Anemia in malaria

INTRODUCTION — 

Malaria is a parasitic infection caused by Plasmodium species. Malaria is a global health problem, causing disease on a vast scale. (See "Malaria: Epidemiology, prevention, and elimination".)

Plasmodium species infect red blood cells (RBCs), leading to hemolysis. Most infections are associated with some degree of anemia; the severity depends on patient-specific characteristics such as age, innate [heritable] and acquired resistance, and comorbid conditions, along with parasite-specific characteristics (species, drug resistance). Malarial anemia can cause severe morbidity and mortality, especially in children and pregnant individuals infected with Plasmodium falciparum.

This topic discusses anemia associated with Plasmodium infection.

Separate topics discuss:

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

●Prophylaxis – (See "Prevention of malaria infection in travelers" and "Malaria: Epidemiology, prevention, and elimination".)

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

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

●General approach to evaluating anemia – (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)

DEFINITIONS — 

The World Health Organization (WHO) has published documents defining severe malarial anemia and general anemia definitions (unrelated to anemia) and severe malarial anemia (SMA).

●Severe malarial anemia (SMA) – SMA is defined as hemoglobin <5 g/dL (<50 g/L) in the presence of malaria parasites [1].

●Anemia – Anemia (general population, unrelated to malaria) is defined based on hemoglobin (table 1) in a 2024 World Health Organization (WHO) document [2]. (See "Approach to the child with anemia", section on 'Definition of anemia' and "Diagnostic approach to anemia in adults", section on 'Anemia definitions'.)  

PATHOGENESIS — 

Plasmodium species infect red blood cells (RBCs), leading to hemolysis. This can affect both infected and uninfected RBCs, due to changes in RBC membrane properties and hyperactivity of the reticuloendothelial system.

The physiologic response to anemia consists of compensatory reticulocytosis with increased RBC production. However, this response may be inhibited by the concomitant inflammation and alterations of developing RBCs in the bone marrow, leading to exacerbation of anemia. (See "Diagnosis of hemolytic anemia in adults", section on 'Hemolysis without reticulocytosis' and "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

The underlying causes of severe malarial anemia (SMA) may include one or more of the following mechanisms [3]:

●Parasite factors. (See 'Impact of malaria species' below.)

●Host genetic factors. (See 'Impact of host genetic variation' below.)

●Reticuloendothelial clearance. (See 'Hypersplenism and reticuloendothelial hyperactivity' below.)

●Hemolysis. (See 'Hemolysis' below.)

●Suppression of erythropoiesis and dyserythropoiesis. (See 'Decreased RBC production' below.)

Much of the pathogenesis research has been for P. falciparum malaria; similar mechanisms appear to apply to P. vivax, particularly when repeated childhood infection may be associated with anemia [4-7].

Parasite life cycle and hemozoin — The mechanism of anemia in malaria is related to the life cycle of the malaria parasite. This is summarized in the figure (figure 1), discussed briefly below, and discussed in detail separately. (See "Pathogenesis of malaria", section on 'Life cycle'.)

●Malaria species – Plasmodium species include P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. These are discussed in more detail separately. (See "Malaria: Epidemiology, prevention, and elimination".)

●Sexual reproduction (in mosquitoes) – A small proportion of merozoites in RBCs transform into male and female gametocytes. These may be ingested by the mosquito following a blood meal. The gametocytes fuse and transform into an oocyst, which divides into many sporozoites that migrate to the salivary gland of the infected mosquito, from which they are released during the next blood meal.

The table summarizes malarial forms and the cell types they infect (table 2).

●Asexual life cycle (in the liver) – The asexual life cycle begins when a female Anopheles mosquito taking a blood meal contains sporozoites in its saliva. These enter the human circulation, travel to the liver, and invade hepatocytes.

The sporozoites divide until mature tissue schizonts are formed, each containing thousands of daughter merozoites. The increasing number of merozoites causes the hepatocytes to rupture and release infective merozoites into the circulation [8].

Merozoites can enter RBCs by binding to specific receptors on the RBC surface [9-14].

•P. falciparum enters RBCs via glycophorin A. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'MNS blood group system (glycophorins A and B)' and "Red blood cell antigens and antibodies", section on 'MNS blood group system'.)

•P. vivax enters RBCs via the Duffy blood group antigen. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Duffy blood group system' and "Red blood cell antigens and antibodies", section on 'Duffy blood group system'.)

●Production of more schizonts (in RBCs) – Once inside the RBC, the parasite makes modifications to the infected cell to facilitate survival and multiplication through the stages of rings, trophozoites and schizonts [15]. Mature schizonts burst to release merozoites that invade new RBCs.

Some changes made by intracellular parasites in RBCs include:

•Formation of rosettes containing infected and uninfected RBCs, which may also bind to and obstruct the microcirculation via binding of RBCs to various endothelial cell receptors [16,17]. IgM can act as a bridge between RBCs [18]. (See "Structure of immunoglobulins", section on 'IgM'.)

•Use of anaerobic glycolysis to generate energy, depleting glucose and increasing production of lactic acid.

•Ingestion and degradation of hemoglobin.

•Reduced RBC membrane deformability, increasing hemolysis and accelerated splenic clearance.

•Addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane of uninfected RBCs.

•RBC lysis, with release of membrane remnants and free heme.

In addition, P. falciparum has unique characteristics; as P. falciparum parasites mature within RBCs, they induce the formation of "knobs" on the RBC surface [19,20]. The parasite's VAR genes (PfEMP-1) that bind to receptors on endothelial cells in post-capillary venules are concentrated at these "knobs" [21-23]. The cytoadherence and sequestration of RBCs within these small vessels leads to microvascular blood flow obstruction. These may help explain the potential of P. falciparum infection to cause severe disease.

●Hemozoin – Hemozoin (malarial pigment, beta hematin) is a byproduct of parasite metabolism of hemoglobin, formed by incomplete hemoglobin digestion [24].

Monocytes and macrophages take up hemozoin. In some cases, this pigment can be seen on the peripheral blood smear (picture 1). (See "Evaluation of the peripheral blood smear", section on 'Microorganisms within neutrophils'.)

Hemozoin may contribute to anemia by multiple mechanisms:

•Induction of TNF-alpha expression, causing an inflammatory block [25-29]. (See 'Decreased RBC production' below.)

•Cytokine-independent effects on human monocyte function and/or erythroid precursors [30-34]. These effects may be mediated by biologically active endoperoxides secreted by monocytes, such as 15(S)-hydroxyeicosatetraenoic and hydroxynonenal [35,36].

-Oxidation of membrane lipids on developing RBCs may interfere with erythropoiesis [31].

-Other cellular damage may cause cell cycle arrest and/or apoptosis [33,37,38].

•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 [39].

•Hemozoin correlates with anemia severity.

-In one study, hemozoin-containing macrophages and plasma hemozoin were associated with anemia and reticulocyte suppression [32].

-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.

-In another study, pigment-containing monocytes correlated with a significantly increased risk of severe malarial anemia [40].

Whether hemozoin was a marker for infection severity or a cause of anemia in these studies could not be determined.

Hypersplenism and reticuloendothelial hyperactivity — Hypersplenism (attributed to sequestration of infected and uninfected RBCs in the spleen) may be an important cause of malarial anemia. In addition, there appears to be an important component of extravascular hemolysis, due to reticuloendothelial macrophages in the spleen and possibly the liver. Immunologic and nonimmunologic mechanisms appear to contribute [41].

●In a 2024 study including 37 individuals residing in a malaria-endemic region who underwent splenectomy (mostly for splenic trauma), 32 were infected with malaria and 26 were anemic; splenic tissue was examined to evaluate how malaria affected splenic sequestration of RBCs [42]. Findings included larger spleens (by weight) with P. falciparum than P. vivax infection, splenomegaly and splenic congestion (correlating with burden of infection), and RBCs (mostly uninfected) trapped in the spleen.

●A study of the spleen from a patient with P. falciparum malaria revealed large numbers of both parasitized and non-parasitized 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 [43].

●Perfusion studies (in vivo and ex vivo) have suggested a primary role for splenic filtration and retention of ring forms [44-46].

Hemolysis — During malaria infection, infected RBCs lyse through schizont lysis. (See 'Parasite life cycle and hemozoin' above and 'Blackwater fever' below.)

Destruction of infected RBCs by reticuloendothelial macrophages also occurs. (See 'Hypersplenism and reticuloendothelial hyperactivity' above.)

However, a very small percentage of RBCs are infected directly; lysis of uninfected RBCs contributes significantly to anemia.

●Infected RBCs – Mechanisms of hemolysis of infected RBCs include:

•Abnormal distribution of membrane phospholipids such as phosphatidylserine (PS), phosphatidylcholine, and phosphatidyl-ethanolamine may cause membrane damage [47]. Exposure of PS on the outer surface of infected RBCs during parasite maturation can trigger macrophage recognition and phagocytosis [48-50]. Heme liberated from hemoglobin may damage RBC membranes [51].

In a case-control study of children with severe malaria, anti-PS and anti-DNA antibody levels correlated with anemia, acute kidney injury, post-discharge mortality, and hospital readmission [49]. These markers were also associated with P. vivax infection [50].

•Infected RBCs may be opsonized by antibodies against parasite antigens such as PfEMP-1 expressed on the RBC surface.

•During acute P. falciparum infection, RBCs containing ring-infected erythrocyte surface antigen (also known as RESA or Pf155) but no intracellular parasite can be detected [52]. This could represent splenic removal of intraerythrocytic parasites without RBC destruction and could explain some of the disparity between anemia and the decrease in parasite count observed in some hyperparasitemic patients.

•These effects may be exaggerated by the associated splenic hyperactivity (hypersplenism). (See 'Hypersplenism and reticuloendothelial hyperactivity' above.)

●Uninfected RBCs – Destruction of uninfected RBCs in the spleen (and possibly the liver) is the major contributor to malarial anemia [44,53,54]. (See 'Hypersplenism and reticuloendothelial hyperactivity' above.)

Based on clinical observations and mathematic modeling, for each infected RBC that is removed from the circulation, approximately 10 uninfected RBCs are removed [53]. 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 [44,45,55].

