mortality in the tropics and subtropics. In Nigeria where the disease is endemic, sickle cell disease is also common. Malaria precipitates crises in patients with sickle cell anaemia and its prevention in this group of patients is of paramount importance to both the clinician and public health practitioner. Many cost-effective prevention options are now available for malaria and these can be deployed in sickle cell anaemia in order to improve the health of those affected.
Asymptomatic malaria parasitaemia in sickle-cell disease patients: how effective is chemoprophylaxis ?  [PDF]
Rachel Kotila,Abiola Okesola,Olufunmilola Makanjuola
Journal of Vector Borne Diseases , 2007,
Abstract: Background & objectives: Sickle-cell trait confers protection against malaria while homozygotesickle-cell disease (SCD) patients are at greater risk of malaria infection, hence the use of malariachemoprophylaxis in SCD patients. The use of malaria chemoprophylaxis and asymptomaticparasitaemia were studied in SCD and non-SCD patients.Study design: A semi-structured questionnaire was administered to both patients and controls; athick blood film was also examined in both the groups.Results: Sixty-nine percent of patients use proguanil, 22% do not use any form of chemoprophylaxis,while 9% use pyrimethamine. There was no significant difference between level of parasitaemia inpatients and controls (p = 0.1), a positive smear was found in equal numbers of patients onchemoprophylaxis and those not on chemoprophylaxis (p = 0.3). In the month preceding the study,31% of patients vs 18% of controls had received treatment for malaria. There were no significantdifferences between patients and controls in frequency of malaria attacks (p = 0.06), last episode ofmalaria (p = 0.2). Ten percent of patients and 2% of controls use bednets.Conclusion: This study did not find any advantage in the use of malaria chemoprophylaxis in SCDpatients over controls or SCD patients not on chemoprophylaxis. Vector control should also beconsidered in the fight against malaria. There is a need to look into why both patients and controlsfail to use bednets in a malaria endemic country.
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