Print version ISSN 0074-0276
Mem. Inst. Oswaldo Cruz vol.106 supl.1 Rio de Janeiro Aug. 2011
Juan Pablo QuinteroI, VII; André Machado SiqueiraII , III; Alberto TobónIV; Silvia BlairIV; Alberto MorenoV, VI; Myriam Arévalo-HerreraI, VII; Marcus Vinícius Guimarães LacerdaII, III; Sócrates Herrera ValenciaI, VII, +
ICaucaseco Scientific Research Center, Cali, Colômbia
IIFundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, AM, Brasil
IIIUniversidade do Estado do Amazonas, Manaus, AM, Brasil
IVUniversidad de Antioquia, Medellin, Colombia
VEmory Vaccine Centre, Yerkes National Primate Research Centre, Atlanta, GA, USA
VIDivision of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA
VIICentro Latino Americano de Investigación en Malaria, Cali, Colombia
Malaria is the most important parasitic disease worldwide, responsible for an estimated 225 million clinical cases each year. It mainly affects children, pregnant women and non-immune adults who frequently die victims of cerebral manifestations and anaemia. Although the contribution of the American continent to the global malaria burden is only around 1.2 million clinical cases annually, there are 170 million inhabitants living at risk of malaria transmission in this region. On the African continent, where Plasmodium falciparum is the most prevalent human malaria parasite, anaemia is responsible for about half of the malaria-related deaths. Conversely, in Latin America (LA), malaria-related anaemia appears to be uncommon, though there is a limited knowledge about its real prevalence. This may be partially explained by several factors, including that the overall malaria burden in LA is significantly lower than that of Africa, that Plasmodium vivax, the predominant Plasmodium species in the region, appears to display a different clinical spectrus and most likely because better health services in LA prevent the development of severe malaria cases. With the aim of contributing to the understanding of the real importance of malaria-related anaemia in LA, we discuss here a revision of the available literature on the subject and the usefulness of experimental animal models, including New World monkeys, particularly for the study of the mechanisms involved in the pathogenesis of malaria.
Key words: Plasmodium falciparum - Plasmodium vivax - malaria - anaemia - haemoglobin - Latin America
Malaria is the most important parasitic disease worldwide, causing 225 million clinical cases and an estimated 781,000 fatalities annually, and represents a major global public health problem (WHO 2010). Although four Plasmodium species have been classically responsible for human malaria, Plasmodium falciparum has been the most prevalent overall, particularly in Africa (86%). On this continent, the greatest mortality is associated with cerebral malaria and severe anaemia, mostly in children less than five years of age, in malaria holoendemic areas (Guerra et al. 2010). In sub-Saharan Africa, pregnant women are also at higher risk of cerebral malaria and anaemia, which are consequently the major causes of perinatal morbidity and mortality. Both of these malarial complications are responsible for a great number of spontaneous abortions, stillbirths, premature deliveries and low birth weight (Dicko et al. 2003).
Because of the higher P. falciparum global prevalence, morbidity and mortality, most research efforts on malaria pathogenesis have been focused on this species (Akhwale et al. 2004). However, Plasmodium vivax represents the second most prevalent species, responsible for an estimated 25-40% of the reported malaria clinical cases (Westenberger et al. 2010). Until recently, there was a mistaken belief that P. vivax was always a benign disease, however, there is growing body of evidence of the high prevalence of severe and complicated P. vivax malaria cases, including severe anaemia (Genton et al. 2008, Tjitra et al. 2008, Kochar et al. 2009, Alexandre et al. 2010, Andrade et al. 2010). Additionally, it is likely that the incidence of anaemia may be higher than what is currently diagnosed. Multiple factors indicate that the public health relevance of P. vivax may be more significant than was traditionally thought: (i) P. vivax has a wider geographical range - potentially exposing more people to the risk of infection, (ii) it is less amenable to control and (iii) most importantly, infections with P. vivax can cause severe clinical syndromes (Tjitra et al. 2008).
Approximately 170 million people live at risk of P. vivax and P. falciparum transmission in 21 countries in Latin America (LA) and the Caribbean (Guerra et al. 2008, 2010). Nearly 60% of the malaria cases in the Americas are reported from Brazil and the other 40% are reported from Colombia (14.2%), Peru (8.8%), Venezuela (5.4%), Bolivia (1.9%) and Ecuador (1.1%). Caribbean cases include those reported in Haiti (2.8%). Central American countries report the occurrence of malaria cases as Guatemala (3.8%), Panama (0.4%) and Honduras (1.5%). In terms of malaria species distribution, 74% of infections are caused by P. vivax, 25% by P. falciparum and < 0.01% by Plasmodium malarie. All the species together contributes a mortality estimated in less than 0.1% to the overall mortality caused by malarial infections (WHO 2009).
The benefits of a detailed knowledge of P. vivax transmission and its clinical burden are identical to those of P. falciparum. The development of the Malaria Atlas Project has shown that the global mapping of malaria is a fundamental step to (i) understand the epidemiology of the disease on a global scale, (ii) appraise the equity of global financing for malaria control and (iii) set the basis for disease burden estimation. Although significant progress has been made in P. falciparum mapping, in the case of P. vivax, such maps have been developed only recently, making any strategic planning in LA more difficult (Guerra et al. 2010).
To elucidate the molecular mechanisms involved in the pathogenesis of malaria-induced anaemia, this review address the malarial anaemia immune pathogenesis process and the relevance of currently available experimental animal models, particularly New World monkeys, which are susceptible to human malaria parasites (Alexandre et al. 2010, Andrade et al. 2010).
Epidemiology of malaria-related anaemia in LA - It has been estimated that nearly 50% of the population, distributed in 21 countries of the American continents, is exposed at some level to the risk of malaria transmission (Gusmao 1999). Of these countries, Brazil and Colombia experience greater than 60% of the malaria cases. In LA, malaria exhibits epidemiological characteristics that appear to be particular to the region. There is an extraordinary parasite genetic differentiation due to bio-geographic barriers such as the Andean ridge, which separates endemic areas on the Pacific coast of the region from those in the Amazon and Orinoco Basins.
In the case of P. falciparum, there is substantial spatial and temporal heterogeneity in the proportion of infections caused by each parasite population (Cortese et al. 2002, McCollum et al. 2007). This has resulted in the isolation of parasite populations and limited dispersion of mutations, such as those associated with anti-malarial drug resistance in P. falciparum populations, which may have consequences for malaria control strategies. Drug resistance associated mutations that are common in the Amazon and Orinoco Basins have not been introduced to the Pacific coast region (Bacon et al. 2009, Corredor et al. 2010). Additionally, there is a dense forest, known as the Darien gap, which geographically separates Central America from South America and maintains parasite populations that harbour significantly different drug sensitivity profiles (Restrepo-Pineda et al. 2008). Interestingly, communities in these distinct geographical areas correspond to highly diverse ethnic groups (e.g., African descendants, native Indians and mestizos) with critical genetic differences in their Duffy (Fy) blood groups, which influence P. vivax malaria susceptibility (Hadley & Peiper 1997). As a consequence of this complexity, but also because of the limited resources traditionally allocated to malaria research in this region, the epidemiology of malaria, including the prevalence of anaemia in these areas, is still poorly understood.
An exhaustive search for studies addressing malaria-related anaemia in the 21 countries of LA known to have malaria transmission has indicated that only 56 studies have been published in this period. This represents the work spanning the more than 60 years since the initiation of the Malaria Eradication Campaign. Twenty-four of the studies reported anaemia and/or information on haemoglobin (Hb) levels in community-based malaria patients (Table I), 18 studies were based on reports of hospitalised malaria patients (Table II) and 14 corresponded to cross-sectional surveys in malaria-endemic communities (Table III). Additionally, 70% of the published studies were contributed by only three countries: Brazil, Venezuela and Colombia, significantly limiting the geographical distribution of the available information.
Unfortunately, not only are studies scarce but they are also not comparable because (i) the designs of the studies were variable, (ii) the populations studied were different, (iii) the definition of anaemia was not universal, (iv) it is difficult to thoroughly understand the history of the infection, as several of the studies were cross-sectional and not prospective, (v) co-infections were frequently present, such as bacteraemia or helminth infection and (vi) patients with haemoglobinopathies or glucose-6-phosphate dehydrogenase (G6PD) deficiencies presented at different prevalence rates. Therefore, although severe anaemia was reported in these studies, it is not possible to determine its prevalence, which appears to be low regardless. These findings indicate the need for better-designed studies of malaria-related anaemia that assess not only its overall prevalence, but also its association with malnutrition and with common co-infections and diseases, such as helminth infections, bacterial infections and hepatitis.