This reduced survival of uninfected RBCs persists for some period after clearance of malarial parasitemia, suggesting persistent nonspecific activation of reticuloendothelial function. The activity and number of macrophages are increased. In addition, the enlarged spleen may contribute to removal of uninfected RBCs [51,56-59]. (See 'Hypersplenism and reticuloendothelial hyperactivity' above 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 including some or all of the following:

•Reduced deformability − Uninfected RBCs from patients with acute P. falciparum malaria have ultrastructural alterations and reduced deformability [60]. The mechanism responsible for the loss of deformability is uncertain but may include increased oxidation of membrane components [61,62]. Reduced RBC deformability is strongly associated with mortality, both in adults and children with severe malaria [63,64]. (See "Red blood cell membrane: Structure and dynamics", section on 'Clinical consequences'.)

•Lipid peroxidation of membranes – This 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 [51,65-67]. 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 [68].

•Surface deposition of immunoglobulin and complement – This may enhance receptor-mediated uptake by macrophages. Studies have shown that a positive direct antiglobulin (Coombs) test was associated with malarial anemia, with the eluted antibodies specific for parasite-derived antigens rather than host antigens [69,70].

Studies of the surface changes in RBCs of patients with severe malarial anemia have shown that RBCs had increased surface IgG and reduced expression of CR1 and CD55 compared with controls [71-74].

The loss of these complement regulatory proteins occurs in both falciparum and vivax malaria and in adults and children and is a pan-species, age-independent mechanism of malarial anemia [74]. However, higher levels of CR1 and CD55 and CD47 (which inhibits red cell phagocytosis) are seen on infected RBCs, suggesting that infected RBCs are at least in part protected from complement-mediated destruction and macrophage clearance.

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) [75,76]. RSP-2 is deposited on uninfected RBCs and anti-RSP-2 antibodies may facilitate complement-mediated phagocytosis of these uninfected RBCs [77]. Damage to developing erythroid cells by RSP-2 and anti-RSP-2 could contribute to the development of SMA. (See 'Decreased RBC production' below.)

Cross-reacting IgM and IgG autoantibodies against RBC antigens have been described [78,79]. These were identified as anti-band 3 and anti-spectrin antibodies in a study in P. vivax malaria [80].

•Surface charge – 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 [81]. Reduction of negative charge (Zeta potential) promotes RBC aggregation, increasing the chances of splenic removal.

•Drug-induced – Anti-malarial medications that can cause hemolysis include primaquine [causing oxidative stress in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency], and quinine (which may contribute to hemolysis by as yet undefined mechanisms). (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'.)

Decreased RBC production — The earliest observations of reduced erythropoiesis in acute malaria were made in the 1930s, when reticulocytopenia was observed in P. vivax and P. falciparum infection, followed by reticulocytosis after parasite clearance [82]. Later, it was demonstrated that reticulocytopenia was accompanied by suppression of erythropoiesis [83]. Erythrophagocytosis was also observed [84]. (See "Evaluation of bone marrow aspirate smears", section on 'Macrophages (histiocytes) with ingested cells or debris'.)

●Decreased RBC precursors – Patients with severe P. falciparum malaria may have reduced numbers of erythroid precursors, assessed in vitro as burst-forming units (BFU-E) and colony-forming units (CFU-E). This reduction 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 [85]. (See "Regulation of erythropoiesis".)

●Dyserythropoiesis – Development of parasite gametocytes in erythroblasts in the bone marrow may also contribute to anemia in some patients [86]. In one study of bone marrow aspirates from children with acute anemia, cellularity was increased and erythroblast numbers were similar to uninfected patients; children with chronic anemia (parasitemia <1 percent) had higher degrees of erythroid hyperplasia and dyserythropoiesis than children with acute malaria [87,88]. Other abnormalities included cytoplasmic vacuolization, stippling, fragmentation, intercytoplasmic bridges, nuclear fragmentation, and multinuclearity. This coincided with reduced reticulocytosis, indicating functional disruption of bone marrow RBC production [87,88]. Signs of dyserythropoiesis have also been seen in patients infected with P. vivax [89].

●Cell cycle arrest – In a small study of six children with chronic disease, there was an increased proportion of polychromatophilic erythroblasts in the G2 phase of the cell cycle [90]. After treatment of malaria, the reticulocyte count increased in these patients, which pointed to P. falciparum as the cause of dyserythropoiesis and ineffective erythropoiesis. In vitro, exposure of erythroid precursors to infected erythrocytes may cause imbalance of alpha and beta globin mRNAs [91].

●Inflammatory block to iron uptake – During the acute phase of malaria there is a strong inflammatory response, resulting in increases in TNF-alpha and interferon (IFN)-gamma [92].

These cytokines can cause an inflammatory block to erythropoiesis by increasing hepcidin and reducing iron availability for RBC production and iron recycling. Other cytokines such as interleukins (ILs) may also contribute. Hepcidin mediates anemia of chronic disease/anemia of inflammation across many inflammatory conditions. Details of this mechanism are discussed separately. (See "Anemia of chronic disease/anemia of inflammation", section on 'Hepcidin (primary regulator of iron homeostasis)'.)

