Malaria: death and disappearing erythrocytes
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《血液学杂志》
Severe anemia is the cause of a large proportion, if not a majority, of the 1 to 2 million deaths of African children that are attributed to malaria each year.
One hundred and twenty-five years after the discovery of malaria parasites, remarkably, the mechanism(s) responsible for severe malarial anemia (SMA) syndrome are not well understood. Certainly, anemic states develop in malaria cases exhibiting hyperparasitemia or blackwater fever through intravascular hemolysis. However, these cases represent a very minor portion of the malarial anemia burden encountered in areas of endemic transmission. SMA in Sub-Saharan Africa and other areas of high to moderate malaria transmission occurs in younger children (1-3 years) after prior experience with malaria parasites and often becomes manifest in chronic infections of relatively low parasite burden (< 1%-2% parasitemia).1
In most SMA cases, intravascular hemolysis is not apparent and destruction of uninfected erythrocytes is more than 10-fold greater than any lysis caused by parasitization. There also maybe impaired reticulocytosis with failure to replace the red blood cell (RBC) pool even as a portion continues to be lost. Thus, one thesis is that a misfunctioning bone marrow and extravascular removal of nonparasitized RBCs combine to bring about an SMA crisis leading to death if treatment is not provided.2 However, because of high rates of drug resistance and HIV in African countries, treatments fail and transfusions can be dangerous with their own fatal consequences. Furthermore, despite adequate therapy, transfused RBCs are often rapidly removed despite declining or absent levels of parasitemia.3 A fuller understanding of SMA etiology could provide for improved treatment protocols, and there is a need for animal models that mimic SMA in human patients to obtain this knowledge.
Evans and colleagues have devised such a model of SMA using Plasmodium berghei infections in semi-immune mice and in malarianaive rats. The rodent models mimic human SMA in that at low parasite burdens hemoglobin levels fall to less than 50% of normal at crisis and are independent of parasite loads but are related to chronicity. Prior studies of SMA in rodent malaria models relied on either fatal nonresolving infections or nonfatal resolving infections that were confounded by high parasitemias and iRBC lysis. Of importance, the investigations of Evans et al indicate that intravascular hemolysis is not a contributory factor to SMA and that there is a near-complete turnover of the blood pool in a week. Further, it is shown that RBCs from naive mice are removed at the same rapid rate in infected mice with SMA with no accelerated clearance in normal mice of RBCs from infected mice, suggesting that changes to RBCs in infected mice to target their removal are not significant factors in SMA. While it has been suspected that changes to the RBC surface such as Ig, complement, or, as recently reported,4 parasite antigen deposition onto bystander cells might underlie an extravascular clearance mechanism in SMA, demonstration of these modifications has been inconsistent in human SMA.
he SMA model developed by Evans and colleagues does differ from SMA in humans since erythropoiesis in the rodent model does function, producing a strong compensatory reticulocytosis with eventual recovery and survival. In Plasmodium falciparum-induced human and nonhuman primate models of malignant tertian SMA there is frequently a lack of compensatory reticulocytosis,2,5 whether parasites are patent or not, which leads to high mortality if unchecked. Survival in the rodent SMA model may occur because the spleen in rodents is a major erythropoietic organ, whereas in primates it is not. Alternatively, it may be that rodent SMA models lack certain features of SMA that occur in P falciparum infections in humans and its nonhuman primate models. Clearly, continued investigations into SMA mechanisms in both the rodent models and the nonhuman primate models are important to gain fresh insight leading to new therapeutic interventions for SMA.
References
Reyburn H, Mbatia R, Drakeley C, et al. Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria. JAMA. 2005;293: 1461-1470.
Ekvall H. Malaria and anemia. Curr Opin Hematol. 2003;10: 108-114.
English M, Ahmed M, Ngando C, et al. Blood transfusion for severe anemia in children in a Kenyan hospital. Lancet. 2002;359: 494-495.
Layez C, Nogueira P, Combes V, et al. Plasmodium falciparum rhoptry protein RSP2 triggers destruction of the erythroid lineage. Blood. 2005;106: 3632-3638.
