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Anemia in malaria

Anemia in malaria
Literature review current through: Jan 2024.
This topic last updated: Jul 29, 2022.

INTRODUCTION — Malaria is a global health problem, causing disease on a vast scale. (See "Malaria: Epidemiology, prevention, and control".)

The majority of malarial infections are associated with some degree of anemia, the severity of which depends upon patient-specific characteristics (eg, age, innate and acquired resistance, comorbid features) as well as parasite-specific characteristics (eg, species, adhesive, and drug-resistance phenotype). Malarial anemia is capable of causing severe morbidity and mortality especially in children and pregnant individuals infected with Plasmodium falciparum.

This topic review will discuss the anemia associated with malarial infection.

Separate topic reviews discuss the following:

Malaria diagnosis – (See "Laboratory tools for diagnosis of malaria" and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

Malaria treatment – (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children" and "Treatment of severe malaria" and "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

Malaria prophylaxis – (See "Prevention of malaria infection in travelers" and "Malaria: Epidemiology, prevention, and control".)

Genetic changes in RBC genes that protect against malaria – (See "Protection against malaria by variants in red blood cell (RBC) genes".)

Pathogenesis of malaria – (See "Pathogenesis of malaria".)

OVERVIEW

The malaria parasite — Five species of the malaria parasite infect humans. The severity of hematologic disease is related to the ability of the parasites to invade and grow in different red blood cell (RBC) populations as well as the intrinsic growth rate of the parasite.

P. vivax and P. ovale have a strong preference to infect only young RBCs (reticulocytes), thereby limiting parasitemia levels to approximately 1 to 2 percent [1]. Anemia due to hemolysis does occur and may be severe, but there is no peripheral sequestration of parasitized RBCs.

P. malariae invades RBCs of all ages, but parasite multiplication during each cycle is relatively low. Infection results in limited parasitemia (<1 to 2 percent) and usually mild symptoms but severe disease including anaemia can develop in 3 percent of cases [2].

P. falciparum can invade RBCs of all ages, including cells as early as orthochromatic erythroblasts [3]. It multiplies 10-fold within each 48-hour cycle and expresses clonally variant antigens on the surface of infected RBCs, which are receptors for ligands on the surface of endothelial cells, RBCs, and platelets. These variant antigens enable late blood-stage infected red cells to sequester in postcapillary venules. Parasitemia is often high, occasionally exceeding 50 percent, and the potential for severe anemia, systemic disease, and death is considerable. Gametocytes (sexual blood-stage parasites) can develop within erythroblasts, so that infectious mature gametocytes develop within reticulocytes, permitting gametocyte maturation to coincide with the release of the RBC from the bone marrow [4].

P. knowlesi was originally described as a malarial infection of macaque monkeys. Morphologically it resembles P. malariae and it can cause significant and severe human infection particularly anemia and acute kidney injury [5]. This organism was previously misdiagnosed as P. malariae, in Borneo, Malaysia, and in other areas of Southeast Asia. It has even been reported in travelers returning from those locations [6,7].

Parasite life cycle — To understand the mechanism of hemolysis in malaria, it is helpful to briefly review the life-cycle of the malaria parasite. (See "Pathogenesis of malaria".)

The asexual life cycle begins when sporozoites from the saliva of a female Anopheles mosquito taking a blood meal enter the circulation and invade hepatocytes. After one to two weeks, up to 10,000 merozoites are formed. Following rupture of the hepatocyte, infective merozoites are released into the circulation and invade RBCs [8]. RBC entry occurs via binding of the malaria parasite to specific receptors on the RBC surface, including glycophorin A for P. falciparum and the Duffy blood group antigen for P. vivax [9-14]. (See "Red blood cell antigens and antibodies", section on 'Duffy blood group system' and "Protection against malaria by variants in red blood cell (RBC) genes", section on 'RBC surface proteins'.)

Once inside the RBC, the parasite makes many modifications to the infected cell [15], ingests and degrades hemoglobin, and develops through the stages of rings, trophozoites and schizonts. Mature schizonts burst to release merozoites that invade new RBCs.

A small proportion of merozoites in RBCs transform into male and female gametocytes, which are ingested by the mosquito following a subsequent blood meal. Male and female gametes fuse and transform into an oocyst, which divides asexually into many sporozoites that migrate to the salivary gland of the infected mosquito, from which they are released during the next blood meal.

P. falciparum has additional unique characteristics that help to explain its distinct potential to cause severe or fatal disease. As P. falciparum parasites mature within RBCs, they induce the formation of "knobs" on the surface of the RBCs [16,17]. The products of the parasite's VAR genes (PfEMP-1) are expressed on these surface projections and bind to receptors on endothelial cells in post-capillary venules [18-20]. The cytoadherence and sequestration of RBCs within these small vessels leads to microvascular pathology and obstruction of blood flow.

Infected RBCs also stick to uninfected RBCs and form rosettes that may also obstruct the microcirculation [21,22]. Multiple serum components, including immunoglobulin (Ig)M, act as bridging molecules for rosette formation [23].