Malaria-specific implications and findings include:

•High hepcidin levels are associated with reduced incorporation of iron into RBCs [93,94].

•The parasite produces glycophosphatidylinositol (GPI) anchors that induce release of TNF-alpha, which in turn inhibits all stages of erythropoiesis [95-97].

•IFN-gamma also inhibits erythroid growth and differentiation by upregulating expression of TRAIL, TWEAK, and CD95L in developing erythroblasts [98].

Some variants in the TNF-alpha promoter show greater association with anemia than with cerebral malaria [99]. (See 'Impact of host genetic variation' below.)

•IL-10 is an anti-inflammatory cytokine that reduces erythrophagocytic activity induced by TNF-alpha and other pro-inflammatory stimuli; a low ratio of plasma IL-10 to TNF-alpha is associated with severe malarial anemia in young children [100,101].

•Other proinflammatory cytokines implicated in malarial anemia include IL-12, IL-18, and migration inhibitory factor (MIF). 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 [15,102,103].

●Decreased erythropoietin – The physiologic response to anemia involves increased production of erythropoietin. Some evidence suggests that the erythropoietin response is inappropriately low in individuals with malaria, although results are conflicting.

•Some studies in adults suggested that erythropoietin levels increased but were inappropriately low for the degree of anemia [104,105].

•Some studies in children with severe malarial anemia have shown appropriate increases in erythropoietin [106-109].

•One study in anemic children found erythropoietin levels were threefold higher in those with malaria than those without malaria [32].

•In mouse models, erythropoietin was able to downregulate inflammatory responses [110,111].

OTHER (CONCOMITANT) CAUSES OF ANEMIA — 

It may be difficult to attribute anemia to a single cause.

Clinical trials of malaria chemoprophylaxis and iron supplementation in infants have consistently shown that malaria infection was the main cause of anemia [112-115]. However, nutritional deficiencies, genetic variation, and other intercurrent infections may all contribute to anemia [9,10,84,116].

The multifactorial etiology of severe malarial anemia was illustrated in a case-control study of 381 preschool children with severe anemia who presented to the outpatient department of a hospital and 757 controls without severe anemia who presented to the outpatient department or lived in the local community [117]. On multivariate analysis, the likelihood of various causes of anemia were as follows:

●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)

●Vitamin A deficiency (OR 2.8, 95% CI 1.3-5.8)

●Vitamin B12 deficiency (OR 2.2, 95% CI 1.4-3.6).

In this population, iron deficiency, folate deficiency, and sickle cell disease were uncommon. However, other studies have shown very high rates of iron deficiency, especially in sub-Saharan Africa (in one study, 130 of 155 children [84 percent] who had iron studies) [118].

●Iron deficiency is widespread across malaria-endemic areas and is particularly common among children <5 years of age, who are most vulnerable to malaria.

●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) [119,120]. In a study of 727 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) [121].

Evaluation and management of iron deficiency are discussed below. (See 'Evaluation' below and 'Iron supplementation' below.)

Hemoglobinopathies such as sickle cell disease and thalassemia may contribute to anemia. Evaluation is discussed separately. (See "Diagnosis of thalassemia (adults and children)" and "Diagnosis of sickle cell disorders" and "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis/hypochromia'.)

Although dietary deficiencies are widespread in malaria-endemic regions, reduced folate levels are not thought to be major contributors to the dyserythropoiesis seen during severe malarial anemia [88]. Subclinical vitamin B12 deficiency may make a hitherto unrecognized contribution to severe anemia or may reflect altered vitamin B12 metabolism or transport during infection [117]. (See 'Decreased RBC production' above.)

EPIDEMIOLOGY

Incidence of malarial anemia — Anemia and severe malarial anemia (SMA) are defined above. (See 'Definitions' above.)

●Decreasing incidence and prevalence of malaria – The incidence of malaria has fallen in many parts of sub-Saharan Africa following implementation of control measures such as impregnated bed nets, indoor residual spraying, and intermittent preventive treatment, with concomitant reductions in malaria-specific admission rates and malaria-specific inpatient mortality [122-125]. This is discussed further separately. (See "Malaria: Epidemiology, prevention, and elimination".)

●Baseline prevalence of anemia in malaria-endemic locations – The total anemia prevalence in 2021 was greatest in western sub-Saharan Africa (47·percent), south Asia (43 percent), and central sub-Saharan Africa (36 percent) [126]. Anemia due to malaria was most prominent in the central, eastern, and western sub-Saharan Africa regions.

In a typical study of children living in 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 [127]. In areas of high endemicity for malaria, the prevalence of anemia is the highest in the six month old to one year age group [128].

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 anemia was [129]:

•Any anemia – 79 percent

•Mild anemia – 21 percent

•Moderate anemia – 50 percent

•Severe anemia – 8 percent

●Incidence of severe malarial anemia (SMA) – SMA has decreased along with the decreased incidence of malaria overall. It is seen most frequently in areas of very high malarial transmission and most commonly in young children and pregnant women [3]. It is also a significant concern for travelers returning from malaria-endemic regions [130,131].