Clinical spectrum of anaemia in human subjects - The clinical manifestations of malaria depend on multiple factors from the parasite, parasite-host interactions and host factors, including socio-economic conditions. Some of the host factors that have been studied more in-depth include immunity, particularly the production of pro and anti-inflammatory cytokines, genetic traits, α or β-thalassemia, Fy phenotype, sickle cell traits and age. Parasite factors such as endemicity, drug resistance, Plasmodium species, parasite multiplication rates and antigenic polymorphism are of great relevance for anaemia development. Moreover, social-geographical factors, such as access to treatment, cultural and economic factors, health policies and transmission intensity greatly contribute to increased risk of anaemia.
Malarial anaemia is usually normocytic and normochromic (Phillips et al. 1986, Bashawri et al. 2002), without spherocytes or schistocytes. However, the anaemia associated with malaria can also be microcytic and hypochromic due to the high frequencies of haemoglobinopathies and iron deficiency in endemic countries (Bashawri et al. 2002).
Another key feature of malarial anaemia is the presence of inadequate reticulocytosis, despite the degree of anaemia. In acute uncomplicated malaria due to P. falciparum, the haematocrit may be normal during the first 24 h after the onset of fever, but afterwards there can be a progressive fall in the haematocrit level (Wickramasinghe & Abdalla 2000) despite the initiation of anti-malarial treatment (Phillips et al. 1986) and even in the absence of parasites in the blood smear (English et al. 2002) or the administration of blood transfusions.
During malaria infection, there are soluble derivatives released by the parasite that induce bone marrow (BM) dysfunction. These derivatives are therefore implicated in the pathogenesis of malarial anaemia (Silverman et al. 1987, Miller et al. 1989, Jootar et al. 1993). This is reinforced by the observation that, as a consequence of repeated infections or suboptimal treatment, children may be partially immunocompromised and so asymptomatic during chronic P. falciparum infections. Despite having very low Hb levels (Kurtzhals et al. 1999), these children display absolute reticulocyte counts lower than expected for the degree of the anaemia (Wickramasinghe & Abdalla 2000). These low counts might indicate some degree of BM dysfunction (Kurtzhals et al. 1997). For P. vivax infection, it has been observed that the decrease in Hb concentrations can be attributed to the activity of the parasites. The destruction of erythrocytes is marked at the beginning of the infection and erythrocytes do not return to pre-infection numbers in a short period of time, despite the elimination of the infection. This can be primarily explained by P. vivax invasion to reticulocytes, which prevents the establishment of the normal erythrocyte population (Collins et al. 2003).
Immunopathology - Although several mechanisms appear to participate in the generation of anaemia in individuals acutely or chronically infected with malaria, the mechanisms can nevertheless be grouped into two main categories: (i) destruction of cells in the peripheral circulation and (ii) a reduction in or alteration of the production of erythroid precursors. Although host genetics may exert some influence for these two mechanisms, its role in anaemia pathogenesis is still poorly understood. For instance, host genetic diversity may explain, to some extent, variations in the frequency of anaemia when distinct areas are compared worldwide. The Fy-negative genotype, which prevails on the Colombian Pacific coast, for example, defines the higher prevalence of P. falciparum in that region, as compared to other regions where P. vivax is more prevalent (Caicedo et al. 2009). Likewise, there is evidence that FY*B/FY*X and FY*A/FY*X genotypes are associated with low levels of P. vivax parasitism, which may favourably impact Hb levels (Albuquerque et al. 2010). Recently, G6PD deficiency (Mediterranean type) was shown to protect against P. vivax infection (Leslie et al. 2010); however, protection by the African type, which is more prevalent in LA (Chagas et al. 2009), has never been shown.
Peripheral destruction of red blood cells (RBC) - An important part of the Plasmodium life cycle occurs as an obligate intraerythrocytic parasite, where it differentiates and multiplies at the expense of the host cell's nutrients up to the induction of its burst. Each merozoite released either from the liver or from an erythrocyte invades a new erythrocyte; in the case of P. vivax, its merozoites have a preference for immature red cells (reticulocytes), whereas in the case of P. falciparum, its merozoites invade erythrocytes of any age (Simpson et al. 1999, Rayner et al. 2005). This parasite-specific invasion preference entails the expression of receptors on the erythrocyte surfaces that are required for an invasion. These include the Fy group antigens and reticulocyte-binding ligands in the case of P. vivax (Galinski et al. 1992) or glycophorins A, B and C, sialoglycoproteins expressed on human erythrocytes, in the case of P. falciparum (JaŚkiewicz 2007). An obvious consequence of the parasite multiplication and the periodic burst of schizonts is the rupture of infected erythrocytes. Although this clearly contributes to the development of anaemia, it does not appear to be sufficient to explain the levels of anaemia attained in individuals exposed to the infection. It has been established that levels of parasitaemia of > 50,000 parasites/µL are indicative of severe falciparum malaria (WHO 2000). An infection level that corresponds to the infection and destruction of approximately 1% of the total erythrocyte mass could be easily replaced by erythropoiesis under normal conditions. However, it seems that simultaneous to this mechanism, depuration of the parasitized erythrocytes also occurs as a consequence of the phenomenon of erythrocyte rigidity. This rigidity is induced by the transport of parasite antigens to the infected erythrocyte membrane and is followed by the deformation of the membrane, opsonisation by antibodies and complement and by macrophage activation (Wickramasinghe & Abdalla 2000). However, in many cases, the severity of malaria anaemia does not directly correlate with the degree of circulating parasitaemia (e.g. < 1%), though detected parasitaemia does not reflect the total parasite load, as it does not take into account parasites sequestered in the microvasculature (Nakazawa et al. 1995). Additionally, erythrocytes of malaria patients have a decreased half-life compared to those of healthy individuals (Looareesuwan et al. 1991). Moreover, epidemiological and mathematical models have shown that between 8-12 non-parasitized erythrocytes may be destroyed for each Pf-RBC parasitized (Jakeman et al. 1999, Price et al. 2001).
Although the precise cause of the destruction of non-parasitized erythrocytes is unknown, several mechanisms have been postulated: (i) the production of auto-antibodies against the proteins that modify RBC membranes (Jakobsen et al. 1995), (ii) antibody-independent phagocytosis of phosphatidyl-serine exposure, secondary to damage mediated by reactive oxygen species (Bratosin et al. 1998, Serghides et al. 2003), (iii) recognition of malarial antigens on infected erythrocytes by immunoglobulins (Igs) and their further clearance by macrophages (Waitumbi et al. 2000), (iv) complement-mediated phagocytosis and/or haemolysis (Ritter et al. 1993) and (v) loss of complement regulatory proteins (CD35, CD55 and CD59) (Waitumbi et al. 2000, Stoute et al. 2003). Furthermore, it has been documented that the activities and absolute numbers of macrophages are increased during infection; together with erythrocyte changes (decreased deformability and deposition of Igs), this could assist in the depuration of non-parasitized erythrocytes during infection (Mohan et al. 1995).
When dealing with the poorly described P. vivax-induced anaemia phenomenon, another relevant issue is the increasing body of evidence of P. vivax chloroquine resistance in many endemic areas, including some regions of LA (Santana Filho et al. 2007), which tends to increase peripheral parasitaemia for a longer period of time. It has been demonstrated that in areas where chloroquine resistance has been identified, severe disease (especially severe anaemia) is also frequent, which raises the possibility of a causal effect (Price et al. 2009). Biomarkers of resistance are urgently needed to validate this ecological association.
BM alterations -The mechanisms of BM dysfunction induced by malaria appear to be multiple but are still only partially known. The first observations of BM dysfunction during malaria infection occurred over 60 years ago, when reticulocytopaenia was documented in humans during P. falciparum and P. vivax infection. Afterwards, it was shown that patients with acute P. falciparum infections had low reticulocytaemia (or inappropriate reticulocytosis), which was accompanied with suppression of erythropoiesis (erythroid hypoplasia) (Camacho et al. 1998). Despite having increased cellularity in BM aspirates, there were no significant differences in the total numbers of erythroblasts (Abdalla & Wickramasinghe 1998). These findings provided evidence of a decrease in the erythroid response at the BM level. Children with chronic malaria, low parasitaemias (< 1%) and severe anaemia display erythroid hyperplasia and dyserythropoiesis (Abdalla et al. 1980, Wickramasinghe et al. 1989, Abdalla & Wickramasinghe 1998) accompanied by ineffective erythropoiesis and decreases in circulating reticulocytes.
