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11/16/2018 Anemia in malaria - UpToDate

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Anemia in malaria

Author: David J Roberts, MA, MB, D Phil

Section Editors: Stanley L Schrier, MD, Johanna Daily, MD, MSc
Deputy Editors: Jennifer S Tirnauer, MD, Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2018. | This topic last updated: Nov 05, 2018.

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 women infected with
Plasmodium falciparum.

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

Separate topic reviews discuss the following:

● Malaria diagnosis – (See "Diagnosis of malaria" and "Clinical manifestations of malaria 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: Plasmodium vivax, Plasmodium
ovale, and Plasmodium malariae".)

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

● Protection against malaria in the hemoglobinopathies – (See "Protection against malaria in the

● Protection against malaria in the red blood cell cytoskeletal defects – (See "Protection against malaria by
abnormalities in red cell surface antigens and cytoskeletal proteins".)

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


The malarial parasite — Five species of the malarial parasite infect humans. The severity of hematologic
disease is related to the ability of the parasites to invade and grow in different red cell populations as well as the
intrinsic growth rate of the parasite. 1/24
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● P. vivax and P. ovale have a strong preference to infect only young red cells (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 red cells.

● P. malariae invades red cells of all ages, but parasite multiplication during each cycle is relatively low.
Infection results in limited parasitemia (<1 to 2 percent) and mild symptoms.

● P. falciparum can invade red cells of all ages, including cells as early as orthochromatic erythroblasts [2],
multiplies 10-fold within each 48-hour cycle, and expresses clonally variant antigens on the surface of
infected red cells, which are receptors for ligands on the surface of endothelial cells, red cells, and platelets.
These variant antigens enable late blood-stage infected red cells to sequester in post-capillary venules.
Parasitemia is often high, occasionally exceeding 50 percent, and the potential for severe anemia, systemic
disease, and death is considerable.

● 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 [3]. 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 [4,5].

Prevalence of anemia — Severe malarial anemia (SMA) is seen most frequently in areas of very high malarial
transmission and most commonly in young children and pregnant women [6]. 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 [7,8]. 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 [9]. In areas of high
endemicity for malaria, the prevalence of anemia is the highest in the six-month-old to one year age group [10].

In epidemiologic studies it is difficult to determine the number of cases of severe anemia attributable to malaria,
as the World Health Organization definition of SMA is quite strict [11]:

● 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, B12, and folate

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 [12-14]. Similarly, intermittent anti-malarial
treatment in pregnant women can substantially reduce the prevalence of severe maternal anemia and use of an
effective anti-malaria regime using artemisinin combination therapy in areas of high drug resistance to malaria
may improve outcomes for women and reduce maternal anemia and low birthweight [15].

The precise etiology of anemia is often complex in endemic areas since nutritional deficiencies, genetic traits,
and intercurrent infection may all contribute to the anemia [16-19]. It seems likely that etiology of SMA in 2/24
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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 [20]:

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

● 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)

● 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) [20].

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 etiological picture of anemia [21].

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) [22,23]. In addition, iron supplementation in endemic areas may increase malaria morbidity and
mortality in children [24]. 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 [25].
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 [26]. Furthermore, growth of P falciparum in vitro is
reduced in red blood cells from anemic pregnant women at baseline but increased during iron supplementation
[27]. 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

The incidence of malaria and severe malarial anemia 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 2015 [28-30]. Data from 2017 show malaria deaths dropped to 446,000 in 2015 and plateaued,
with 446,000 deaths in 2016 as well [31].

FEATURES OF MALARIAL ANEMIA — 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 cells. Anemia, thrombocytopenia, splenomegaly (occasionally massive [32]), hepatomegaly, and jaundice
can develop, and splenic rupture can occasionally occur. (See "Clinical manifestations of malaria in nonpregnant
adults and children".)

However, the clinical setting of 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 3/24
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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 [33].

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.)

Non-immune patients may exhibit a number of clinical syndromes including anemia, coma, respiratory distress,
and hypoglycemia, and may have a high frequency of concurrent bacteremia [34,35]. 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) [34,36-38].