Impact of malaria species — The severity of anemia 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. falciparum can invade RBCs and RBC precursors of all stages, from orthochromatic erythroblasts onward [132]. This species is capable of multiplying 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 RBCs to sequester in postcapillary venules. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

P. falciparum parasitemia is often high, 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 [86].

Of travelers returning to the United States with malaria in 2018, 7.3 percent had parasitemia levels ≥5 percent [131].

●P. vivax and P. ovale are restricted to infecting reticulocytes (young RBCs), thereby limiting parasitemia levels to approximately 1 to 2 percent of RBCs [133]. Anemia due to hemolysis does occur and may be severe, but there is no peripheral sequestration of parasitized RBCs. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

●P. malariae multiplication rate in RBCs is relatively low. Infection results in limited parasitemia (<1 to 2 percent of RBCs) and usually mild symptoms but severe disease including anemia can develop in 3 percent of cases [134]. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

●P. knowlesi infection can result in high levels of peripheral parasitemia and is associated with anemia, acute kidney injury, and death [135]. (See "Non-falciparum malaria: Plasmodium knowlesi".)

There is genetic variation within species, as discussed separately. (See "Pathogenesis of malaria", section on 'Genetic diversity'.)

Impact of host genetic variation — Malaria severity may reflect genetic variation in the infected individual. Variation is distributed across numerous genes [136].

Examples include:

●Genetic variation affecting RBC proteins (hemoglobin, surface proteins, metabolic enzymes) have strong evidence for effects on malaria risk and disease severity, as discussed separately. (See "Protection against malaria by variants in red blood cell (RBC) genes" and "Sickle cell disease in sub-Saharan Africa", section on 'Malaria'.)

●A variant in the gene for ferroportin (SLC40A1, also called FPN1) appears to have become prevalent in African populations in response to the selection pressure exerted by malaria [137]. This variant, which results in substitution of histidine for glutamine at amino acid 248 (Q248H), prevented hepcidin-induced degradation of ferroportin and protected against severe malaria disease. (See "Regulation of iron balance".)

●Variants in the promoter region of the tumor necrosis factor-alpha gene (TNF) may attenuate or increase the risks for developing complications of malaria, such as cerebral malaria and anemia [99,138,139]. In a cohort of 780 children living in a malaria-endemic environment, one TNF haplotype was associated with an increased risk of iron deficiency and iron deficiency anemia at the end of the malaria season [140].

●In Mali, the Fulani peoples, who are exposed to the same hyperendemic transmission of P. falciparum, have less parasitemia, higher antibody responses, and less morbidity compared with the Dogon peoples, and this is associated with higher frequency of blood group O, and differences in a FcγRIIa polymorphism and allele frequency [141].

CLINICAL FEATURES — 

The clinical presentation and severity of P. falciparum infection is broad.

Acute/severe malarial anemia — Infected red blood cells (RBCs) may be seen on the peripheral blood smear (picture 2).

●Patients with prior immunity – 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), hepatomegaly, and jaundice can develop, and splenic rupture can occasionally occur [142]. (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 [143,144]. 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 [106].

However, the clinical setting of severe malarial anemia (SMA) is varied and complex. Acute infection may present with anemia and/or cerebral malaria, respiratory distress, and hypoglycemia. Chronic, repeated malarial infection may also lead to severe anemia. In either case, there may be a background of anemia due to other factors [145]. (See 'Other (concomitant) causes of anemia' above.)

●Non-immune patients – Malaria infection among non-immune patients is often associated with a sudden drop in hemoglobin concentration, associated with increased hemolysis and bone marrow suppression [130,131]. (See 'Pathogenesis' above and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Infections (RBC parasites and intracellular bacteria)'.)

Non-immune patients may exhibit anemia, coma, respiratory distress, and hypoglycemia, and 12 percent of children with severe malaria had concomitant bacteremia [146,147]. 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) [146,148-150].

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). Older children and adults have acquired immunity. 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 severe malarial disease varies with age and transmission intensity [151]. As transmission intensity declines, severe malaria is most frequently found in older age groups.

P. falciparum infection is most commonly associated with severe disease. On occasion, P. vivax can also cause severe hemolysis [152,153]. Some studies in rural India suggest that severe disease is associated with P. vivax infection more frequently than with P. falciparum infection [154].

●Returning travelers – Travelers returning from malaria-endemic regions constitute a heterogeneous population; some have no prior immunity, while others have a history of malaria exposure (but may have waning immunity in the absence of ongoing exposure). SMA is a potential complication of severe malaria in this population; careful evaluation and monitoring are required [130,131].

Chronic infection — Anemia can also occur with chronic or repeated malarial infections.

●Children may present with severe anemia but negative blood smear for malaria parasites, yet the anemia responds to antimalarial treatment [143,155].

●In a series of children with chronic P. falciparum malaria, those with moderate to severe anemia and hepatosplenomegaly had a lower level of parasitemia than seen in acute malaria but greater degrees of hemolysis, neutropenia, atypical lymphocytosis, and thrombocytopenia [9]. Hypersplenism and bone marrow suppression may contribute to neutropenia and thrombocytopenia seen in such cases.

●In otherwise asymptomatic children, low levels of parasitemia may be associated with increased hepcidin, which causes an inflammatory block with reduced iron availability [93,94,156,157]. (See 'Decreased RBC production' above.)