Inadequate production of reticulocytes suggests insufficient erythropoiesis, which may be the result of either hypoproliferative erythropoiesis or hyperproliferative but ineffective erythropoiesis. Ineffective erythropoiesis is generally associated with intramedullar destruction of erythroid precursors by erythrophagocytosis or dysplastic changes of these precursors, which can be recognised by cytoplasmic vacuolation, abnormal nucleus (bilobed), nuclear budding, formation of interchromatin and intracytoplasmatic bridges and nuclear fragmentation.
It appears that in acute and some chronic anaemia patients, there are two major forms of anaemia: (i) anaemia with erythroid hypoplasia with or without dyserythropoiesis and (ii) anaemia with erythroid hyperplasia and dyserythropoiesis. Acute malaria infection in adults may be accompanied by a reduction in total erythropoietic activity. In these cases, there may be normal BM or reduced cellularity with erythroid hypoplasia. In cases of high parasitaemia, there may even be ineffective erythropoiesis of the residual erythropoietic activity (hypoproliferative erythropoiesis).
Several studies have documented a loss of precursor cells in the BM (Dörmer et al. 1983), reduced use of iron by the erythrocytes and dysplasic changes in the BM (Knuttgen 1987). However, in other studies, no evidence of dyserythropoiesis was found in children with acute P. falciparum infection (Das et al. 1999). Therefore, it has been proposed that, in contrast to chronic malaria, dyserythropoiesis plays a minor role in the pathogenesis of anaemia during an acute malaria infection (Das et al. 1999, Jakeman et al. 1999). Some studies suggest that ineffective erythropoiesis and dyserythropoiesis play greater roles (Abdalla et al. 1980, Weatherall et al. 1983) in chronic malaria infection, which may be accompanied by a severe anaemia characterised by an erythroid hyperplasia and dysplasia, some degree of erythrophagocytosis and low levels of reticulocytes. In this case, the dyserythropoiesis is directly related to malaria and is not caused by deficiencies of folate, vitamin B12 or iron (Abdalla et al. 1984).
However, ineffective erythropoiesis during malaria could develop through different mechanisms, such as altered Hb synthesis in vitro and premature death of normoblasts (Srichaikul et al. 1973, 1976).
Susceptible populations - In malaria-endemic regions, the most susceptible populations to suffer severe and complicated disease, including anaemia, are children < five years of age and pregnant women. Although older children and adults still suffer repeated malaria infections, the disease frequency and severity is progressively reduced. This clinical immunity does not develop in areas of low endemicity or seasonal exposure to parasites; therefore, the disease affects all groups in these regions (Miller et al. 1994). Pregnant women, although previously clinically immune, become more susceptible to developing the pathogenic processes that affect both the mother and the foetus, and subsequently the newborn.
Two of the most feared malaria complications that are associated with an increased mortality, especially in children and pregnant women, are cerebral malaria and severe anaemia, with mortality rates of 5.6-16% in children (Marsh et al. 1995) and approximately 6% in pregnant women (Granja et al. 1998, Menendez et al. 2000, Weatherall et al. 2002). As mentioned, immunological factors and mechanisms appear to have great relevance in the anaemia pathogenesis during a malaria infection. Beside the role of the antibodies that are specific to malarial antigens and are exported to erythrocyte membranes, the potential role of the erythrocyte-targeted auto-antibodies and that of complement activation and cytokine imbalances are associated with an increased anaemia severity in children with malaria. Pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6, are elevated during an acute malarial infection (Kern et al. 1989, Lyke et al. 2004) while anti-inflammatory cytokines, such as IL-10, are substantially decreased (Kurtzhals et al. 1998, 1999, Akanmori et al. 2000). Furthermore, elevated TNF-α levels are associated with an increased anaemia severity in children with malaria (Shaffer et al. 1991) and a low IL-10/TNF-α ratio is associated with an enhanced anaemia severity, suggesting that the relative expression of cytokines in the inflammatory milieu is an important determinant of severe malarial anaemia (Othoro et al. 1999, Perkins et al. 2000). It has also been observed that increased levels of TNF-α are associated with a decrease in erythroid progenitor cells, decreased iron uptake by erythrocytes, erythrophagocytosis of nucleated erythroblasts and dyserythropoiesis (Phillips et al. 1986, Silverman et al. 1987, Clark & Chaudhri 1988, Miller et al. 1989, Taverne et al. 1994). Moreover, recent studies show that hepcidin, a 25-amino-acid protein produced in the liver, is associated with the anaemia of inflammation in humans, where its production is increased 100-fold, resulting in both an impaired iron uptake in the gut and iron sequestration in macrophages (Ganz 2003, Means 2004).
Between 60-80% of Hb is degraded during the intraerythrocytic cycle, releasing haemozoin (Hz) and amino acids, which are used by the parasite to produce proteins. The presence of Hz in the cytoplasm of polymorphonuclear leukocytes and monocytes appears to be associated with the severity of the malarial infection, as it seems that cytoplasmic Hz is more frequently found in the complicated malaria cases than in the uncomplicated cases (Nguyen et al. 1995, Amodu et al. 1998, Lyke et al. 2003, López et al. 2004).
Experimental animal models of malarial anaemia - In-depth haematological studies in humans with malarial anaemia pose a number of ethical and technical challenges that preclude invasive procedures, particularly BM analyses over the course of the infection. The development of experimental animal models is therefore critical for understanding the mechanisms involved in the pathogenesis of severe anaemia. Although some molecular bases of malarial anaemia could be shared by several Plasmodium species, experimental evidence suggests that species-specific factors play significant roles. For example, a larger proportion of the non-infected RBCs are removed by erythrophagocytosis in P. vivax-infected individuals - it is estimated that ~32 non-infected RBCs are destroyed per every P. vivax-infected RBC (Collins et al. 2003), compared to approximately eight non-infected RBCs destroyed per every P. falciparum-infected RBC (Jakeman et al. 1999).
Four rodent malaria parasite species (Plasmodium berghei, Plasmodium chabaudi, Plasmodium vinckei and Plasmodium yoelii), have been extensively used to study malaria pathogenesis, including anaemia, due to their distinctive erythrocyte invasion profiles, which are similar to those observed with human parasites (Lamb et al. 2006). However, several features, such as anaemia in the presence of hyperparasitaemia and extramedullar erythropoiesis, which are frequently observed in rodents, are rare events in human malarial infections (Silverman et al. 1987, Yap & Stevenson 1992). Anaemia research in rodent models allows immunological studies and manipulations that are more difficult in other animal models, such as primates. Examples include in vivo depletion of macrophages and CD4+ T cells, comparisons of resistant vs. susceptible strains, experiments involving cytokine knockout mice, such as IL-10 (Linke et al. 1996) and macrophage migration inhibitory factor-deficient mice (Stevenson et al. 2001, McDevitt et al. 2006). Non-human primate models appear to be more relevant in LA, due to their abundance in the region and the availability of several primate colonies.
New World monkeys (Aotus and Saimiri) have been used extensively for vaccine trials and drug testing using P. falciparum and P. vivax-adapted strains (Collins 1992, Obaldia 2001, Herrera et al. 2002). Malaria semi-immune Aotus monkeys immunised with merozoite vaccine candidates or exposed to P. falciparum were protected from hyperparasitaemia, but were more likely to develop severe anaemia after a second challenge (Egan et al. 2002, Jones et al. 2002). In this experimental model, low Hb levels were associated with low reticulocyte counts, suggesting that the ineffective erythropoiesis and removal of non-infected erythrocytes are at least part of the aetiological factors involved (Egan et al. 2002). Aotus monkeys that self-control parasite patency or that received anti-malaria treatment exhibited a robust reticulocytosis, indicating a direct effect of the parasite on erythroid progenitors. Interestingly, immunisation of Aotus monkeys with the P. falciparum CIDR1α domain of PfEMP1, a protein involved in sequestration, prevents the development of anaemia after re-infection (Makobongo et al. 2006). Aotus also appears to be a good model to study the role of hepcidin homeostasis. Although little is known about the relationship between hepcidin and malarial anaemia, one study developed in Colombia with the Aotus model showed that hepcidin levels decreased throughout the experiment in malaria and mock-infected animals (Llanos 2008). Regardless of this finding, it remains an area for further research.
Methodologies have been implemented to study the BM compartment in Aotus monkeys experimentally infected with P. falciparum and P. vivax (Llanos et al. 2006). Interestingly, on-going studies have confirmed that high numbers of normoblasts are present in BM aspirates, suggesting that erythropoiesis is effective (unpublished data) (Llanos 2008). However, the molecular mechanisms involved in severe anaemia in semi-immune Aotus monkeys remain unknown (Egan et al. 2002).