PREVALENCE — According to the 2018 World Health Organization (WHO) World Malaria Report, anemia remains common in individuals with malaria [24]. Severe malarial anemia (SMA) is seen most frequently in areas of very high malarial transmission and most commonly in young children and pregnant women [25]. The prevalence of anemia, defined as a hematocrit <33 percent, in malarial endemic areas of Africa varies between 31 and 91 percent in children, and between 60 and 80 percent in pregnant women [26,27]. In a typical study of children living a malarial endemic area in Uganda from 2015, the prevalence of anemia (hemoglobin <11 g/dL [<110 g/L]) was over 60 percent in children less than five years old, and half of these children tested positive for malaria [28]. In areas of high endemicity for malaria, the prevalence of anemia is the highest in the six-month-old to one year age group [29].

These data are representative of the burden of anemia in young children in countries with a high burden of malaria. Anemia and anemia associated with malaria represent a major public health problem in endemic areas.

Household surveys between 2015 and 2017 in African countries with a high burden of malaria have shown anemia of any cause is present in 61 percent of children under five; in those testing positive for malaria, the prevalence of any anemia was 79 percent, mild anemia 21 percent, moderate anemia 50 percent, and severe anemia 8 percent [30].

In epidemiologic studies, it is difficult to determine the number of cases of severe anemia attributable to malaria, as the WHO definition of SMA is quite strict [31]:

Hemoglobin concentration ≤5 g/dL or hematocrit ≤15 percent in children <12 years of age (hemoglobin <7 g/dL and hematocrit <20 percent in adults)

Parasitemia

For P. falciparum – >10,000 parasites/microL of blood

For P. vivax – No parasite threshold

For P. knowlesi – >100,000 parasites/microL of blood or jaundice plus >20,000 parasites/microL

We also look for a normocytic blood film (thus excluding thalassemia as well as iron, vitamin B12, and folate deficiencies)

In individual cases, it may be difficult to attribute anemia to a single cause, although randomized placebo-controlled trials of malaria chemoprophylaxis and iron supplementation in infants have consistently shown that malaria infection was the main etiologic factor underlying anemia [32-34]. Similarly, intermittent anti-malarial treatment during pregnancy can substantially reduce the prevalence of severe maternal anemia, and use of an effective antimalaria regimen using artemisinin combination therapy in areas of high drug resistance to malaria may improve outcomes and reduce maternal anemia and low birthweight [35].

The precise etiology of anemia is often complex in endemic areas since nutritional deficiencies, genetic traits, and intercurrent infection may all contribute to anemia [9,10,36,37]. It seems likely that etiology of SMA in endemic areas is likely to be multifactorial and variable in both time and place. This was illustrated in a case-control study of severe anemia in hospitalized children in Malawi, in which severe anemia was associated with the following conditions [38]:

Malarial infection (odds ratio [OR] 2.3, 95% CI 1.6-3.3)

Human immunodeficiency virus (HIV) infection (OR 2.0, 95% CI 1.0-3.8)

Hookworm (OR, 4.8, 95% CI 2.0-12)

Bacteremia (OR 5.3, 95% CI 2.6-11)

Glucose-6-phospate dehydrogenase (G6PD) deficiency (OR 2.4, 95% CI 1.3-4.4)

Deficiencies of vitamin A (OR 2.8, 95% CI 1.3-5.8) and vitamin B12 (OR 2.2, 95% CI 1.4-3.6).

In this population, folate deficiency and sickle cell disease were uncommon. Iron deficiency was not prevalent and was negatively associated with bacteremia (OR 0.37, 95% CI 0.22-0.60) [38].

In community surveys, young age and asymptomatic malaria infection are strong risk factors for anemia. The youngest children are at risk of iron deficiency anemia, while in older children malaria and many other infections present a more complex, multifactorial etiologic picture of anemia [39].

The incidence of malaria and SMA has fallen in many parts of sub-Saharan Africa following widespread application of public health measures (eg, impregnated bed nets, indoor residual spraying, intermittent preventive treatment), with concomitant reductions in malaria-specific admission rates, use of blood transfusions, and malaria-specific inpatient mortality of 50 percent or more up to 2007, with a slower rate of decrease up to 2019 [24,40-42].

The WHO 2021 Global Malaria Report noted that malaria deaths reduced steadily between 2000 and 2019, from 896,000 to 558,000 [24]. However, in 2020, malaria deaths increased by 12 percent compared with 2019, to an estimated 627,000; an estimated 68 percent of the additional deaths were due to service disruptions during the coronavirus disease 2019 (COVID-19) pandemic. The percentage of total malaria deaths among children <5 years fell between 2000 and 2020, from 87 to 77 percent. The major burden of mortality remains concentrated in highly endemic countries in Africa; six nations accounted for just over half of all global malaria deaths in 2020: Nigeria (27 percent), the Democratic Republic of the Congo (12 percent), Uganda (5 percent), Mozambique (4 percent), Angola (3 percent), and Burkina Faso (3 percent).

FEATURES — The spectrum of the clinical presentation and severity of P. falciparum infection is broad. In endemic areas many malarial infections present in semi-immune and immune children and adults as an uncomplicated febrile illness. Fever develops with the release of merozoites from ruptured, infected red blood cells (RBCs). Anemia, thrombocytopenia, splenomegaly (occasionally massive [43]), hepatomegaly, and jaundice can develop, and splenic rupture can occasionally occur. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

The anemia of P. falciparum malaria is typically normocytic and normochromic, with a notable absence of reticulocytes [44,45]. Microcytosis and hypochromia may be present due to the very high frequency of thalassemia trait and/or iron deficiency in many, but not all, of the endemic areas [46].