Blackwater fever — Blackwater fever (BWF) is an uncommon complication of malaria characterized by intravascular hemolysis, sudden appearance of hemoglobin in the urine, and kidney failure [158-160]. Disseminated intravascular coagulation (DIC) and RBC fragmentation may accompany severe intravascular hemolysis. (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.

Antimalarial therapies may contribute. Case 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 [159,161]. Among European expatriates living in Africa, BWF has been associated with use of the antimalarial agents halofantrine, quinine, and mefloquine [162]. (See 'Medication adjustment' below.)

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 [162].

Post-artesunate delayed hemolysis (PADH)

●Definition – Artemisinin derivatives were first reported to be associated with transient reticulocytopenia. However, artesunate has also been associated with delayed-onset hemolytic anemia.

Post-artesunate delayed hemolysis (PADH) refers to a decrease in hemoglobin concentration following parenteral artesunate, typically seven days to four weeks after treatment, likely secondary to extravascular hemolysis. It is characterized by a hemoglobin decline by at least 10 percent with a lactate dehydrogenase level >390 units/L and a haptoglobin level <0.1 g/L [163,164].

●Incidence – Estimates of PADH incidence vary widely. 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 [165-167]. 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 [168,169]. A 2019 to 2021 analysis of PADH in the United States reported an incidence of 2.7 percent [164].

●Assessment – Monitoring for PADH following parenteral artesunate treatment should include weekly laboratory evaluation of hemoglobin, haptoglobin, lactate dehydrogenase, total bilirubin, and reticulocyte count. Evaluation should continue from seven days post-treatment through four weeks.

●Management – Management of PADH follows a general approach to hemolysis, with transfusion given as needed and monitoring for hemolysis resolution. (See "Drug-induced hemolytic anemia", section on 'Management'.)

●Mechanism – PADH may be due to the shortened lifespan of "pitted" RBCs from which infecting parasites have been removed by the spleen. Artesunate treatment kills parasites, but these RBCs can persist in circulation after resealing until they are removed in the spleen; they are short-lived. Higher levels of these pitted RBCs are found in individuals with PADH than those who do not experience PADH [170].

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 [171].

Other potential mechanisms of PADH include oxidative stress, autoimmune hemolysis, or drug-dependent autoantibodies. The relative contributions of these processes have not been systematically studied.

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".)

Effect on pregnancy — P. falciparum malaria is more likely to be severe and complicated during pregnancy, as the placenta contains high levels of parasites due to parasite attachment to chondroitin sulfate A in the placental intervillous space [172]. The diagnosis of malaria can be difficult if parasites are concentrated in the placenta and reduced in the maternal circulation.

Pregnant individuals may experience a variety of adverse consequences from malarial infection, including [172-174]:

●Maternal anemia

●Low birth weight from prematurity

●Intrauterine growth retardation

●Fetal parasite exposure and congenital infection

●Spontaneous miscarriage

●Increased infant mortality

P. vivax malaria has been clearly associated with anemia during pregnancy, along with low birth weight of the children of infected mothers [175].

It has been estimated that 75,000 to 200,000 infant deaths are associated with malarial infection in pregnancy each year [173].

In one study, high levels of maternal IgG antibodies against a variant surface antigen (VSA) expressed on pregnancy-associated P. falciparum malaria (PAM)-infected RBCs protected against low birth weight and maternal anemia [176]. This observation suggests an area of investigation for future therapeutic strategies (eg, VSA-PAM-based vaccination).

Supplemental folic acid should be continued during pregnancy regardless of malarial infection. (See "Preconception and prenatal folic acid supplementation".)

For pregnant individuals living in malaria endemic areas, the World Health Organization (WHO) recommends intermittent oral iron and folic acid supplementation, with 120 mg of elemental iron (equivalent to 600 mg ferrous sulfate heptahydrate, 360 mg ferrous fumarate, or 1000 mg ferrous gluconate) and 2.8 mg folic acid once weekly if daily iron is not acceptable due to side-effects, and in populations with an anemia prevalence of <20 percent in pregnant individuals [177].

In malaria-endemic areas, iron and folic acid supplementation programs should be implemented in conjunction with adequate measures to prevent, diagnose, and treat malaria during pregnancy.

EVALUATION — 

The extent of evaluation should be individualized based on the patient's clinical history and symptom severity, and diagnostic capacity of the clinical setting.

Testing for anemia — If possible, a hemoglobin level should be checked when evaluating for malaria.

Evaluating causes of anemia — If possible, iron studies should be considered for individuals with anemia, including serum ferritin or serum transferrin receptor (also called soluble transferrin receptor) [178].

Low serum ferritin or elevated serum transferrin receptor is indicative of iron deficiency. However, iron study results can be affected by infection (ferritin is an acute phase reactant that is increased by inflammation, making diagnosis of iron deficiency in acute malaria challenging), and there should be consideration of testing upon recovery from malaria [125,179,180]. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)

Diagnosis of iron deficiency in patients with inflammatory conditions is discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Diagnosis of iron deficiency and iron deficiency anemia in adults".)