Simian malaria parasites have been a critical resource for understanding the biology of Plasmodium (Brown & Brown 1965, Coatney 1968) for facilitating the development of anti-malarial drugs (Omar et al. 1973) and for characterising the mechanisms involved in the physiopathology of severe malaria (Davison et al. 1998). Unfortunately, comprehensive investigations on malaria pathogenesis have not been addressed using these experimental models (Galinski & Barnwell 2008). Plasmodium coatneyi and Plasmodium fragile share with P. falciparum the ultrastructural features that are involved in parasite sequestration and rosetting. Therefore, these parasite species mimic clinical complications of cerebral malaria associated with P. falciparum infections in humans (Kawai et al. 1993, Fujioka et al. 1994). P. coatneyi infection in macaques has also been associated with placental malaria, thrombocytopaenia, anaemia and disseminated intravascular coagulation (Kawai et al. 1993, Sein et al. 1993, Nakano et al. 1996, Smith et al. 1996, Davison et al. 1998, Collins et al. 2001, Moreno et al. 2007). Plasmodium cynomolgi is phylogenetically related to P. vivax and shares its capacity to produce hypnozoites (Krotoski et al. 1982). The patterns of relapses described in P. vivax are also present in rhesus macaques exposed to P. cynomolgi sporozoites, making this model ideal for studying the mechanisms of chronic anaemia (Schmidt 1986). Comparative experiments using P. coatneyi and P. cynomolgi in rhesus macaques are required to define whether the molecular mechanisms underlying the pathogenesis of malarial anaemia are shared between these two species. Unfortunately, such studies are restricted to primate centres outside LA.
Conclusions and perspectives - Beside the acknowledged importance of anaemia as a cause of morbidity and mortality in Africa and other endemic regions, little is known about its prevalence and burden in the malaria-endemic regions of LA. The few studies reported from this region appear to indicate that the incidence of severe anaemia is significantly lower than that reported from Africa or Asia. However, considering that specific haematological changes associated with malaria infection may vary with the level of malaria endemicity (Idro et al. 2006), nutritional status (Friedman et al. 2005), demographic factors (Barcus et al. 2007), malaria immunity (Langhorne et al. 2008) and the parasite species, it is essential to study and characterise the epidemiology and mechanisms involved in malarial anaemia in endemic regions of LA. The National Institutes of Health-National Institute of Allergy and Infectious Diseases is currently funding the establishment of the Centro Latino Americano de Investigación en Malaria (CLAIM) as a Centre of Excellence for Malaria Research (ICEMR). The Centre aims, as a priority, to determine the prevalence and severity of haematological manifestations attributable to malaria infection and their association with concomitant immune status, including nutritional factors and hel-minth coinfection. Although studies would initially cover only Colombia, Panama, Peru and Guatemala, further expansion of malaria research, including anaemia, would be extended to other countries of LA, to the Caribbean region and Brazil. CLAIM already interacts with the Brazilian Malaria Network, which aims to describe the determinants of P. vivax-related severe anaemia in hospitalised patients from a tertiary care institution, specifically focussing on the impacts of host genetics (G6PD deficiency and Fy genotypes) and chloroquine resistance.
These multi-country regional projects will allow the comparison of pathologies in settings with different malaria transmission intensities in communities with great ethnic, occupational and immune diversities. Moreover, the availability of the Aotus monkey animal model in several countries of the LA region represents a valuable resource to address important questions regarding malaria pathogenesis that cannot be studied in the human populations. Indeed, the accessibility to BM aspirates of non-human primates vaccinated with human malaria vaccine candidates opens an interesting new area of research to complement the analyses of the influences of specific antimalarial immune responses in the generation of anaemia.
To the participation of endemic communities from malaria endemic areas of Colombia and Brazil, who kindly accepted to participate in part of the studies mentioned here, and to Paola Rojas, for her technical support to prepare this paper.
Abdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M 1980. The anaemia of P. falciparum malaria. Br J Haematol 46: 171-183. [ Links ]
Abdalla SH, Wickramasinghe SN 1998. A study of erythroid progenitor cells in the bone marrow of Gambian children with falciparum malaria. Clin Lab Haematol 10: 33-40. [ Links ]
Abdalla SH, Wickramasinghe SN, Weatherall DJ 1984. The deoxyuridine suppression test in severe anaemia following Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 78: 60-63. [ Links ]
Akanmori BD, Kurtzhals JA, Goka BQ, Adabayeri V, Ofori MF, Nkrumah FK, Behr C, Hviid L 2000. Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria. Eur Cytokine Netw 11: 113-118. [ Links ]
Akhwale WS, Lum JK, Kaneko A, Eto H, Obonyo C, Björkman A, Kobayakawa T 2004. Anemia and malaria at different altitudes in the western highlands of Kenya. Acta Trop 91: 167-175. [ Links ]
Albuquerque SR, Cavalcante F de O, Sanguino EC, Tezza L, Chacon F, Castilho L, dos Santos MC 2010. FY polymorphisms and vivax malaria in inhabitants of Amazonas State, Brazil. Parasitol Res 106: 1049-1053. [ Links ]
Alexandre MA, Ferreira CO, Siqueira AM, Magalhaes BL, Mourao MP, Lacerda MV, Alecrim MG 2010. Severe Plasmodium vivax malaria, Brazilian Amazon. Emerg Infect Dis 16: 1611-1614. [ Links ]
Amaral CNd, Albuquerque YDd, Pinto AYDN, Souza JMD 2003. A importancia do perfil clínico-laboratorial no diagnostico diferencial entre malaria e hepatite aguda viral. J Pediatr 79: 429-434. [ Links ]
Amodu OK, Adeyemo AA, Olumese PE, Gbadegesin RA 1998. Intraleucocytic malaria pigment and clinical severity of malaria in children. Trans R Soc Trop Med Hyg 92: 54-56. [ Links ]
Andrade BB, Reis-Filho A, Souza-Neto SM, Clarencio J, Camargo LM, Barral A, Barral-Netto M 2010. Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malar J 9: 13. [ Links ]
Bacon DJ, McCollum AM, Griffing SM, Salas C, Soberon V, Santolalla M, Haley R, Tsukayama P, Lucas C, Escalante AA, Udhayakumar V 2009. Dynamics of malaria drug resistance patterns in the Amazon Basin region following changes in Peruvian national treatment policy for uncomplicated malaria. Antimicrob Agents Chemother 53: 2042-2051. [ Links ]
Barcus MJ, Basri H, Picarima H, Manyakori C, Sekartuti, Elyazar I, Bangs MJ, Maguire JD, Baird JK 2007. Demographic risk factors for severe and fatal vivax and falciparum malaria among hospital admissions in northeastern Indonesian Papua. Am J Trop Med Hyg 77: 984-991. [ Links ]
Bardales Tuesta F, De la Puente-Olortegui C 2000. Manejo en UCI de la malaria falciparum severa y complicada. Bol Soc Peru Med Interna 13: 30-39. [ Links ]
Barraviera B, Machado PE, Meira DA 1988. Glutathione reductase activity and its relation with riboflavin levels measured by methemoglobin reduction by cystamine in patients with malaria (preliminary report). Rev Inst Med Trop Sao Paulo 30: 107-108. [ Links ]