However, the clinical setting of severe malarial anemia (SMA) is varied and complex. Not only may acute infection present with anemia and/or cerebral malaria, respiratory distress and hypoglycemia, but chronic, repeated malarial infection may also lead to severe anemia. In either case, there may be a background of a low hemoglobin level due to the presence of other factors, as noted above, and malaria itself can predispose to bacteremia [47].

Severe malarial anemia — New malarial infections are often associated with a sudden drop in hemoglobin concentration associated with increased hemolysis and bone marrow suppression. (See 'Pathogenesis' below and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Infections (RBC parasites and intracellular bacteria)'.)

Non-immune patients may exhibit a number of clinical syndromes including anemia, coma, respiratory distress, and hypoglycemia, and they may have a high frequency of concurrent bacteremia [48,49]. Children may present with mild, moderate or even severe anemia with or without other syndromes of severe disease (eg, malaise, fatigue, dyspnea, or respiratory distress as metabolic acidosis supervenes) [48,50-52].

The age distribution of the syndromes of severe disease is striking but poorly understood. Children born in endemic areas are largely protected from severe malaria during the first six months of life by the passive transfer of maternal immunoglobulins and by the presence of fetal, rather than adult hemoglobin. Further discussion of how fetal hemoglobin is relatively resistant to digestion of malarial proteases and slows parasite growth can be found elsewhere. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Fetal hemoglobin'.)

The presentation of disease changes from severe anemia in children ages one to three years in areas of high transmission to cerebral malaria in older children in areas of lower transmission [53]. As transmission intensity declines, severe malaria is most frequently found in older age groups.

Chronic anemia — Anemia is also present in those with chronic malarial infection. Many children may present with severe anemia and a blood smear negative for malaria parasites but the anemia responds to antimalarial treatment [44,54]. In an Indian series of children with chronic falciparum malaria, those with moderate to severe anemia and hepatosplenomegaly had a greater degree of hemolysis, neutropenia, atypical lymphocytosis, and thrombocytopenia, but a lower level of parasitemia than patients with acute malaria [9]. Reduced production, increased clearance of cells and hypersplenism (causing neutrophils and platelets to be sequestered in the spleen) may be responsible for the neutropenia and thrombocytopenia seen in such cases. It is now recognized that low levels of parasitemia in otherwise asymptomatic children may be associated with raised levels of hepcidin [55-57]. High hepcidin levels restrict iron absorption and transfer of iron from bone marrow macrophages to developing RBCs during chronic disease or inflammation and in malaria [57,58], and may therefore contribute to chronic anemia secondary to malaria infection. (See "Anemia of chronic disease/anemia of inflammation".)

Iron deficiency — Concomitant iron deficiency is a significant concern in sub-Saharan Africa; it represents a diagnostic and management challenge. The laboratory diagnosis of iron deficiency anemia in acute malaria is challenging because inflammation increases the serum ferritin level [24,59]. Approaches to diagnosing iron deficiency are discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

Iron deficiency may be protective against malaria infection; it has been associated with reduced parasitemia, reduced incidence of severe malaria (30 to 38 percent decrease), and reduced all-cause mortality (60 percent reduction) [60,61]. In addition, iron supplementation in endemic areas may increase malaria morbidity and mortality in children [62]. There is less concern for adverse effects of daily oral iron in pregnancy, and a 2015 systematic review concluded that iron supplementation may reduce the risk of maternal anemia and iron deficiency in pregnancy, possibly also reducing the incidence of low birthweight and preterm births [63].

However, it may be difficult to generalize about the relationship between iron deficiency and malaria outcomes, as a study from Papua New Guinea showed that iron deficiency in pregnancy was associated with higher birth weight, and this was not related to protection from malaria [64]. Furthermore, growth of P. falciparum in vitro is reduced in RBCs from anemic pregnant individuals at baseline but increased during iron supplementation [65].

Issues related to altered iron metabolism and management of iron deficiency are discussed further below. (See 'Altered iron metabolism' below and 'Management' below.)

Deficiencies of folate and vitamin B12 — Although dietary deficiencies are widespread in malaria-endemic regions, the influence of reduced folate levels are not thought to be major contributors to the dyserythropoiesis seen during SMA [66]. The finding of low vitamin B12 levels in malaria suggests that subclinical deficiency of vitamin B12 may play a hitherto unrecognized contribution to severe anemia or may reflect altered vitamin B12 metabolism or transport during infection [38].

Blackwater fever — "Blackwater Fever" (BWF) is an uncommon form of anemia in malaria characterized by intravascular hemolysis, sudden appearance of hemoglobin in the urine, and kidney failure [67-69]. Disseminated intravascular coagulation (DIC) and RBC fragmentation may accompany this presentation. (See "Diagnosis of hemolytic anemia in adults", section on 'Intravascular hemolysis'.)

BWF may be difficult to correlate with malarial infection; parasitemia may not be detected due to synchronous lysis of all infected RBCs. Cases series of BWF in Africa and Southeast Asia have noted an association between sudden hemolysis and malarial infection in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency or quinine use [68,70]. Among European expatriates living in Africa, BWF has been associated with use of the antimalarial agents halofantrine, quinine, and mefloquine [71]. A causal association between BWF and quinine is supported by the virtual disappearance of BWF from Africa in the period leading up to 2010, following replacement of quinine with chloroquine [71].