If available, there should be consideration of evaluation for additional contributors to anemia (such as helminth infection and HIV infection). (See "Pediatric HIV infection: Diagnostic testing in children younger than 18 months" and "Screening and diagnostic testing for HIV infection in adults".)

Malaria testing — This is discussed separately. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'Diagnosis' and "Laboratory tools for diagnosis of malaria".)

MANAGEMENT

Supportive care for intravascular hemolysis — Intravascular hemolysis is a life-threatening emergency that can occur with blackwater fever, acute hemolytic transfusion reactions, some drug-induced hemolysis, and some other forms of hemolytic anemia. (See "Diagnosis of hemolytic anemia in adults", section on 'Intravascular hemolysis'.)

Treatment is largely supportive and includes:

●Removal or discontinuation of the inciting cause (infectious organism, drug, incompatible transfusion). (See "Diagnosis of hemolytic anemia in adults", section on 'Immediate management issues before the cause is identified' and "Diagnosis of hemolytic anemia in adults", section on 'Post-diagnostic testing to determine the cause'.)

●Aggressive hydration to reduce the risk of acute kidney injury from heme pigment. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)

●Testing and supportive care for disseminated intravascular coagulation if present. (See "Disseminated intravascular coagulation in infants and children" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Transfusion — Indications for transfusion and the role of exchange transfusion are discussed separately. (See "Treatment of severe malaria", section on 'Anemia and coagulopathy'.)

Iron supplementation — Advice regarding iron supplementation presumes that the patient's iron status is known, although this often may not be the case.

For iron-deficient individuals, we suggest iron repletion after infection has resolved rather than during active malarial infection (and any other active infection) [181]. The rationale for delaying supplementation includes:

●Iron may worsen outcomes.

•A randomized trial in >24,000 children (age <5 years) residing in a malaria-endemic region who were assigned to receive one of three treatments (iron plus folic acid, iron plus folic acid plus zinc, or placebo) was stopped early because iron supplements led to trends towards increased risks of death, hospital admission, and serious adverse effects, along with an increased risk of cerebral malaria (relative risk [RR] 1.22; 95% CI 1.02-1.46) [182]. However, subgroup analysis restricted to children with iron deficiency anemia found that supplemental iron decreased the risk of hospitalization and death (5.1 events per 100 child-years, versus 10.1 events per 100 child-years with placebo).

•In vitro studies demonstrate iron is helpful to parasite growth. One study of anemic pregnant individuals found that P. falciparum growth was reduced at baseline but increased during iron supplementation [183].

●Oral iron will not be efficiently absorbed.

In infection and inflammation, there is an inflammatory block to iron absorption and utilization. This is due to increased hepcidin levels, which in turn reduces iron absorption from the gastrointestinal tract and utilization of storage iron. (See "Anemia of chronic disease/anemia of inflammation", section on 'Treatment of the underlying disorder'.)

●Adverse effects may be better tolerated when the patient is well.

Oral iron has a high risk of gastrointestinal adverse events and may cause oxidative stress and/or tissue damage. (See "Iron requirements and iron deficiency in adolescents", section on 'Adverse effects and toxicity' and "Treatment of iron deficiency anemia in adults", section on 'Side effects (oral iron)'.)

Once the malarial infection has resolved, individuals with iron deficiency should receive supplemental iron and have the cause of deficiency determined and treated as appropriate, as discussed separately. The World Health Organization recommends that iron supplementation be given in combination with malaria prevention and treatment services in malaria-endemic areas.

●Children – (See "Iron deficiency in infants and children <12 years: Treatment".)

●Adolescents – (See "Iron requirements and iron deficiency in adolescents", section on 'Management'.)

●Adults – (See "Treatment of iron deficiency anemia in adults".)

If iron status is unknown, the baseline risk of iron deficiency is high, and testing is not pursued, iron supplementation may be reasonable. This may be especially relevant in pregnancy if iron status is not tested, although UpToDate authors suggest specific testing. Iron deficiency cannot be inferred from the CBC, as anemia is a late finding. (See "Anemia in pregnancy", section on 'Prevention of iron deficiency'.)

Supporting data for supplemental iron on a population level include:

●A 2016 Cochrane review of randomized trials (35 trials, 31,955 children) concluded that iron probably does not cause excess malaria risk and may reduce malaria risk in areas where malaria prevention services are available (7 trials with 5586 participants, RR 0.91; 95% CI 0.84-0.97) [184].

●A trial in 1958 children with access to insecticide-treated bed nets who were randomly assigned to receive micronutrient powder with or without iron found a reduced risk of malaria in those treated with the powder containing iron (malaria incidence 76.1 and 86.1 episodes per 100 child-years; risk ratio [RR] 0.87; 95% CI 0.79-0.97); these differences were no longer statistically significant after adjusting for baseline iron deficiency and anemia status [185].

There is no role for iron supplementation in individuals who are fully iron-replete or who have iron overload.

Other issues with iron supplementation in children are discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Associated disorders and effects of treatment'.)

Medication adjustment — Discontinuation and/or change in medications may be required in patients with severe drug-induced hemolysis or hemolytic anemia.

This applies to anti-malarial medications as well as other medications unrelated to malaria treatment.