Bashawri LA, Mandil AA, Bahnassy AA, Ahmed MA 2002. Malaria: hematological aspects. Ann Saudi Med 22: 372-376. [ Links ]
Blair S, Alvares G, Campuzano G 1997. Relación entre anemia y malaria en una población rural de Colombia. Boletín de la direccion de malariologia y saneamiento ambiental 37: 7-12. [ Links ]
Bratosin D, Mazurier J, Tissier JP, Estaquier J, Huart JJ, Ameisen JC, Aminoff D, Montreuil J 1998. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie 80: 173-195. [ Links ]
Brown KN, Brown IN 1965. Immunity to malaria: antigenic variation in chronic infections of Plasmodium knowlesi. Nature 208: 1286-1288. [ Links ]
Caicedo O, Ramirez O, Mourao MP, Ziadec J, Perez P, Santos JB, Quinones F, Alecrim MG, Arevalo-Herrera M, Lacerda MV, Herrera S 2009. Comparative hematologic analysis of uncomplicated malaria in uniquely different regions of unstable transmission in Brazil and Colombia. Am J Trop Med Hyg 80: 146-151. [ Links ]
Caicedo O, Villamor E, Forero Y, Ziade J, Pérez P, Quiñones F, Arévalo-Herrera M, Herrera S 2010. Relation between vitamin B12 and folate status and hemoglobin concentration and parasitemia during acute malaria infections in Colombia. Acta Tropica 114: 17-21. [ Links ]
Camacho LH, Gordeuk VR, Wilairatana P, Pootrakul P, Brittenham GM, Looareesuwan S 1998. The course of anaemia after the treatment of acute, falciparum malaria. Ann Trop Med Parasitol 92: 525-537. [ Links ]
Cardoso MA, Ferreira MU, Camargo LM, Szarfarc SC 1992. Anemia in a population from an endemic area of malaria, Rondonia (Brazil). Rev Saude Publica 26: 161-166. [ Links ]
Cardoso MA, Ferreira MU, Camargo LM, Szarfarc SC 1994. Anaemia, iron deficiency and malaria in a rural community in Brazilian Amazon. Eur J Clin Nutr 48: 326-332. [ Links ]
Carmona-Fonseca 2008. Vivax malaria in children: clinical features and response to chloroquine. Colomb Med 39: 364-377. [ Links ]
Castano AT, Pineros Jimenez JG, Trujillo SB, Carmona-Fonseca J 2006. Clinica de la malaria complicada debida a P. falciparum. Estudio de casos y controles en Tumaco y Turbo (Colombia). Iatreia 19: 339-355. [ Links ]
Chagas EC, Nascimento CT, Santana Filho FS, Botto-Menezes CH, Martinez-Espinosa FE 2009. Impact of malaria during pregnancy in the Amazon Region. Rev Panam Salud Publica 26: 203-208. [ Links ]
Chiriboga J, Machiavello S, Luglio M, Aiscorbe R 1950. Malaria, uncinariasis, nutricion y anemia en los tropicos. Medicina 10: 353-366. [ Links ]
Clark IA, Chaudhri G 1988. Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis. Br J Haematol 70: 99-103. [ Links ]
Coatney GR 1968. Simian malarias in man: facts, implications and predictions. Am J Trop Med Hyg 17: 147-155. [ Links ]
Collins WE 1992. South American monkeys in the development and testing of malarial vaccines - A review. Mem Inst Oswaldo Cruz 87 (Suppl. III): 401-406. [ Links ]
Collins WE, Jeffery GM, Roberts JM 2003. A retrospective examination of anemia during infection of humans with Plasmodium vivax. Am J Trop Med Hyg 68: 410-412. [ Links ]
Collins WE, Warren M, Sullivan JS, Galland GG 2001. Plasmodium coatneyi: observations on periodicity, mosquito infection and transmission to Macaca mulatta monkeys. Am J Trop Med Hyg 64: 101-110. [ Links ]
Corredor V, Murillo C, Echeverry DF, Benavides J, Pearce RJ, Roper C, Guerra AP, Osorio L 2010. Origin and dissemination across the Colombian Andes mountain range of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum. Antimicrob Agents Chemother 54: 3121-3125. [ Links ]
Cortese JF, Caraballo A, Contreras CE, Plowe CV 2002. Origin and dissemination of Plasmodium falciparum drug-resistance mutations in South America. J Infect Dis 186: 999-1006. [ Links ]
Das BS, Nanda NK, Rath PK, Satapathy RN, Das DB 1999. Anaemia in acute, Plasmodium falciparum malaria in children from Orissa state, India. Ann Trop Med Parasitol 93: 109-118. [ Links ]
Davison BB, Cogswell FB, Baskin GB, Falkenstein KP, Henson EW, Tarantal AF, Krogstad DJ 1998. Plasmodium coatneyi in the rhesus monkey (Macaca mulatta) as a model of malaria in pregnancy. Am J Trop Med Hyg 59: 189-201. [ Links ]
De Souza JM 1983. A Phase II clinical trial of mefloquine in Brazilian male subjects. Bull World Health Organ 61: 815-820. [ Links ]
Dicko A, Mantel C, Thera MA, Doumbia S, Diallo M, Diakite M, Sagara I, Doumbo OK 2003. Risk factors for malaria infection and anemia for pregnant women in the Sahel area of Bandiagara, Mali. Acta Trop 89: 17-23. [ Links ]
Dörmer P, Dietrich M, Kern P, Horstmann RD 1983. Ineffective erythropoiesis in acute human P. falciparum malaria. Blut 46: 279-288. [ Links ]
Echeverri M, Tobón A, Alvarez G, Carmona J, Blair S 2003. Clinical and laboratory findings of Plasmodium vivax malaria in Colombia, 2001. Rev Inst Med Trop Sao Paulo 45: 29-34. [ Links ]
Egan AF, Fabucci ME, Saul A, Kaslow DC, Miller LH 2002. Aotus New World monkeys: model for studying malaria-induced anemia. Blood 99: 3863-3866. [ Links ]
English M, Ahmed M, Ngando C, Berkley J, Ross A 2002. Blood transfusion for severe anaemia in children in a Kenyan hospital. Lancet 359: 494-495. [ Links ]
Espinoza E, Hidalgo L, Chedraui P 2005. The effect of malarial infection on maternal-fetal outcome in Ecuador. J Matern Fetal Neonatal Med 18: 101-105. [ Links ]
Faich GA, Mason J 1975. The prevalence and relationships of malaria, anemia and malnutrition in a coastal area of El Salvador. Am J Trop Med Hyg 24: 161-167. [ Links ]
Fernandes AAM, Carvalho LJM, Zanini GM, Ventura AMRS, Souza JM, Cotias PM, Silva-Filho IL, Daniel-Ribeiro CT 2008. Similar cytokine responses and degrees of anemia in patients with Plasmodium falciparum and Plasmodium vivax infections in the Brazilian Amazon Region. Clin Vaccine Immunol 15: 650-658. [ Links ]
Fernandez RD, Garcia Y, Alger J 2001. Malaria y embarazo: observaciones clinico-epidemiologicas en dos zonas geograficas de Honduras. Rev Med Hondur 69: 8-18. [ Links ]
Ferreira MU, da Silva-Nunes M, Bertolino CN, Malafronte RS, Muniz PT, Cardoso MA 2007. Anemia and iron deficiency in school children, adolescents and adults: a community-based study in rural Amazonia. Am J Public Health 97: 237-239. [ Links ]
Friedman JF, Kwena AM, Mirel LB, Kariuki SK, Terlouw DJ, Phillips-Howard PA, Hawley WA, Nahlen BL, Shi YP, ter Kuile FO 2005. Malaria and nutritional status among pre-school children: results from cross-sectional surveys in western Kenya. Am J Trop Med Hyg 73: 698-704. [ Links ]
Fujioka H, Millet P, Maeno Y, Nakazawa S, Ito Y, Howard RJ, Collins WE, Aikawa M 1994. A nonhuman primate model for human cerebral malaria: rhesus monkeys experimentally infected with Plasmodium fragile. Exp Parasitol 78: 371-376. [ Links ]
Galinski M, Barnwell J 2008. Plasmodium vivax: who cares? Malaria J 7: S9. [ Links ]
Galinski MR, Medina CC, Ingravallo P, Barnwell JW 1992. A reticulocyte-binding protein complex of Plasmodium vivax merozoites. Cell 69: 1213-1226. [ Links ]
Ganz T 2003. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102: 783-788. [ Links ]
García-Casal MN, Leets I, Bracho C, Hidalgo M, Bastidas G, Gomez A, Peña A, Pérez H 2008. Prevalence of anemia and deficiencies of iron, folic acid and vitamin B12 in an indigenous community from the Venezuelan Amazon with a high incidence of malaria. Arch Latinoam Nutr 58: 12-18. [ Links ]