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 in the hemoglobinopathies", section on 'Neonatal red cells
and hemoglobin F'.)

The presentation of disease changes from severe anemia in children aged between one and three years in areas
of high transmission to cerebral malaria in older children in areas of lower transmission [39]. 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 will respond to antimalarial treatment
[40,41]. 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 [18]. Reduced production,
increased clearance of cells and hypersplenism 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 [42-44]. High hepcidin levels restrict iron absorption and also transfer
of iron from bone marrow macrophages to developing red cells during chronic disease or inflammation and in
malaria [44,45], and may therefore contribute to chronic anemia secondary to malaria infection. (See "Anemia of
chronic disease/inflammation".)

Hematologic features — The anemia of P. falciparum malaria is typically normocytic and normochromic, with a
notable absence of reticulocytes [41,46]. 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 [47].

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 renal failure [48-50]. Disseminated
intravascular coagulation (DIC) and red blood cell (RBC) fragmentation may accompany this presentation.

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
that sudden hemolysis and malarial infection, glucose-6-phosphate dehydrogenase deficiency and quinine use
[49,51]. Among European expatriates living in Africa, BWF has been associated with use of the antimalarial
agents halofantrine, quinine, and mefloquine [52]. 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 [52].

Subsequently, there has been a series of reports of BWF after treatment with artemisinin derivatives. Artemisinin
derivatives were first reported to be associated with transient reticulocytopenia. However, artesunate has also 4/24
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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 [53-55]. 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 [56,57].

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 [58].

Additional information about delayed hemolytic anemia following treatment with artemisinins is presented
separately. (See "Treatment of severe malaria", section on 'Artemisinins' and "Hemolytic anemia due to drugs
and toxins", section on 'The antimalarial drug artesunate'.)

The pathophysiology of BWF is not completely understood, either for classical BWF or BWF associated with
artemisinin derivatives. Possible mechanisms are oxidative stress, a primary 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
[59,60]. P. vivax malaria has been clearly associated with anemia during pregnancy, along with low birth weight
of the children of these infected mothers [61]. Indeed, some studies in rural India suggest that severe disease is
associated with P. vivax infection more frequently than with P. falciparum infection [62]. Anemia has been
associated with increased red cell clearance, reticulocytopenia, and dyserythropoiesis [63-65].

PARASITE LIFE CYCLE — To understand the mechanism of hemolysis in malaria, it is helpful to briefly review
the life-cycle of the malarial 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 red cells
[66]. Red cell entry occurs via binding of the malarial parasite to specific receptors on the red cell surface,
including glycophorin A for P. falciparum and the Duffy blood group antigen for P. vivax [18,19,67-70]. (See
"Protection against malaria by abnormalities in red cell surface antigens and cytoskeletal proteins", section on
'Red cell surface antigens' and "Red blood cell antigens and antibodies", section on 'Duffy blood group system'.)

Once inside the red cell, the parasite makes many modifications to the infected cell [71], ingests and degrades
hemoglobin and develops through the stages of rings, trophozoites and schizonts. Mature schizonts burst to
release merozoites which invade new red cells.

A small proportion of merozoites in red cells 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 oöcyst
which divides asexually into many sporozoites that migrate to the salivary gland of the infected mosquito, from
which site 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 red cells, they induce the formation of "knobs" on the
surface of erythrocytes [72,73]. The products of the parasite's VAR gene (PfEMP-1) are expressed on these
surface projections and bind to receptors on endothelial cells in post-capillary venules [74-76]. The 5/24
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cytoadherence and sequestration of red cells within these small vessels leads to microvascular pathology and
obstruction to blood flow.

Infected red cells also stick to uninfected red cells and form rosettes that may also obstruct the microcirculation
[77,78]. Multiple serum components, one of which is IgM, act as bridging molecules for rosette formation [79].