Subsequently, a series of reports have described BWF after treatment with artemisinin derivatives. Artemisinin derivatives were first reported to be associated with transient reticulocytopenia. However, artesunate has also been associated with delayed-onset hemolytic anemia sometimes requiring transfusion. Prospective studies in Europe showed that delayed hemolysis is seen in 25 to 30 percent of travelers treated for malaria with intravenous artesunate and may be severe in up to 10 percent of patients [72-74]. There have been reports of similar intravascular hemolysis in children treated with artesunate-based therapies in regions of Africa including Ghana, Gabon, and Eastern Uganda [75,76].

Artesunate-based therapies cause expulsion of parasites from their host RBCs by pitting. In travelers who became infected with malaria in Africa and were treated with artesunate, the parasite protein histidine-rich protein 2 (HRP2) was deposited at the membrane of previously infected RBCs. A high titer of anti-HRP2 antibodies (detected at 1:500 dilution of whole blood by HRP2 dipstick tests) predicted subsequent hemolysis with 89 percent sensitivity and 73 percent specificity [77].

Additional information about delayed hemolytic anemia following treatment with artemisinins is presented separately. (See "Drug-induced hemolytic anemia", section on 'Other mechanisms' and "Treatment of severe malaria".)

The pathophysiology of BWF is not completely understood, either for classical BWF or BWF associated with artemisinin derivatives. Possible mechanisms are oxidative stress, an autoimmune process, or drug-dependent autoantibodies. The relative contributions of these processes have not been systematically studied.

Anemia in P. vivax malaria — Although most work describes the association of P. falciparum malaria with anemia, infection with P. vivax can, on occasion, cause severe disease, including anemia and severe hemolysis [78,79]. P. vivax malaria has been clearly associated with anemia during pregnancy, along with low birth weight of the children of infected mothers [80]. Some studies in rural India suggest that severe disease is associated with P. vivax infection more frequently than with P. falciparum infection [81]. Anemia has been associated with increased RBC clearance, reticulocytopenia, and dyserythropoiesis [82-84].

EFFECT ON PREGNANCY — Falciparum malaria in pregnancy is more likely to be severe and complicated as the placenta contains high levels of parasites. The diagnosis of malaria can be difficult if parasites are concentrated in the placenta and scanty in the blood.

Pregnant women may experience a variety of adverse consequences from malarial infection. These include maternal anemia, placental accumulation of parasites via attachment to chondroitin sulfate A in the placental intervillous space [85], low birth weight from prematurity and intrauterine growth retardation, fetal parasite exposure and congenital infection, and increased infant mortality. It has been estimated that 75,000 to 200,000 infant deaths are associated with malarial infection in pregnancy each year [86].

Imported cases of malaria in pregnancy may present with severe anemia, and the somewhat heterogeneous case series suggest that these infections not infrequently lead to spontaneous abortion [87].

In one study, high levels of maternal IgG antibodies against a variant surface antigen (VSA) expressed on pregnancy-associated P. falciparum malaria (PAM)-infected red blood cells protected against low birth weight and maternal anemia [88]. This observation suggests an area of investigation for future therapeutic strategies (eg, VSA-PAM-based vaccination).

PATHOGENESIS — The underlying causes of severe malarial anemia (SMA) in humans may include one or more of the following mechanisms [89]:

Extravascular clearance and/or intravascular destruction of infected red blood cells (RBCs)

Clearance of uninfected RBCs

Activation of the monocyte/macrophage system

Suppression of erythropoiesis along with dyserythropoiesis

Hemolysis

Parasitized red blood cells — During malarial infection there is obvious loss of infected RBCs through parasite maturation as well as through recognition by macrophages. The removal of infected RBCs in humans with parasitemias of <1 percent is unlikely to have a significant impact on the degree of anemia. However, the lysis of uninfected RBCs contributes directly to the onset of anemia in individuals with acute malarial infection, in particular children, in whom parasitemias are frequently >10 percent.

Mechanisms leading to hemolysis of infected RBCs include:

Abnormal distribution of membrane phospholipids, such as phosphatidylserine (PS), phosphatidylcholine, and phosphatidyl-ethanolamine [90]. PS may be exposed on the outer surface of infected cells in conjunction with parasite maturation, triggering macrophage recognition and phagocytosis [91].

In a case-control study of children with severe malaria in Uganda, anti-PS and antideoxyribonucleic acid (DNA) antibody levels were associated with anemia, acute kidney injury, postdischarge mortality, and hospital readmission [92]. Anti-PS autoantibodies, atypical B cells, and anemia were also associated with P. vivax infection in longitudinal studies of patients from Colombia, South America [93].

RBC membrane damage due to lipid peroxidation induced by heme liberated from digestion of hemoglobin by the parasite [94].

Infected RBCs may be opsonized by specific antibodies directed against the variant parasite antigens (PfEMP-1) expressed on the surface of the RBC.

The contribution of each of these indirect mechanisms of hemolysis of infected cells in vivo in human infection is uncertain. However, all of these effects may be exaggerated by the associated splenic hyperactivity (hypersplenism) described below.