Egan AF, Fabucci ME, Saul A, et al. Aotus New World monkeys: model for studying malaria-induced anemia. Blood. 2002;99: 3863-3866.(John W. Barnwell)
One hundred and twenty-five years after the discovery of malaria parasites, remarkably, the mechanism(s) responsible for severe malarial anemia (SMA) syndrome are not well understood. Certainly, anemic states develop in malaria cases exhibiting hyperparasitemia or blackwater fever through intravascular hemolysis. However, these cases represent a very minor portion of the malarial anemia burden encountered in areas of endemic transmission. SMA in Sub-Saharan Africa and other areas of high to moderate malaria transmission occurs in younger children (1-3 years) after prior experience with malaria parasites and often becomes manifest in chronic infections of relatively low parasite burden (< 1%-2% parasitemia).1
In most SMA cases, intravascular hemolysis is not apparent and destruction of uninfected erythrocytes is more than 10-fold greater than any lysis caused by parasitization. There also maybe impaired reticulocytosis with failure to replace the red blood cell (RBC) pool even as a portion continues to be lost. Thus, one thesis is that a misfunctioning bone marrow and extravascular removal of nonparasitized RBCs combine to bring about an SMA crisis leading to death if treatment is not provided.2 However, because of high rates of drug resistance and HIV in African countries, treatments fail and transfusions can be dangerous with their own fatal consequences. Furthermore, despite adequate therapy, transfused RBCs are often rapidly removed despite declining or absent levels of parasitemia.3 A fuller understanding of SMA etiology could provide for improved treatment protocols, and there is a need for animal models that mimic SMA in human patients to obtain this knowledge.
Evans and colleagues have devised such a model of SMA using Plasmodium berghei infections in semi-immune mice and in malarianaive rats. The rodent models mimic human SMA in that at low parasite burdens hemoglobin levels fall to less than 50% of normal at crisis and are independent of parasite loads but are related to chronicity. Prior studies of SMA in rodent malaria models relied on either fatal nonresolving infections or nonfatal resolving infections that were confounded by high parasitemias and iRBC lysis. Of importance, the investigations of Evans et al indicate that intravascular hemolysis is not a contributory factor to SMA and that there is a near-complete turnover of the blood pool in a week. Further, it is shown that RBCs from naive mice are removed at the same rapid rate in infected mice with SMA with no accelerated clearance in normal mice of RBCs from infected mice, suggesting that changes to RBCs in infected mice to target their removal are not significant factors in SMA. While it has been suspected that changes to the RBC surface such as Ig, complement, or, as recently reported,4 parasite antigen deposition onto bystander cells might underlie an extravascular clearance mechanism in SMA, demonstration of these modifications has been inconsistent in human SMA.
he SMA model developed by Evans and colleagues does differ from SMA in humans since erythropoiesis in the rodent model does function, producing a strong compensatory reticulocytosis with eventual recovery and survival. In Plasmodium falciparum-induced human and nonhuman primate models of malignant tertian SMA there is frequently a lack of compensatory reticulocytosis,2,5 whether parasites are patent or not, which leads to high mortality if unchecked. Survival in the rodent SMA model may occur because the spleen in rodents is a major erythropoietic organ, whereas in primates it is not. Alternatively, it may be that rodent SMA models lack certain features of SMA that occur in P falciparum infections in humans and its nonhuman primate models. Clearly, continued investigations into SMA mechanisms in both the rodent models and the nonhuman primate models are important to gain fresh insight leading to new therapeutic interventions for SMA.
References
Reyburn H, Mbatia R, Drakeley C, et al. Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria. JAMA. 2005;293: 1461-1470.
Ekvall H. Malaria and anemia. Curr Opin Hematol. 2003;10: 108-114.
English M, Ahmed M, Ngando C, et al. Blood transfusion for severe anemia in children in a Kenyan hospital. Lancet. 2002;359: 494-495.
Layez C, Nogueira P, Combes V, et al. Plasmodium falciparum rhoptry protein RSP2 triggers destruction of the erythroid lineage. Blood. 2005;106: 3632-3638.
Egan AF, Fabucci ME, Saul A, et al. Aotus New World monkeys: model for studying malaria-induced anemia. Blood. 2002;99: 3863-3866.(John W. Barnwell)