PATHOGENESIS — The underlying causes of severe malarial anemia (SMA) in humans may include one or
more of the following mechanisms [80]:

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

● Clearance of uninfected RBCs

● Activation of the monocyte/macrophage system (see "Extracorpuscular non-immune hemolytic anemia:

Fragmentation hemolysis and hypersplenism", section on 'Splenomegaly')

● Suppression of erythropoiesis along with dyserythropoiesis

Hemolysis of parasitized red cells — During malarial infection there is obvious loss of infected erythrocytes
through parasite maturation as well as through recognition by macrophages. The removal of infected
erythrocytes in humans with parasitemias of less than 1 percent is unlikely to have a significant impact on the
degree of anemia. However, the lysis of uninfected red cells contributes directly to the onset of anemia in
individuals suffering from an acute malarial infection, in particular children in whom parasitemias are frequently
greater than 10 percent.

Mechanisms leading to hemolysis of infected red cells include:

● Abnormal distribution of membrane phospholipids, such as phosphatidylserine (PS), phosphatidylcholine,

and phosphatidyl-ethanolamine [81]. PS is confined to the inner half of the membrane bilayer in normal red
cells, but is exposed on the outer half in infected cells in conjunction with parasite maturation. When PS is
exposed on the outer half of the membrane bilayer, it can be recognized by macrophages as a signal for
attachment and phagocytosis [82]. The extent to which this occurs in vivo in humans is uncertain, but PS is
exposed in malaria-infected erythrocytes in rodent models of malaria [83].

● Red cell membrane damage due to lipid peroxidation induced by heme liberated from digestion of
hemoglobin by the parasite [84].

● Infected red cells may be opsonized by specific antibodies directed against the variant parasite antigens
(PfEMP-1) expressed on the surface of the red cell.

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

During acute P. falciparum malaria, red cells can be detected that contain ring-infected erythrocyte surface
antigen (also known as RESA or Pf155) but no intracellular parasite [85]. This could represent an in vivo
mechanism, presumably occurring in the spleen, for the removal of intraerythrocytic parasites without red cell
destruction. Such a mechanism could explain, at least in part, the disparity between the fall in hematocrit and the
decrease in parasite count observed in some hyperparasitemic patients.

Hemolysis of non-infected red cells — During human malarial infection, many uninfected red cells are
destroyed in the spleen and possibly the liver; their destruction has been identified as the major contributor to
malarial anemia [86-88]. Markers of extravascular and intravascular hemolysis were raised in patients with 6/24
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severe malarial anemia (Hb <50 g/L) compared with children with mild malaria [89]. Both mathematical modeling
and clinical observations suggest that 10 uninfected red cells are removed from the circulation for each infected
red cell that is removed [87]. Although few direct measurements of red cell survival have been made in human
malarial infection, a reduced half-life of normal red cells and increased clearance of heat-treated red cells have
been demonstrated in patients with malaria, consistent with these observations [86,90,91].

This reduction in red cell survival persists for some period after clearance of malarial parasitemia, a possible
reflection of persistent nonspecific activation of reticuloendothelial function. The activity and the number of
macrophages are increased and the spleen is enlarged during human malarial infection; these factors may
therefore contribute to the increased removal of uninfected cells [84,92-95]. (See 'Splenic and reticuloendothelial
hyperactivity' below.)

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

● Uninfected RBCs have reduced deformability leading to enhanced clearance in the spleen. The mechanism
responsible for the loss of deformability is not completely understood but may include increased oxidation of
membrane components. Such reduction in red cell deformability is strongly associated with mortality, both in
adults and children with severe malaria [96,97]. (See "Red blood cell membrane: Structure, organization,
and dynamics", section on 'Clinical consequences'.)

● Lipid peroxidation of RBC membranes may be mediated as an indirect effect of pro-inflammatory 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 [84,98-100]. Levels of the antioxidant alpha-
tocopherol are reduced in the membrane of red cells from children with malaria, consistent with the
hypothesis that local antioxidant depletion may contribute to erythrocyte loss [101].

● 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 were likely to arise from immune complexes formed by the combination of parasite
antigens with host antibodies [102,103]. 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 [104-106].

● Parasite products which may be part of the immunoglobulin- antigen complexes deposited on uninfected
RBC include the P. falciparum ring surface protein 2 (RSP-2) [107,108]. RSP-2 is deposited on uninfected
RBCs and the opsonization of these RSP-2-bearing uninfected RBCs provides a mechanism of removing
uninfected RBCs.