During acute P. falciparum malaria, RBCs can be detected that contain ring-infected erythrocyte surface antigen (also known as RESA or Pf155) but no intracellular parasite [95]. This could represent splenic removal of intraerythrocytic parasites without RBC destruction and could explain some of the disparity between the fall in hematocrit and the decrease in parasite count observed in some hyperparasitemic patients.

Uninfected red blood cells — During malarial infection, destruction of uninfected RBCs in the spleen (and possibly the liver) is the major contributor to malarial anemia [96-98]. Markers of extravascular and intravascular hemolysis are elevated in patients with severe malarial anemia (Hb <5 g/dL) compared with children with mild malaria [99]. Based on clinical observations and mathematic modeling, for each infected RBC that is removed from the circulation, approximately 10 uninfected RBCs are removed [97]. A diminished half-life of normal RBCs and increased clearance of heat-treated RBCs have been demonstrated in patients with malaria, consistent with these observations [96,100,101].

This reduction in RBC survival persists for some period after clearance of malarial parasitemia, suggesting persistent nonspecific activation of reticuloendothelial function. The activity and the number of macrophages are increased and the spleen is enlarged during human malarial infection and may therefore contribute to the increased removal of uninfected cells [94,102-105]. (See 'Splenic and reticuloendothelial hyperactivity' below and "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

The increased clearance of uninfected RBCs is due to extrinsic and intrinsic changes that enhance recognition by phagocytes. These changes include some or all of the following:

Reduced deformability of uninfected RBCs − The mechanism responsible for the loss of deformability is uncertain but may include increased oxidation of membrane components [106,107]. Reduced RBC deformability is strongly associated with mortality, both in adults and children with severe malaria [108,109]. (See "Red blood cell membrane: Structure and dynamics", section on 'Clinical consequences'.)

Lipid peroxidation of RBC membranes may be mediated by proinflammatory cytokines associated with acute malaria or as a direct effect of parasite products or parasite-induced lipoperoxides, which have been shown to cause loss of RBC deformability [94,110-112]. Levels of the antioxidant alpha-tocopherol are reduced in the membrane of RBCs from children with malaria, consistent with the hypothesis that local antioxidant depletion may contribute to erythrocyte loss [113].

The deposition of immunoglobulin and complement on uninfected RBCs may enhance receptor-mediated uptake by macrophages. Early studies have shown that a positive direct antiglobulin (Coombs) test was associated with malarial anemia. The eluted antibodies were specific for parasite-derived antigens rather than host antigens and may arise from immune complexes formed by the combination of parasite antigens with host antibodies [114,115]. Studies of the surface changes in RBCs of patients with severe malarial anemia have shown that RBCs were more susceptible to phagocytosis. They have also showed increased surface IgG and deficiencies in CR1 and CD55 compared with controls [116-118].

Parasite products that may be part of the immunoglobulin-antigen complexes deposited on uninfected RBCs include the P. falciparum ring surface protein 2 (RSP-2) [119,120]. RSP-2 is deposited on uninfected RBCs and anti-RSP-2 antibodies may facilitate complement-mediated phagocytosis of these uninfected RBCs [121]. Damage to developing erythroid cells by RSP-2 and anti-RSP-2 could contribute to the development of SMA.

Cross-reacting IgM and IgG autoantibodies directed against RBCs have been described [122,123]. These were identified as anti-band 3 and anti-spectrin antibodies in a study in P. vivax malaria [124].

A progressive reduction in cell surface net negative charge and reduced resistance to linoleic-induced lysis occurs before the appearance of parasites in the blood [125]. Reduction of negative charge (Zeta potential) promotes RBC aggregation, increasing the chances of splenic removal.

Uninfected RBCs from patients with acute P. falciparum malaria have ultrastructural alterations [126].

Hemolysis may also result from drugs given to treat malaria. These include primaquine causing oxidative stress in patients with glucose-6-phosphate deficiency as well as quinine which may contribute to hemolysis by as yet undefined mechanisms. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'.)

The relationship and relative contribution of these factors to enhanced removal of uninfected RBCs in vivo has not been established.

Splenic and reticuloendothelial hyperactivity — Ultrastructural studies of the spleen in P. falciparum malaria reveal large numbers of both parasitized and nonparasitized RBCs in the cytosol of macrophages, littoral, and reticular cells, congestion and parasitized RBCs in splenic sinusoids, and splenic cords containing rosettes of erythrocytes surrounding antigen-presenting cells [127]. These findings suggest both immunologic and nonimmunologic interactions between the spleen and RBCs in patients with malaria [128].

A number of changes to infected RBCs may play a role in the increased splenic filtration of RBCs [129]. However, as mentioned above, the persistent increased clearance of uninfected cells after the clearance of malarial parasitemia, suggests a primary increase in splenic filtration [101].

This hypothesis was evaluated in a study of the clearance of heat-treated 51Cr-labeled autologous RBCs in patients with acute P. falciparum malaria [96]. The clearance half-time of infused heat-treated RBCs was markedly shortened in the patients with splenomegaly (8.4 versus 63 minutes in controls), but was normal in the patients without splenomegaly who had a lesser degree of anemia.

Host genetic factors — There is enormous variability among individuals in response to malaria that may reflect host genetic factors. As an example, among West African ethnic groups, similar infection rates, morbidity, and antibody responses are found among the Mossi and Rimaibe in the Northeast of Ouagadougou in Burkina Faso [130]. In contrast, the Fulani, who live together and are exposed to the same hyperendemic transmission of P. falciparum, have less parasitemia, less morbidity, and a higher antibody response. The better outcome in the Fulani could not be explained by differences in the use of malaria protective measures, sociocultural or environmental factors, or genetic factors known to be associated with resistance to malaria.