●Antimalarial treatments – Specific treatments and risk of hemolysis are discussed separately. (See "Treatment of severe malaria", section on 'Anemia and coagulopathy'.)

•Intravenous artesunate and possibly oral artemisinin derivatives may cause delayed-onset hemolytic anemia, sometimes severe enough to require transfusion. This phenomenon is described above. (See 'Post-artesunate delayed hemolysis (PADH)' above.)

•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 [186].

●Oxidant drugs – Individuals with G6PD deficiency may have hemolysis with certain other medications and exposures. In some cases, oxidant drugs can cause hemolysis in individuals without G6PD deficiency. Pathophysiology, evaluation, and management are discussed separately. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

●Other drug-induced hemolysis – Other drug-induced causes may be present, some of which are immune and some non-immune. (See "Drug-induced hemolytic anemia".)

●Heritable hemolytic anemia medications – Some individuals with chronic hemolytic anemias due to heritable factors may require adjustment of treatment during malarial infection.

Post-discharge malaria chemoprevention — In regions of moderate to high malaria transmission, children with severe anemia have a high risk of re-admission or death after discharge, a vulnerable period during which they are recovering from anemia and are particularly at risk for malaria re-infection and for anemia secondary to malaria.

Antimalarial chemoprophylaxis in the months after discharge can reduce readmission risk and mortality [187-190]. This is discussed further separately. (See "Treatment of severe malaria", section on 'Role of post-discharge malaria chemoprevention'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (See "Patient education: Malaria (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Malarial anemia is multifactorial and includes the following mechanisms (figure 1):

•Hypersplenism – Includes reticuloendothelial clearance of infected and uninfected red blood cells (RBCs). (See 'Hypersplenism and reticuloendothelial hyperactivity' above.)

•Hemolysis – Affects infected and uninfected RBCs. Massive intravascular hemolysis causes blackwater fever. (See 'Hemolysis' above and 'Blackwater fever' above.)

•Bone marrow suppression – Includes dyserythropoiesis. (See 'Decreased RBC production' above.)

•Hepcidin – Reduces iron availability and causes functional iron deficiency. (See 'Decreased RBC production' above and "Anemia of chronic disease/anemia of inflammation".)

•Hemozoin – Heme degradation product with pleiotropic effects. (See 'Parasite life cycle and hemozoin' above.)

•Host and pathogen genetics – The severity of anemia is influenced by host and pathogen gene variation (table 2). (See 'Impact of host genetic variation' above and 'Impact of malaria species' above.)

●Other causes of anemia – Other causes of anemia may be present. (See 'Other (concomitant) causes of anemia' above.)

●Epidemiology – Baseline rates of anemia are high in malaria-endemic areas, and malaria contributes to anemia (table 1). The incidence of malarial anemia has fallen in many parts of sub-Saharan Africa following widespread public health interventions (impregnated bed nets, indoor residual spraying, intermittent preventive treatment), reducing malaria rates and mortality. (See "Malaria: Epidemiology, prevention, and elimination", section on 'Epidemiology'.)

●Clinical findings – Anemia and splenomegaly (occasionally massive, with or without rupture) may occur, along with hepatomegaly and jaundice. Specific findings depend on whether the infection is acute or chronic and whether the individual has prior immunity. The anemia is generally normocytic and normochromic with a striking absence of reticulocytes. Malarial anemia can cause severe morbidity and mortality, especially in children and pregnant women. Blackwater fever refers to severe intravascular hemolysis with hemoglobinuria. (See 'Clinical features' above.)

●Evaluation – The extent of evaluation is individualized based on medical history, symptom severity, likely diagnosis, treatment(s), and diagnostic testing capabilities. If possible, a hemoglobin level should be checked, and iron studies obtained for those with anemia, including ferritin and serum (soluble) transferrin receptor. Diagnostic testing for additional contributors to anemia such as helminth infection and HIV may be appropriate if available. (See 'Evaluation' above.)

●Management – The following may be required, depending on anemia severity and whether there is intravascular hemolysis and/or iron deficiency:

•Supportive care – Intravascular hemolysis may require aggressive hydration and treatment of disseminated intravascular coagulation (DIC). (See 'Supportive care for intravascular hemolysis' above.)

•Transfusion – Severe anemia may require transfusion; exchange transfusion is controversial. (See "Treatment of severe malaria", section on 'Anemia and coagulopathy'.)

•Iron (see 'Iron supplementation' above)

-We suggest treating iron deficiency after treatment of malaria infection, rather than during active infection (Grade 2C).

-Individuals with unknown iron status and high risk of iron deficiency may benefit from iron supplementation, especially during pregnancy, although direct assessment of iron stores is preferred. Iron status cannot be inferred from the complete blood count (CBC). (See "Anemia in pregnancy", section on 'Prevention of iron deficiency'.)

•Medications – Medication-induced hemolysis can exacerbate anemia; identification of culprit medications requires knowledge of mechanisms and close review of exposures and heritable risk factors. Medication adjustments may be required. (See 'Medication adjustment' above.)

•Prevention – Children with severe anemia have a high risk of re-admission or death after discharge; antimalarial chemoprophylaxis in the months after discharge can reduce readmission risk and mortality. (See 'Post-discharge malaria chemoprevention' 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.