High levels of anti-RSP-2 antibodies that facilitate complement-mediated phagocytosis of cells expressing RSP-2
are found in sera from immune adults and children with SMA [109]. This antigen is also present on the surface of
erythroblasts in bone marrows of P. falciparum-infected patients, suggesting that clearance or damage to
circulating or 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 red cells have been described [110,111]. These
were identified as anti-band 3 and anti-spectrin antibodies in a study in P. vivax malaria [112].

● 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 [113]. Reduction of negative charge (Zeta potential)
promotes red cell aggregation, increasing the chances of splenic removal. 7/24
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● Uninfected red cells from patients with acute P. falciparum malaria have ultrastructural alterations [114].

● 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 red cells 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 red cells in the cytosol of macrophages, littoral, and
reticular cells, congestion and parasitized red cells in splenic sinusoids, and splenic cords containing rosettes of
erythrocytes surrounding antigen-presenting cells [115]. These findings suggest both immunologic and
nonimmunologic interactions between the spleen and red cells in patients with malaria [116].

A number of changes to infected red cells may play a role in the increased splenic filtration of red cells [117].
However, as mentioned above, there is also increased clearance of uninfected cells that persists for some period
after the clearance of malarial parasitemia, suggesting that there may be a primary increase in splenic filtration

This hypothesis was evaluated in a study of the clearance of heat-treated 51Cr-labeled autologous red cells in
patients with acute P. falciparum malaria [86]. The clearance half-time of infused heat-treated red cells 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. After treatment, the clearance half-times of
infused heat-treated red cells in the patients without splenomegaly accelerated to levels comparable to those
with splenomegaly. By six weeks after infection, normal clearance rates were restored in most patients. The
clinical implications of this phenomenon are uncertain, since heated red cells might have properties different from
parasitized native red cells.

Host genetic factors — There is enormous variability among individuals in their 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 [118]. 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 abnormalities in red cell surface antigens and cytoskeletal proteins" and "Protection against malaria in the
hemoglobinopathies" 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. For example, in a case-control study of malaria in West African children [119,120], a class II HLA
haplotype (DRB1*1302-DQB1*0501), common in West Africa but much less frequent in other populations, was
associated with protection from SMA due to P. falciparum. This has not been confirmed in other regions and the
mechanism of protection has not been determined.

In relation to iron metabolism, a prevalent ferroportin (FPN) mutation, Q248H (glutamine to histidine at position
248), prevented hepcidin-induced degradation of FPN and protected against severe malaria disease. FPN 8/24
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Q248H appears to have become prevalent in African populations in response to the selection pressure exerted
by malaria disease [121]. (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
[122-124]. 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 [125].

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 the adult".)

However, this compensatory mechanism appears to be defective in patients with malaria, since reduced
erythrocyte production has been shown to play a crucial role in the genesis of malarial anemia. One or more of
the following factors appear to be responsible: a primary decrease in erythroid progenitors, dyserythropoiesis,
inappropriately low serum erythropoietin concentrations, and/or reduced incorporation of iron into red cells
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 appears to be due, at least in part, to circulating factors capable of inhibiting erythropoiesis. This was
illustrated in a study in which serum obtained during parasitemia in complicated cases suppressed BFU-E and
CFU-E in cultures of bone marrow obtained both during and after parasitemia [126]. (See "Regulation of

Erythropoietic suppression and dyserythropoiesis — The earliest observations of reduced erythropoiesis in

acute human malaria were made over 60 years ago when reticulocytopenia was observed in P. vivax and P.
falciparum infection, followed by reticulocytosis after parasite clearance had taken place [127]. Later, it was
demonstrated that reticulocytopenia in Thai patients with malaria was accompanied by suppression of
erythropoiesis [128] and was characterized by a defect in erythroid maturation along with increased
erythrophagocytosis [16].

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 [129,130].