Genton B, D'Acremont V, Rare L, Baea K, Reeder JC, Alpers MP, Muller I 2008. Plasmodium vivax and mixed infections are associated with severe malaria in children: a prospective cohort study from Papua New Guinea. PLoS Med 5: e127. [ Links ]
Gomez E, Lopez E, Ache A 2009. Malaria y embarazo. Parroquia San Isidro, municipio Sifontes, estado Bolivar, Venezuela, anos 2005-2006. Invest Clin 50: 455-464. [ Links ]
González L, Guzmán M, Carmona-Fonseca J, Lopera T, Blair S 2000. Características clínicoepidemiológicas de 291 pacientes hospitalizados por malaria en Medellín (Colombia). Acta Med Col 25: 163-170. [ Links ]
Granja AC, Machungo F, Gomes A, Bergström S, Brabin B 1998. Malaria-related maternal morbidity in urban Mozambique. Ann Trop Med Parasitol 92: 257-263. [ Links ]
Grenfell P, Fanello CI, Magris M, Goncalves J, Metzger WG, Vivas-Martínez S, Curtis C, Vivas L 2008. Anaemia and malaria in Yanomami communities with differing access to healthcare. Trans R Soc Trop Med Hyg 102: 645-652. [ Links ]
Guerra CA, Gikandi PW, Tatem AJ, Noor AM, Smith DL, Hay SI, Snow RW 2008. The limits and intensity of Plasmodium falciparum transmission: implications for malaria control and elimination worldwide. PLoS Med 5: e38. [ Links ]
Guerra CA, Howes RE, Patil AP, Gething PW, Van Boeckel TP, Temperley WH, Kabaria CW, Tatem AJ, Manh BH, Elyazar IRF, Baird JK, Snow RW, Hay SI 2010. The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis 4: e774. [ Links ]
Gusmao R 1999. Overview of malaria control in the Americas. Parassitologia 41: 355-360. [ Links ]
Gutierrez M, Maldonado I, Balliache N, Contreras I 1998. Anticuerpos antifosfolipidos en malaria. Med Interna (Caracas) 14: 142-152. [ Links ]
Hadley TJ, Peiper SC 1997. From malaria to chemokine receptor: the emerging physiologic role of the Duffy blood group antigen. Blood 89: 3077-3091. [ Links ]
Hamer DH, MacLeod WB, Addo-Yobo E, Duggan CP, Estrella B, Fawzi WW, Konde-Lule JK, Mwanakasale V, Premji ZG, Sempertegui F, Ssengooba FP, Yeboah-Antwi K, Simon JL 2003. Age, temperature and parasitaemia predict chloroquine treatment failure and anaemia in children with uncomplicated Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 9: 422-428. [ Links ]
Herrera S, Perlaza BL, Bonelo A, Arevalo-Herrera M 2002. Aotus monkeys: their great value for anti-malaria vaccines and drug testing. Int J Parasitol 32: 1625-1635. [ Links ]
Idro R, Aloyo J, Mayende L, Bitarakwate E, John CC, Kivumbi GW 2006. Severe malaria in children in areas with low, moderate and high transmission intensity in Uganda. Trop Med Int Health 11: 115-124. [ Links ]
Jakeman GN, Saul A, Hogarth WL, Collins WE 1999. Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes. Parasitology 119: 127-133. [ Links ]
Jakobsen PH, Bate CA, Taverne J, Playfair JH 1995. Malaria: toxins, cytokines and disease. Parasite Immunol 17: 223-231. [ Links ]
Jarude R, Trindade R, Tavares-Neto J 2003. Malária em grávidas de uma maternidade pública de Rio Branco (Acre, Brasil). Rev Bras Ginecol Obstet 25: 149-154. [ Links ]
JaŚkiewicz E 2007. Glycophorins of human erythrocytes as receptors for the malaria parasite Plasmodium falciparum. Postepy Hig Med Dosw 61: 718-724. [ Links ]
Jones TR, Stroncek DF, Gozalo AS, Obaldia N 3rd, Andersen EM, Lucas C, Narum DL, Magill AJ, Sim BK, Hoffman SL 2002. Anemia in parasite- and recombinant protein-immunized Aotus monkeys infected with Plasmodium falciparum. Am J Trop Med Hyg 66: 672-679. [ Links ]
Jootar S, Chaisiripoomkere W, Pholvicha P, Leelasiri A, Prayoonwiwat W, Mongkonsvitragoon W, Srichaikul T 1993. Suppression of erythroid progenitor cells during malarial infection in Thai adults caused by serum inhibitor. Clin Lab Haematol 15: 87-92. [ Links ]
Kawai S, Aikawa M, Kano S, Suzuki M 1993. A primate model for severe human malaria with cerebral involvement: Plasmodium coatneyi-infected Macaca fuscata. Am J Trop Med Hyg 48: 630-636. [ Links ]
Kern P, Hemmer CJ, Van Damme J, Gruss HJ, Dietrich M 1989. Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am J Med 87: 139-143. [ Links ]
Knuttgen H 1987. The bone marrow of non-immune Europeans in acute malaria infection: a topical review. Ann Trop Med Parasitol 81: 567-576. [ Links ]
Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, Kochar A, Khatri MP, Gupta V 2009. Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg 80: 194-198. [ Links ]
Krotoski WA, Garnham PC, Bray RS, Krotoski DM, Killick-Kendrick R, Draper CC, Targett GA, Guy MW 1982. Observations on early and late post-sporozoite tissue stages in primate malaria. I. Discovery of a new latent form of Plasmodium cynomolgi (the hypnozoite) and failure to detect hepatic forms within the first 24 hours after infection. Am J Trop Med Hyg 31: 24-35. [ Links ]
Kurtzhals JA, Adabayeri V, Goka BQ, Akanmori BD, Oliver-Commey JO, Nkrumah FK, Behr C, Hviid L 1998. Low plasma concentrations of interleukin-10 in severe malarial anaemia compared with cerebral and uncomplicated malaria. Lancet 351: 1768-1772. [ Links ]
Kurtzhals JA, Akanmori BD, Goka BQ, Adabayeri V, Nkrumah FK, Behr C, Hviid L 1999. The cytokine balance in severe malarial anemia. J Infect Dis 180: 1753-1755. [ Links ]
Kurtzhals JA, Rodrigues O, Addae M, Commey JO, Nkrumah FK, Hviid L 1997. Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria. Br J Haematol 97: 169-174. [ Links ]
Lamb TJ, Brown DE, Potocnik AJ, Langhorne J 2006. Insights into the immunopathogenesis of malaria using mouse models. Expert Rev Mol Med 8: 1-22. [ Links ]
Langhorne J, Ndungu FM, Sponaas AM, Marsh K 2008. Immunity to malaria: more questions than answers. Nat Immunol 9: 725-732. [ Links ]
Leslie T, Briceno M, Mayan I, Mohammed N, Klinkenberg E, Sibley CH, Whitty CJ, Rowland M 2010. The impact of phenotypic and genotypic G6PD deficiency on risk of Plasmodium vivax infection: a case-control study amongst Afghan refugees in Pakistan. PLoS Med 7: e1000283. [ Links ]
Linke A, Kühn R, Müller W, Honarvar N, Li C, Langhorne J 1996. Plasmodium chabaudi chabaudi: differential susceptibility of gene-targeted mice deficient in IL-10 to an erythrocytic-stage infection. Exp Parasitol 84: 253-263. [ Links ]
Lisker R, Loria A, Cordova MS 1965. Studies on several genetic hematological traits of the Mexican population. 8. Hemoglobin S, glucose-6-phosphate dehydrogenase deficiency and other characteristics in a malarial region. Am J Hum Genet 17: 179-187. [ Links ]
Llanos C 2008. Plasmodium falciparum-induced anemia and dyserythropoiesis in naÏve Aotus monkeys, Valle University, 95 pp. [ Links ]
Llanos C, Quintero G, Castellanos A, Arevalo-Herrera M, Herrera S 2006. Surgical bone marrow aspiration in Aotus lemurinus griseimembra. J Med Primatol 35: 131-135. [ Links ]
Looareesuwan S, Davis TM, Pukrittayakamee S, Supanaranond W, Desakorn V, Silamut K, Krishna S, Boonamrung S, White NJ 1991. Erythrocyte survival in severe falciparum malaria. Acta Trop 48: 263-270. [ Links ]
López ML, Arango EM, Arias LR, Carmona-Fonseca J 2004. Hemozoína intraleucocitaria como indicador de malaria complicada por Plasmodium falciparum. Acta Med Colomb 29: 80-87. [ Links ]
Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, Kone A, Harley R, Plowe CV, Doumbo OK, Sztein MB 2004. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun 72: 5630-5637. [ Links ]
Lyke KE, Diallo DA, Dicko A, Kone A, Coulibaly D, Guindo A, Cissoko Y, Sangare L, Coulibaly S, Dakouo B, Taylor TE, Doumbo OK, Plowe CV 2003. Association of intraleukocytic Plasmodium falciparum malaria pigment with disease severity, clinical manifestations and prognosis in severe malaria. Am J Trop Med Hyg 69: 253-259. [ Links ]