Genetic variation affecting hemoglobin (eg, sickle hemoglobin mutation) or various RBC cytoskeletal/membrane proteins affect malaria risk and the severity of disease, as presented separately. (See "Protection against malaria by variants in red blood cell (RBC) genes" and "Sickle cell disease in sub-Saharan Africa", section on 'Malaria'.)

Many other genetic traits have been associated with protection from malaria. However, none of these associations has been consistently reported as specific for protection with one syndrome of malaria as opposed to others.

In relation to iron metabolism, a common variant in the gene for ferroportin (FPN), Q248H (glutamine to histidine at position 248), prevented hepcidin-induced degradation of FPN and protected against severe malaria disease. FPN Q248H appears to have become prevalent in African populations in response to the selection pressure exerted by malaria disease [131]. (See "Regulation of iron balance".)

Various polymorphisms of the promoter region of the tumor necrosis factor-alpha gene (TNF2 allele) may attenuate or increase the risks for developing complications of malaria, such as cerebral malaria and anemia [132-134]. In a study of children living in a malaria-endemic environment, a specific tumor necrosis factor gene single nucleotide polymorphism was associated with an increased risk of iron deficiency and iron deficiency anemia at the end of the malaria season [135].

BONE MARROW SUPPRESSION — The normal response to hemolytic anemia is stimulation of erythropoiesis due to enhanced secretion of erythropoietin. (See "Diagnosis of hemolytic anemia in adults".)

However, this compensatory mechanism appears to be defective in patients with malaria; typical erythrocyte production is reduced due to a combination of a primary decrease in erythroid progenitors, dyserythropoiesis, inappropriately low serum erythropoietin concentrations, and/or reduced incorporation of iron into red blood cells (RBCs) secondary to high hepcidin levels. These are discussed further below.

Abnormalities of erythroid progenitors — Patients with severe falciparum malaria may have reduced numbers of erythroid burst-forming units (BFU-E) and colony-forming units (CFU-E). The reduction in erythroid progenitor numbers may be due to circulating factors capable of inhibiting erythropoiesis, as shown by a study in which serum obtained during parasitemia in complicated cases suppressed BFU-E and CFU-E in cultures of bone marrow [136]. Development of gametocytes in erythroblasts in the bone marrow may also contribute to anemia in malaria patients [4]. (See "Regulation of erythropoiesis".)

Erythropoietic suppression and dyserythropoiesis — The earliest observations of reduced erythropoiesis in acute human malaria were made over 80 years ago when reticulocytopenia was observed in P. vivax and P. falciparum infection, followed by reticulocytosis after parasite clearance had taken place [137]. Later, it was demonstrated that reticulocytopenia in Thai patients with malaria was accompanied by suppression of erythropoiesis [138] and was characterized by a defect in erythroid maturation and increased erythrophagocytosis [36].

Bone marrow aspirates taken from Gambian children with acute anemia revealed an increase in cellularity but no significant difference in the total number of erythroblasts when compared with uninfected patients. Children who presented with chronic anemia (parasitemia <1 percent) had higher degrees of erythroid hyperplasia and dyserythropoiesis than children with acute malaria [66,139], with abnormal production of RBCs demonstrated by cytoplasmic vacuolization, stippling, fragmentation, intercytoplasmic bridges, nuclear fragmentation and multinuclearity. This coincided with reduced reticulocytosis, indicating functional disruption of bone marrow RBC production [66,139]. Signs of dyserythropoiesis have also been seen in patients infected with P. vivax [82].

In a small study of six children with chronic disease, an increased proportion of polychromatic erythroblasts in the G2 phase of division was observed [140]. After treatment of malaria, the reticulocyte count increased in these patients, which pointed to P. falciparum as the cause of dyserythropoiesis and ineffective erythropoiesis.

Hemozoin and suppression of erythropoiesis — Hemozoin (malarial pigment, beta hematin), a parasite by-product due to incomplete hemoglobin digestion [141], may have a role in the impaired erythroid development through its direct effects on human monocyte function and/or erythroid precursors [142-145] and this is independent of impaired RBC production caused by inflammatory cytokines [146].

Hemozoin reduces human macrophage oxidative burst activity, prevents up-regulation of activation markers [147,148], and stimulates the secretion of biologically active endoperoxides from monocytes, such as 15(S)-hydroxyeicosatetraenoic and hydroxynonenal [149,150]. Hemozoin may therefore affect erythroid growth through oxidation of membrane lipids [143] or other cellular damage leading to cell-cycle arrest and/or apoptosis [145,147,151]. These endoperoxides may affect erythroid growth through oxidation of membrane lipids [143]. (See "Evaluation of the peripheral blood smear", section on 'Pigmented inclusions'.)

Ingestion of hemozoin by macrophages may result in reduced expression of prostaglandin-E2 (PGE2); reduced levels of PGE2 were associated with anemia and reticulocytopenia in children with malaria [152].