Dyserythropoiesis or morphologically and/or functionally abnormal production of red cells was demonstrated by
the presence of cytoplasmic vacuolization, stippling, fragmentation, intercytoplasmic bridges, nuclear
fragmentation and multinuclearity. This coincided with reduced reticulocytosis, indicating functional disruption of
bone marrow red cell production [129,130]. Signs of dyserythropoiesis have also been seen in patients infected
with P. vivax [63].

In a small study of six children with chronic disease, an increased proportion of polychromatic erythroblasts in the
G2 phase of division was observed [131]. 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 [132], may have a role in the impaired erythroid development
through its direct effects on human monocyte function and/or erythroid precursors [133-136] and this is
independent of impaired red cell production caused by inflammatory cytokines [137]. 9/24
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Hemozoin reduces human macrophage oxidative burst activity, prevents up-regulation of activation markers
[138,139], and stimulates the secretion of biologically active endoperoxides from monocytes, such as 15(S)-
hydroxyeicosatetraenoic (HETE) and hydroxy-nonenal (HNE) [140,141]. Hemozoin may therefore affect erythroid
growth through oxidation of membrane lipids [134] or other cellular damage leading to cell-cycle arrest and/or
apoptosis [136,138,142]. These endoperoxides may affect erythroid growth through oxidation of membrane lipids
[134]. (See "Evaluation of the peripheral blood smear", section on 'Pigmented inclusions'.)

● Ingestion of hemozoin by macrophages may result in reduced expression of prostaglandin-E2 (PGE(2));

reduced levels of PGE(2) were associated with anemia and reticulocytopenia in children with malaria [143].

● In a clinical study, hemozoin-containing macrophages and plasma hemozoin were associated with anemia
and reticulocyte suppression [135]. 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) [144].

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 [145]. TNF-alpha inhibits all stages of
erythropoiesis [146] while IFN-gamma, along with TNF-alpha, inhibits erythroid growth and differentiation by up-
regulating expression of TRAIL, TWEAK and CD95L in developing erythroblasts [147].

While severe disease in children is associated with elevated levels of pro- and anti-inflammatory cytokines, the
severity of anemia seems to be dependent on levels of TNF-alpha relative to its regulator, IL-10. 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 SMA in young children [148,149]. In addition, a number
of polymorphisms in the human TNF-alpha promoter show greater association with anemia than with cerebral
malaria [123].

Many other pro-inflammatory 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 [150], 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 [151] and are elevated in those with more
severe anemia [152].

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 [150,151], 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 [152,153].

The glycophosphatidylinositol (GPI) anchor for the merozoite proteins, MSP-1, MSP-2 and MSP-4 [154], the
parasite product found in plasma during malaria infections, may be implicated in the pro-inflammatory cytokine
effects on SMA. GPIs may induce the release of TNF-alpha from human macrophages [155], which could
contribute to the pathology of SMA. The pro-inflammatory response from human monocytes is through 10/24
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interaction of GPIs with TLR2, and TLR4 [156]. 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 [157].

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 [158-160]. Data from murine models of malaria have suggested that
hemozoin stimulates an innate pro-inflammatory response [161] via a MyD88-dependent TLR9 pathway [162]. It
now appears that stimulation of TLR9 may be through DNA associated with hemozoin.

Altered iron metabolism — Impaired utilization 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) inflammation [128].
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/inflammation", section on

Hepcidin is regulated by pro-inflammatory mediators such as tumor necrosis factor 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 [42-44,153,163-165]. Hepcidin levels
fall in the most severely ill children as hypoxia inhibits hepcidin production [166]. High hepcidin levels stimulated
by blood stage malaria infection are associated with inhibition of liver stage malaria infection in mice [167] and
reduced incorporation of iron into red cells in humans [44,45]. Evidence from murine malaria suggests that low
serum iron caused by elevated hepcidin reduced parasite growth and progression to severe disease [168].
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

Concomitant iron deficiency — 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 [169]:

● Iron deficiency is widespread across malaria-endemic areas and is particularly common among children <5
years of age, who are most vulnerable to malaria. A trial in Tanzania demonstrated excess morbidity and
mortality among children under five who received iron supplementation [24].