Magris M, Rubio-Palis Y, Alexander N, Ruiz B, Galván N, Frias D, Blanco M, Lines J 2007. Community-randomized trial of lambdacyhalothrin-treated hammock nets for malaria control in Yanomami communities in the Amazon Region of Venezuela. Trop Med Int Health 12: 392-403. [ Links ]
Makobongo MO, Keegan B, Long CA, Miller LH 2006. Immunization of Aotus monkeys with recombinant cysteine-rich interdomain region 1 alpha protects against severe disease during Plasmodium falciparum reinfection. J Infect Dis 193: 731-740. [ Links ]
Marquino W, Ylquimiche L, Hermenegildo Y, Palacios AM, Falconi E, Cabezas C, Arrospide N, Gutierrez S, Ruebush ITK 2005. Efficacy and tolerability of artesunate plus sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine alone for the treatment of uncomplicated Plasmodium falciparum malaria in Peru. Am J Trop Med Hyg 72: 568-572. [ Links ]
Marsh K, Forster D, Waruiru K, Mwangi I, Winstanley M, Marsh V, Newton C, Winstanley P, Warn P, Peshu N, Pasvol G 1995. Indicators of life-threatening malaria in African children. N Engl J Med 332: 1399-1404. [ Links ]
McCollum AM, Mueller K, Villegas L, Udhayakumar V, Escalante AA 2007. Common origin and fixation of Plasmodium falciparum dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance in a low-transmission area in South America. Antimicrob Agents Chemother 51: 2085-2091. [ Links ]
McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R 2006. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203: 1185-1196. [ Links ]
Means RT Jr. 2004. Hepcidin and anaemia. Blood Rev 18: 219-225. [ Links ]
Melo GC, Reyes-Lecca RC, Vitor-Silva S, Monteiro WM, Martins M, Benzecry SG, Alecrim MG, Lacerda MV 2010. Concurrent helminthic infection protects schoolchildren with Plasmodium vivax from anemia. PLoS ONE 5: e11206. [ Links ]
Menendez C, Fleming AF, Alonso PL 2000. Malaria-related anaemia. Parasitol Today 16: 469-476. [ Links ]
Menendez-Capote R, Diaz Perez L, Luzardo Suarez C 1997. Hemolisis y tratamiento con primaquina. Informe preliminar. Rev Cubana Med Trop 49: 136-138. [ Links ]
Miller KL, Silverman PH, Kullgren B, Mahlmann LJ 1989. Tumor necrosis factor alpha and the anemia associated with murine malaria. Infect Immun 57: 1542-1546. [ Links ]
Miller LH, Good MF, Milon G 1994. Malaria pathogenesis. Science 264: 1878-1883. [ Links ]
Mohan K, Dubey ML, Ganguly NK, Mahajan RC 1995. Plasmodium falciparum: role of activated blood monocytes in erythrocyte membrane damage and red cell loss during malaria. Exp Parasitol 80: 54-63. [ Links ]
Moreno A, García A, Cabrera-Mora M, Strobert E, Galinski MR 2007. Disseminated intravascular coagulation complicated by peripheral gangrene in a rhesus macaque (Macaca mulatta) experimentally infected with Plasmodium coatneyi. Am J Trop Med Hyg 76: 648-654. [ Links ]
Moyano M, Mendez F 2005. Defectos eritrociticos y densidad de la parasitemia en pacientes con malaria por Plasmodium falciparum en Buenaventura, Colombia. Rev Panam Salud Publica/Pan Am J Public Health 18: 25-32. [ Links ]
Nakano Y, Fujioka H, Luc KD, Rabbege JR, Todd GD, Collins WE, Aikawa M 1996. A correlation of the sequestration rate of Plasmodium coatneyi-infected erythrocytes in cerebral and subcutaneous tissues of a rhesus monkey. Am J Trop Med Hyg 55: 311-314. [ Links ]
Nakazawa S, Looareesuwan S, Fujioka H, Pongponratn E, Luc KD, Rabbege J, Aikawa M 1995. A correlation between sequestered parasitized erythrocytes in subcutaneous tissue and cerebral malaria. Am J Trop Med Hyg 53: 544-546. [ Links ]
Navarro P, Baez A, Vera Y, Figueira I, Garrido E, Martin A 2003. Paludismo como infeccion del viajero adquirido en el Estado Sucre. Rev Fac Med (Caracas) 26: 34-38. [ Links ]
Navarro P, Martin A, Garrido E, Insausti C, Gutierrez H 1998. Palu-dismo en ninos: experiencia del Hospital Universitario de Caracas. Arch Venez Pueric Pediatr 61: 109-112. [ Links ]
Nguyen PH, Day N, Pram TD, Ferguson DJ, White NJ 1995. Intraleucocytic malaria pigment and prognosis in severe malaria. Trans R Soc Trop Med Hyg 89: 200-204. [ Links ]
Noronha E, Costa Alecrim M, Sierra Romero GA, Macêdo V 2000. Clinical study of falciparum malaria in children in Manaus, AM, Brazil. Rev Soc Bras Med Trop 33: 185-190. [ Links ]
Obaldia N 2001. Evaluation of drug and vaccine candidates in the human malaria/Aotus monkey model, Panama, p. 1-94. [ Links ]
Omar MS, Collins WE, Contacos PG 1973. Gametocytocidal and sporontocidal effects of antimalarial drugs on malaria parasites: I. Effect of single and multiple doses of primaquine on Plasmodium cynomolgi. Exp Parasitol 34: 229-241. [ Links ]
Osorio L, Gonzalez I, Olliaro P, Taylor WRJ 2007. Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia. Malaria J 6: 25. [ Links ]
Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V 1999. A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis 179: 279-282. [ Links ]
Pérez Mato S 1998. Anemia and malaria in a Yanomami Amerindian population from the southern Venezuelan Amazon. Am J Trop Med Hyg 59: 998-1001. [ Links ]
Perkins DJ, Weinberg JB, Kremsner PG 2000. Reduced interleukin-12 and transforming growth factor-beta1 in severe childhood malaria: relationship of cytokine balance with disease severity. J Infect Dis 182: 988-992. [ Links ]
Phillips RE, Looareesuwan S, Warrell DA, Lee SH, Karbwang J, Warrell MJ, White NJ, Swasdichai C, Weatherall DJ 1986. The importance of anaemia in cerebral and uncomplicated falciparum malaria: role of complications, dyserythropoiesis and iron sequestration. Q J Med 58: 305-323. [ Links ]
Price RN, Douglas NM, Anstey NM 2009. New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance. Curr Opin Infect Dis 22: 430-435. [ Links ]
Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ 2001. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg 65: 614-622. [ Links ]
Ramos Junior WM, Sardinha JFJ, Costa MRF, Santana MS, Alecrim MGC, Lacerda MVG 2010. Clinical aspects of hemolysis in patients with P. vivax malaria treated with primaquine in the Brazilian Amazon. Braz J Infect Dis 14: 410-412. [ Links ]
Rayner JC, Tran TM, Corredor V, Huber CS, Barnwell JW, Galinski MR 2005. Dramatic difference in diversity between Plasmodium falciparum and Plasmodium vivax reticulocyte binding-like genes. Am J Trop Med Hyg 72: 666-674. [ Links ]
Restrepo-Pineda E, Arango E, Maestre A, Do Rosario VE, Cravo P 2008. Studies on antimalarial drug susceptibility in Colombia in relation to Pfmdr1 and Pfcrt. Parasitology 135: 547-553. [ Links ]
Ritter K, Kuhlencord A, Thomssen R, Bommer W 1993. Prolonged haemolytic anaemia in malaria and autoantibodies against triosephosphate isomerase. Lancet 342: 1333-1334. [ Links ]
Rodríguez-Morales AJ, Ferrer MV, Barrera MA, Pacheco M, Daza V, Franco-Paredes C 2009. Imported cases of malaria admitted to two hospitals of Margarita Island, Venezuela, 1998-2005. Travel Med Infect Dis 7: 44-48. [ Links ]
Rodríguez-Morales AJ, Sánchez E, Arria M, Vargas M, Piccolo C, Colina R, Franco-Paredes C 2007. Haemoglobin and haematocrit: the threefold conversion is also non valid for assessing anaemia in Plasmodium vivax malaria-endemic settings. Malaria J 6: 166. [ Links ]
Rodríguez-Morales AJ, Sánchez E, Vargas M, Piccolo C, Colina R, Arria M 2006a. Anemia and thrombocytopenia in children with Plasmodium vivax malaria. J Trop Pediatr 52: 49-51. [ Links ]