In a clinical study, hemozoin-containing macrophages and plasma hemozoin were associated with anemia and reticulocyte suppression [144]. Bone marrow sections from children who died with severe malaria have shown a significant association between the quantity of hemozoin located in erythroid precursors and macrophages and the proportion of abnormal erythroid cells. This effect was shown to be independent of tumor necrosis factor (TNF)-alpha.

The presence of pigment-containing monocytes has been shown to be associated with a significantly increased risk for the development of severe malarial anemia (ie, hemoglobin <60 g/L) in pre-school children from Kenya infected with P. falciparum (OR 4.37; 95% CI 2.39-7.97) [153].

Cytokine suppression of erythropoiesis — During the acute phase of malaria there is a strong inflammatory response, resulting in increases in TNF-alpha and interferon (IFN)-gamma [154]. TNF-alpha inhibits all stages of erythropoiesis [155] while IFN-gamma, along with TNF-alpha, inhibits erythroid growth and differentiation by up-regulating expression of TRAIL, TWEAK, and CD95L in developing erythroblasts [156].

Interleukin (IL) 10, a potent anti-inflammatory cytokine, may protect against bone marrow suppression and erythrophagocytic activity induced by TNF-alpha and/or mitigate other pro-inflammatory stimuli. Several clinical studies have demonstrated that a low ratio of plasma IL-10 to TNF-alpha is associated with severe malarial anemia (SMA) in young children [157,158]. In addition, a number of polymorphisms in the human TNF-alpha promoter show greater association with anemia than with cerebral malaria [133].

Many other proinflammatory cytokines such as IL-12, IL-18, and migration inhibitory factor (MIF) have also been implicated in the pathogenesis of malarial anemia. In humans, the secretion of IL-12 and IL-18 from macrophages induces production of IFN-alpha from natural killer (NK), B and T cells [159], while MIF is produced by activated T cells and macrophages and inhibits the anti-inflammatory activity of glucocorticoids. The data on serum levels of MIF in patients with malaria are consistent with its role as a hematopoietic suppressor in mice in that MIF concentrations are decreased in those with moderate anemia [160] and are elevated in those with more severe anemia [161].

The association of IL-12 with severe falciparum malaria is less clear. While some studies observe moderate increases in IL-12 and IL-18 in patients with severe anemia [159,160], others report decreases in IL-12 in patients with severe anemia (Hb <75 g/L) compared with uncomplicated controls (Hb >100 g/L), or no significant increases in patients with severe disease compared with uncomplicated malaria [161,162].

The glycophosphatidylinositol (GPI) anchor for the merozoite proteins MSP-1, MSP-2, and MSP-4 [163], parasite products found in the circulation during malaria infections, may be implicated in the proinflammatory cytokine effects on SMA. GPIs may induce the release of TNF-alpha from human macrophages [164], which could contribute to the pathology of SMA. The pro-inflammatory response from human monocytes is through interaction of GPIs with TLR2 and TLR4 [165]. Antibodies to GPIs are found in sera of adults from endemic regions in Kenya, but at reduced levels in children who, in general, have more severe disease and anemia [166].

The heme degradation product hemozoin may also be more intimately linked to an innate immune response, and thus pro-inflammatory cytokine release, than previously thought. In humans, some studies have shown that synthetic hemozoin pigment induces expression of TNF-alpha, which has been linked to the ability of hemozoin to induce the metalloproteinase MMP-9 [167-169]. Data from murine models of malaria have suggested that hemozoin stimulates an innate pro-inflammatory response [170] via a MyD88-dependent TLR9 pathway [171]. It now appears that stimulation of TLR9 may be through DNA associated with hemozoin.

Altered iron metabolism — Clinical aspects of iron deficiency in malaria are discussed above (see 'Chronic anemia' above); issues related to management of iron deficiency in malaria are discussed below. (See 'Management' below.)

Impaired use and recycling of iron may contribute to the severity of disease in children presenting with SMA, which shares many similarities with the anemia of chronic disease/anemia of inflammation [138]. The peptide hormone hepcidin has been implicated in mediating the anemia of chronic inflammation by reducing the availability of iron stores for erythropoiesis. (See "Anemia of chronic disease/anemia of inflammation", section on 'Hepcidin (primary regulator of iron homeostasis)'.)

Hepcidin is regulated by pro-inflammatory mediators such as TNF and IL-6, which are elevated in both murine infections and in patients presenting with severe falciparum malaria, although other parasite-derived and host factors may be involved in stimulating hepcidin production [55-57,162,172-174]. Hepcidin levels fall in the most severely ill children as hypoxia inhibits hepcidin production [175]. High hepcidin levels stimulated by blood stage malaria infection are associated with inhibition of liver stage malaria infection in mice [176] and reduced incorporation of iron into RBCs in humans [57,58]. Evidence from murine malaria suggests that low serum iron caused by elevated hepcidin reduced parasite growth and progression to severe disease [177]. These experimental and clinical findings are consistent with a role for iron as a growth factor for malaria parasites and a role for raised hepcidin and reduction in available iron as a protective innate response to malaria infection.

Erythropoietin — A fall in circulating hemoglobin levels and subsequent tissue hypoxia should normally stimulate elevated levels of erythropoietin (Epo). However, the clinical evidence for appropriately raised levels of Epo in SMA is somewhat contradictory. Studies in adults from Thailand and Sudan have suggested that Epo concentrations, although raised, were inappropriately low for the degree of anemia [178,179]. However, several studies of malaria in African children with SMA have shown appropriately raised Epo concentrations [46,180-182]. In fact, Epo levels in SMA are more than threefold higher when compared with anemic children without malaria [144].