● 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 (HR 0.55; 95% CI 0.41-0.74) and clinical malaria (HR 0.49; 95% CI 0.33-0.73)

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 [171,172]. Determining the need for iron supplementation depends on
individual 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 11/24
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supplementation is appropriate in the absence of other infection and if iron stores are low, as evidenced by
low serum ferritin level. Serum hepcidin levels may be a useful indicator for whether iron supplementation is
needed, as well as when iron may be efficiently absorbed, although this test remains a research tool at
present [173].

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 [174,175]. However, several
studies of malaria in African children suffering from SMA have shown appropriately raised Epo concentrations
[47,176-178]. In fact, Epo levels in SMA are more than threefold higher when compared with anemic children
without malaria [135].

Experimental evidence in murine malaria suggests that exogenous Epo can downregulate inflammatory
responses induced by T cells and myeloid cells, reduced endothelial activation and improved integrity of the
blood-brain barrier [179,180].

Although ineffective or inadequate Epo synthesis 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 inflammation, and not an inappropriately low level of Epo, is the more significant
contribution to pathology. (See "Anemia of chronic disease/inflammation", section on 'Pathogenesis'.)

Deficiencies of folate and vitamin B12 — Although dietary deficiencies are widespread in malarial endemic
regions, the influence of reduced folate levels are not thought to be major contributors to the dyserythropoiesis
seen during SMA [130]. The finding of low vitamin B12 levels in malaria suggests that subclinical deficiency of
B12 may play a hitherto unrecognized contribution to severe anemia or may reflect altered vitamin B12
metabolism or transport during infection [20].

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 [181], 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 [182].

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 [183].

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 cells protected against low birth weight and
maternal anemia [184]. This observation suggests an area of investigation for future therapeutic strategies (eg,
VSA-PAM-based vaccination).

TREATMENT — The approach to iron supplementation is discussed above. (See 'Concomitant iron deficiency'

Treatment of anemia in malaria is discussed further separately. (See "Treatment of severe malaria", section on
'Anemia and coagulopathy'.) 12/24
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There are two situations where anemia may be a complication of therapy. First, there is the well-recognized risk
that primaquine used to treat the dormant liver stage of vivax malaria in people with glucose-6-phosphate
dehydrogenase (G6PD) deficiency can cause significant, transient falls in hemoglobin that may occasionally
require transfusion [185]. Second, 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 [53].


● Malarial anemia is capable of causing severe morbidity and mortality, especially in children and pregnant
women. (See 'Overview' above and 'Effect on pregnancy' above.)

● 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 cells may be seen on the peripheral blood smear (picture 1). (See
'Features of malarial anemia' above.)

● Malarial anemia is multi-factorial and includes direct destruction of parasitized and non-parasitized red cells,
splenic and hepatic sequestration and destruction of red cells, bone marrow suppression, and
dyserythropoiesis. Host factors, both genetic and acquired, may also play a part. (See 'Pathogenesis' above
and 'Bone marrow suppression' above.)

● Treatment of anemia in the setting of malaria is discussed separately. In general, concomitant iron deficiency
is treated after resolution of parasitemia. (See "Treatment of severe malaria", section on 'Anemia and
coagulopathy' and 'Concomitant iron deficiency' above.)

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Topic 7112 Version 25.0 22/24
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Malaria: Red cell containing intraerythrocytic ring forms


Peripheral smear from a patient with malaria shows intraerythrocytic ring forms
(trophozoites) (arrows).

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 77517 Version 4.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets

(arrowheads) and a normal lymphocyte (arrow) can also be seen. The red
cells are of relatively uniform size and shape. The diameter of the normal red
cell should approximate that of the nucleus of the small lymphocyte; central
pallor (dashed arrow) should equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 5.0 23/24
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Contributor Disclosures
David J Roberts, MA, MB, D Phil Nothing to disclose Stanley L Schrier, MD Nothing to disclose Johanna
Daily, MD, MSc Nothing to disclose Jennifer S Tirnauer, MD Nothing to disclose Elinor L Baron, MD,
DTMH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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