Page 2559 - Hematology_ Basic Principles and Practice ( PDFDrive )

2282 Part XIII Consultative Hematology

The prime candidates for the host factors mediating dyserythro- Modulation of Erythropoiesis by Infection
poiesis are imbalances of TNF-α, IFN-γ, and interleukin-10 (IL-10).
The concentrations of TNF-α and IFN-γ have been correlated with In children presenting with acute malaria, bacteremia is associated
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the severity of the disease. 51–53 Whereas low concentrations of TNF-α not only with anemia but also with excess mortality. Parvovirus B19
(<1 ng/mL) stimulate erythropoiesis, higher levels of TNF-α have may cause a transient reticulocytopenia and thus severe and sudden
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been shown to suppress erythropoiesis. Furthermore, it is possible anemia in those with a hemolytic anemia or fetal anemia and intra-
that high levels of these inflammatory cytokines may contribute to uterine death. Most children in Africa have serologic evidence of
reduced and abnormal production of erythrocytes and also to infection early in life. However, acute infection with this virus is
increased erythrophagocytosis. uncommon in those presenting with severe malarial anemia. 46,70
Recent evidence has suggested that the release of hepcidin is
associated with malarial infection and that high levels of hepcidin
could contribute to the sequestration of iron and impair erythropoi- Prevalence and Etiology of Anemia in the
esis. 54,55 The stimulus for hepcidin secretion may be proinflammatory Developing World
cytokines such as IL-6, but malaria-infected erythrocytes may also
enhance hepcidin production by peripheral blood mononuclear cells. In endemic areas the etiology of anemia is complex. Acute or chronic
Intriguingly, hepcidin released during blood-stage parasitemia may malarial infection is a major precipitating factor in children with
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be a key regulator of P. falciparum liver-stage development. These severe anemia causing admission to hospital. 47
data now support suggestions from large-scale studies of iron supple- Longitudinal studies from The Gambia have shown that whereas
mentation that iron may be unhelpful and possibly even harmful the mean hemoglobin levels in children vary significantly through the
when given during acute malarial infection. Indeed, there are both year, anemia is much more common in the rainy season, when
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clinical and experimental evidence that iron deficiency may confer malaria transmission is at its highest. However, the rains are also
protection from severe malaria. Malaria parasites show reduced associated with an increase in waterborne diarrheal disease and poor
growth in RBCs from subjects with iron deficiency, and infection is food supplies. So the seasonal increase in anemia in malaria-endemic
augmented during the phase of iron supplementation after severe iron areas arises on a background of low or frankly deficient stores of
deficiency. 57 hematinics and/or other micronutrients. Iron deficiency, which
High levels of the T-helper cell type 2 (Th2)-type cytokine, IL-10, affects at least 20% of the world’s population, is a major factor in the
might prevent the development of severe malarial anemia. Low levels seasonal surge of anemia in the tropical rainy season. Low iron stores
of IL-10 have been described in African children with severe malarial at birth and dietary iron deficiency may be exacerbated by hookworm
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anemia. Similarly, defective IL-12 production has been shown or schistosomal infection. It is now also clear that malarial infection
experimentally to be associated with increased severity of malaria in is associated with reduced uptake of available iron and reduced
a rodent model, and low IL-12 levels have been associated with severe incorporation of iron into developing erythroid cells. 54,55 Folate
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malaria in African children. The role of IL-12 in clinical malaria deficiencies and/or increased requirements may occur in many popu-
appears complex, but in toxoplasma infection in mice, IL-12 has been lations, although frank folate deficiency is uncommon.
shown to have a key role in activating natural killer (NK) cells that A low baseline hemoglobin level at the start of the season for
primes monocytes in the bone marrow for a regulatory function, malaria transmission is a major risk factor for developing severe
which could be important in malaria. 59 malarial anemia and has encouraged studies aimed at preventing the
development of anemia by hematinic supplementation with or
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Modulation of Erythropoiesis by without antimalarial prophylaxis or surveillance.
Quantifying the contribution of these individual factors to anemia
Infected Erythrocytes reliably requires intervention studies. In Tanzania, Menendez et al
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and Schellenberg et al have shown that iron supplementation and
There is also substantial evidence that lysate of infected erythrocytes antimalarial prophylaxis prevented 30% and 60%, respectively, of all
may directly modulate the function of host cells. During its blood cases of moderate anemia presenting during the malaria transmission
stage, the malaria parasite proteolyses host hemoglobin in an acidic season in children and in infants.
vacuole to obtain amino acids, releasing heme as a byproduct, which Translating the results of these studies from well-defined and
is auto-oxidized to potentially toxic hematin (aquaferriprotoporphyrin carefully controlled study areas has not been easy. Considerable
IX [H 2 O−Fe III PPIX]). β-Hematin forms as a crystalline cyclic dimer of concerns about iron supplementation programs for children have
Fe III PPIX and is complexed with protein and lipid products as malarial been raised in sub-Saharan Africa and in areas of high malaria ende-
pigment or hemozoin. Schwarzer et al 60–62 showed that the function of micity. One large trial of iron supplementation was stopped because
monocytes and of monocyte-derived macrophages is severely inhibited of increased hospital admission and death in the group receiving iron.
after ingestion of malaria pigment or hemozoin. These cells were However, meta-analysis of iron supplementation in malaria-endemic
unable to repeat phagocytosis and to generate oxidative burst when areas has shown that iron alone or with antimalarial treatment does
appropriately stimulated. Furthermore, after phagocytosis of hemo- not increase the risk for clinical malaria or death when regular malaria
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zoin, human and murine myeloid cells were unable to kill ingested surveillance and treatment services are provided. It is increasingly
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fungi, bacteria, and tumor cells or to respond to IFN-β stimulation, clear that iron supplementation in these areas must be based on either
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but instead responded by increased release of IL-1β, TNF-α, macro- defining iron-deficient children or combining iron administration
phage inflammatory protein-1α (MIP-1α), and MIP-1β. 65 with effective infection control and treatment strategies. 75,76
The hemozoin polymer of heme moieties may be complexed
with biologically active compounds. The oxidation of membrane Features of Malarial Anemia
lipids catalyzed by the ferric heme produces the lipoperoxides. 62,66
There is accumulating evidence that 4-hydroxynonenal (HNE) and
other lipoperoxides, including 15-hydroxyarachidonic acid [15-(R,S)- The Spectrum of Disease Caused by
HETE], may play a role in the pathophysiology of malaria. It has been Malarial Infection
shown that HNE and HETE are generated in parasitized erythrocytes
and that HNE and endoperoxides produced in pigment-containing The signs and symptoms of malarial infection in humans are caused
monocytes or macrophages may cause cell-cycle arrest and impair by the asexual blood stage of the parasite. Infection with blood-stage
erythroid growth. 66,67 Hemozoin may also directly inhibit erythroid parasites may result in a wide range of outcomes and pathologic
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development in vitro and cause apoptosis of erythroid precursors. conditions. Indeed, the spectrum of severity ranges from asymptom-
Furthermore, increased levels of plasma hemozoin and pigment in atic infection to rapidly progressive, fatal illness. The clinical presen-
monocytes have been associated with anemia. 49 tation of malarial infection is also wide and influenced by age,