Experimental evidence in murine malaria suggests that exogenous Epo can downregulate inflammatory responses induced by T cells and myeloid cells, reduce endothelial activation, and improve integrity of the blood-brain barrier [183,184].

Although ineffective or inadequate Epo production may contribute to SMA in some settings, in African children with malaria Epo synthesis is elevated more than expected. It is more likely that a reduced response to Epo, as seen in the anemia of chronic disease/anemia of inflammation, and not an inappropriately low level of Epo, is the more significant contribution to pathology. (See "Anemia of chronic disease/anemia of inflammation", section on 'Pathogenesis'.)

MANAGEMENT — Management of anemia may include transfusion, adjustment of antimalarial medication (for patients with severe drug-induced hemolysis), and iron supplementation (generally after resolution of acute infection resolves).

Transfusion – The role of transfusion (and exchange transfusion) is discussed separately. (See "Treatment of severe malaria", section on 'Anemia and coagulopathy'.)

Iron supplementation – There has been considerable interest in the relationship between iron deficiency and malaria and the question of whether to treat iron deficiency if it coexists with malaria. This is an important issue for the following reasons [185]:

Iron deficiency is widespread across malaria-endemic areas and is particularly common among children <5 years of age, who are most vulnerable to malaria. One trial in Tanzania demonstrated excess morbidity and mortality among children <5 years who received iron supplementation [62].

Low serum iron may reduce growth of the malaria parasite and/or reduce the progression to severe disease. In a study including 727 Malawian children, baseline iron deficiency was correlated with a significantly lower incidence of parasitemia (hazard ratio [HR] 0.55, 95% CI 0.41-0.74) and clinical malaria (HR 0.49, 95% CI 0.33-0.73) [186].

The net health benefits of iron supplementation in multinutrient powders vary between countries; benefits are greatest in areas where the prevalence of moderate and severe anemia is high and the prevalence of other infections, such as diarrheal illnesses, is low [187].

The complex links between iron metabolism, iron deficiency, and malaria infection and lack of a simple, effective, and inexpensive point-of-care test to identify those who would benefit from iron supplementation have precluded community-wide iron supplementation [188,189]. Determining the need for iron supplementation depends on individual and local clinical circumstances:

When not to treat − Oral iron given during active malaria infection is not efficiently absorbed because hepcidin, which reduces iron absorption from the gastrointestinal tract, is present at high levels during malaria infection. In addition, administered iron may cause gastrointestinal inflammation, cause oxidative stress and tissue damage, and act as a growth factor for parasites, bacteria, and viruses.

When to treat − Oral iron administered after clearance of parasitemia is absorbed efficiently because hepcidin levels are low after clearance of infection and at the end of the malaria season. Iron supplementation is appropriate when iron stores are low (as evidenced by low serum ferritin) in the absence of other infections. Serum hepcidin levels may be a useful indicator for whether iron may be efficiently absorbed, although this test is not available clinically [190].

The World Health Organization recommends that iron supplementation be given in combination with malaria prevention and treatment services in malaria-endemic areas. (See "Anemia in pregnancy", section on 'Management'.)

Drug-induced hemolytic anemia – Drug-induced hemolytic anemia may be a complication of antimalarial treatment (See "Treatment of severe malaria", section on 'Anemia and coagulopathy'.):

Intravenous artesunate and possibly oral artemisinin derivatives may cause delayed-onset hemolytic anemia sometimes requiring transfusion. Prospective studies have suggested that delayed hemolysis is seen in 25 to 30 percent of travelers treated for malaria, although it is mild in 85 percent of cases [72]. (See "Drug-induced hemolytic anemia", section on 'Management' and "Treatment of severe malaria", section on 'Anemia and coagulopathy'.)

Use of primaquine to treat the dormant liver stage of vivax malaria in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency can cause significant, transient hemolytic anemia that may occasionally require transfusion [191]. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

SUMMARY

Scope of the problem – Malarial anemia can cause severe morbidity and mortality, especially in children and pregnant women. (See 'Overview' above and 'Effect on pregnancy' above.)

Clinical findings – Anemia, thrombocytopenia, splenomegaly (occasionally massive with or without rupture), hepatomegaly, and jaundice can develop. The anemia is generally normocytic and normochromic, with a striking absence of reticulocytes. Microcytosis and hypochromia may be present due to the very high frequency of thalassemia trait and/or iron deficiency. Infected red blood cells (RBCs) may be seen on the peripheral blood smear (picture 1). (See 'Features' above.)

Mechanisms – Malarial anemia is multifactorial and includes direct destruction of parasitized and non-parasitized RBCs, splenic and hepatic sequestration and destruction of RBCs, bone marrow suppression, and dyserythropoiesis. Host factors, both genetic and acquired, may also play a part. (See 'Pathogenesis' above and 'Bone marrow suppression' above and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Infections (RBC parasites and intracellular bacteria)'.)

Management – Management of anemia may include transfusion, adjustment of antimalarial medication (for patients with severe drug-induced hemolysis, and iron supplementation (generally after resolution of acute infection resolves). (See 'Management' above.)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

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Topic 7112 Version 36.0

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