Rodríguez-Morales AJ, Sanchez E, Vargas M, Piccolo C, Colina R, Arria M, Franco-Paredes C 2006b. Pregnancy outcomes associated with Plasmodium vivax malaria in northeastern Venezuela. Am J Trop Med Hyg 74: 755-757. [ Links ]
Rodríguez-Morales AJ, Sánchez E, Vargas M, Piccolo C, Colina R, Arria M, Franco-Paredes C 2006c. Is anemia in Plasmodium vivax malaria more frequent and severe than in Plasmodium falciparum? Am J Med 119: e9-10. [ Links ]
Rodríguez-Morales M, Brito Llano L, Fortun Prieto A, Diaz Dominguez MDLA, Montano Diaz MA, Rodriguez Martinez S 1986. Anemia hemolitica por antipaludicos: estudio de 38 casos. Rev Cuba Med 25: 609-613. [ Links ]
Ronnefeldt F 1956. Endemische malaria und anamie. Z Tropenmed Parasit 7: 48-63. [ Links ]
Roshanravan B, Kari E, Gilman RH, Cabrera L, Lee E, Metcalfe J, Calderon M, Lescano AG, Montenegro SH, Calampa C, Vinetz JM 2003. Endemic malaria in the Peruvian Amazon Region of Iquitos. Am J Trop Med Hyg 69: 45-52. [ Links ]
Ruiz-Gil W, Tokeshi Gusukuda-Shirota A, Pichilingue Prieto O 1994. Malaria por Plasmodium vivax: aspectos clinicos y hematologicos. Rev Med Hered 5: 118-128. [ Links ]
Sanchez Perovani JA, Gonzalez Gonzalez BA, Valdes Dopaso LM 1983. Anemia hemolitica primaquinosensible. Rev Cuba Med 22: 1-4. [ Links ]
Santana Filho FS, Arcanjo AR, Chehuan YM, Costa MR, Martinez-Espinosa FE, Vieira JL, Barbosa MG, Alecrim WD, Alecrim MG 2007. Chloroquine-resistant Plasmodium vivax, Brazilian Amazon. Emerg Infect Dis 13: 1125-1126. [ Links ]
Sarabia E, Ching S, Unamuno M, Ramos A 1996. Paludismo y embarazo. Medicina (Guayaquil) 2: 129-132. [ Links ]
Schmidt LH 1986. Compatibility of relapse patterns of Plasmodium cynomolgi infections in Rhesus monkeys with continuous cyclical development and hypnozoite concepts of relapse. Am J Trop Med Hyg 35: 1077-1099. [ Links ]
Sein KK, Brown AE, Maeno Y, Smith CD, Corcoran KD, Hansukjariya P, Webster HK, Aikawa M 1993. Sequestration pattern of parasitized erythrocytes in cerebrum, mid-brain, and cerebellum of Plasmodium coatneyi-infected rhesus monkeys (Macaca mulatta). Am J Trop Med Hyg 49: 513-519. [ Links ]
Sempertegui F, Estrella B, Toapanta FR, Torres DS, Calahorrano DE, Yeboah-Antwi K, Addo-Yobo E, Arthur P, Newton S, Premji Z, Hubert M, Makwaya CS, Ssengooba F, Konde-Lule J, Mukisa E, Hamer DH, MacLeod W, Duggan C, Fawzi W, Simon J, Mwanakasale V, Mulenga M, Sukwa T, Tshiula J 2002. Effect of zinc on the treatment of Plasmodium falciparum malaria in children: a randomized controlled trial. Am J Clin Nutr 76: 805-812. [ Links ]
Serghides L, Smith TG, Patel SN, Kain KC 2003. CD36 and malaria: friends or foes? Trends Parasitol 19: 461-469. [ Links ]
Shaffer N, Grau GE, Hedberg K, Davachi F, Lyamba B, Hightower AW, Breman JG, Phuc ND 1991. Tumor necrosis factor and severe malaria. J Infect Dis 163: 96-101. [ Links ]
Silverman PH, Schooley JC, Mahlmann LJ 1987. Murine malaria decreases hemopoietic stem cells. Blood 69: 408-413. [ Links ]
Simpson JA, Silamut K, Chotivanich K, Pukrittayakamee S, White NJ 1999. Red cell selectivity in malaria: a study of multiple-infected erythrocytes. Trans R Soc Trop Med Hyg 93: 165-168. [ Links ]
Smith CD, Brown AE, Nakazawa S, Fujioka H, Aikawa M 1996. Multi-organ erythrocyte sequestration and ligand expression in rhesus monkeys infected with Plasmodium coatneyi malaria. Am J Trop Med Hyg 55: 379-383. [ Links ]
Srichaikul T, Siriasawakul T, Poshyachinda M 1976. Ferrokinetics in patients with malaria: haemoglobin synthesis and normoblasts in vitro. Trans R Soc Trop Med Hyg 70: 244-246. [ Links ]
Srichaikul T, Siriasawakul T, Poshyachinda M, Poshyachinda V 1973. Ferrokinetics in patients with malaria: normoblasts and iron incorporation in vitro. Am J Clin Path 60: 166-174. [ Links ]
Stevenson MM, Su Z, Sam H, Mohan K 2001. Modulation of host responses to blood-stage malaria by interleukin-12: from therapy to adjuvant activity. Microbes Infect 3: 49-59. [ Links ]
Stoute JA, Odindo AO, Owuor BO, Mibei EK, Opollo MO, Waitumbi JN 2003. Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia. J Infect Dis 187: 522-525. [ Links ]
Taverne J, Sheikh N, de Souza JB, Playfair JH, Probert L, Kollias G 1994. Anaemia and resistance to malaria in transgenic mice expressing human tumour necrosis factor. Immunology 82: 397-403. [ Links ]
Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, Lampah DA, Price RN 2008. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med 5: e128. [ Links ]
Torres R JR, Magris M, Villegas L, Torres V MA, Dominguez G 2000. Spur cell anaemia and acute haemolysis in patients with hyperreactive malarious splenomegaly. Experience in an isolated Yanomamo population of Venezuela. Acta Tropica 77: 257-262. [ Links ]
Uscategui RM, Correa AM, Carmona-Fonseca J 2009. Cambios en las concentraciones de retinol, hemoglobina y ferritina en ninos paludicos colombianos. Biomedica 29: 270-281. [ Links ]
Ventura AMRS, Pinto AYN, Silva RSU, Calvosa VSP, Silva Filho MG, Souza JM 1999. Malaria por Plasmodium vivax em crianças e adolescentes - aspectos epidemiologicos, clínicos e laboratoriais. J Pediatr (Rio J) 75: 187-194. [ Links ]
Vitor-Silva S, Reyes-Lecca RC, Pinheiro TR, Lacerda MV 2009. Malaria is associated with poor school performance in an endemic area of the Brazilian Amazon. Malar J 8: 230. [ Links ]
Waitumbi JN, Opollo MO, Muga RO, Misore AO, Stoute JA 2000. Red cell surface changes and erythrophagocytosis in children with severe Plasmodium falciparum anemia. Blood 95: 1481-1486. [ Links ]
Weatherall DJ, Abdalla S, Pippard MJ 1983. The anaemia of Plasmodium falciparum malaria. Ciba Found Symp 94: 74-97. [ Links ]
Weatherall DJ, Miller LH, Baruch DI, Marsh K, Doumbo OK, Casals-Pascual C, Roberts DJ 2002. Malaria and the red cell. Hematology Am Soc Hematol Educ Program: 35-57. [ Links ]
Westenberger SJ, McClean CM, Chattopadhyay R, Dharia NV, Carlton JM, Barnwell JW, Collins WE, Hoffman SL, Zhou Y, Vinetz JM, Winzeler EA 2010. A systems-based analysis of Plasmodium vivax lifecycle transcription from human to mosquito. PLoS Negl Trop Dis 4: e653. [ Links ]
WHO - World Health Organization 2000. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 94 (Suppl. 1): S1-90. [ Links ]
WHO - World Health Organization 2009. World Malaria Report 2009. Available from: who.int/malaria/world_malaria_report_2009/en/index.html. [ Links ]
WHO - World Health Organization 2010. World Malaria Report 2010. Available from: who.int/malaria/world_malaria_report_2010/en/index.html. [ Links ]
Wickramasinghe SN, Abdalla SH 2000. Blood and bone marrow changes in malaria. Baillieres Best Pract Res Clin Haematol 13: 277-299. [ Links ]
Wickramasinghe SN, Looareesuwan S, Nagachinta B, White NJ 1989. Dyserythropoiesis and ineffective erythropoiesis in Plasmodium vivax malaria. Br J Haematol 72: 91-99. [ Links ]
Yap GS, Stevenson MM 1992. Plasmodium chabaudi AS: erythropoietic responses during infection in resistant and susceptible mice. Exp Parasitol 75: 340-352. [ Links ]
Zamora F, Ramírez O, Vergara J, Arévalo-Herrera M, Herrera S 2005. Hemoglobin levels related to days of illness, race and Plasmodium species in Colombian patients with uncomplicated malaria. Am J Trop Med Hyg 73: 50-54. [ Links ]
Received 4 April 2011
Accepted 4 July 2011
Financial support: COLCIENCIAS (2304-13-17756 cont. 255-2005), PRONEX, CNPq, FAPEAM, DECIT, NIH-NIAID (R01-AI064766, U19AI089702), ICEMR, CLAIM