++
Malaria is among the leading infectious
causes of morbidity and mortality in children worldwide. Each year,
there are 300 to 500 million clinical cases, causing between 1.5
and 2.7 million deaths, most in sub-Saharan African children under
the age of 5 years. Increasing drug resistance, climatic changes,
population shifts, economic changes, abandonment of malaria control
programs, and insecticide resistance all contributed to a resurgence
of malaria in the developing world from the 1970s to the 2000s. Recent
World Health Organization, governmental, and nonprofit foundation
support for effective preventative measures—such as insecticide-treated bednets,
indoor residual spraying, and the implementation of artemisinin combination
therapy as first-line treatment for malaria in many sub-Saharan
African countries—appears to have significantly reduced
malaria incidence and deaths in some countries.1
++
More than 40% of the world’s population, or
2.5 billion people, are at risk for malaria in 90 countries in Africa,
Asia, South and Central America, and Oceania (Fig.
352-1). For many years, it appeared that malaria in humans
was caused by four species of Plasmodium: P
falciparum, P vivax, P ovale, and P malariae.
There is now evidence that P knowlesi, a Plasmodium species
that usually infects monkeys, has crossed over to cause malaria
in humans in Southeast Asia, notably in Malaysia4;
it is now considered a fifth human malaria species. Plasmodium
falciparum is found mainly in tropical areas, where warm
weather ensures the relatively constant presence of the Anopheles vector. Plasmodium
vivax has the widest geographic distribution of the four
species and is found in both tropical and temperate areas. Plasmodium
ovale is found primarily in sub-Saharan West Africa, where
it appears to have almost completely replaced Plasmodium
vivax. Plasmodium malariae can be seen
in both tropical and temperate zones but is the least common of
the malaria species.
++
Diagnostic and treatment approaches differ significantly in malaria
endemic countries as compared to countries like the United States, where
almost all malaria is imported. In the United States, all of the
approximately 1500 cases of malaria that were reported to the Centers
for Disease Control and Prevention (CDC) in 2005 occurred in travelers
to or immigrants from malaria-endemic countries, with the exception
of two cases of congenital malaria, in which the mothers were immigrants
from malaria-endemic countries.2 Rare cases of local transmission have
been reported in the United States.3
++
Malaria can be a life-threatening illness. Delay in seeking treatment,
misdiagnosis, or both are often seen in individuals who die from
malaria in the United States.2 Any febrile child who has
been in a malaria-endemic area in the preceding year should be assessed
for this illness.
+++
Organisms and
Life Cycle
++
Plasmodium species can infect many different animals
but most are host-specific. P falciparum is the
only Plasmodium species that infects all ages of
red blood cells, so it generally causes a much higher level of parasitemia than
the other Plasmodium species. P vivax and P
ovale preferentially infect reticulocytes and tend to cause
a lower level of parasitemia than does P falciparum. P
malariae preferentially infects senescent red cells and
causes the lowest level parasitemia of the human Plasmodium species,
but this low-level parasitemia may persist for decades. It is not
clear at this point if P knowlesi preferentially
infects a subset of red cells, but it multiplies rapidly and can
cause very high levels of parasitemia. Morphologically, it can be
confused with P malariae on microscopic examination.
++
Understanding the malaria parasite life cycle is crucial to understanding
malarial infection and disease. The malaria life cycle is summarized
in Figure 352-2. Sporozoites are inoculated
into the bloodstream by the Anopheles mosquito
and migrate within minutes to the liver, where they invade hepatic
parenchymal cells. Here, the sporozoites undergo asexual multiplication
(hepatic schizogony), forming schizonts that rupture the hepatic
cells and release merozoites into the bloodstream. Very few hepatic
cells are invaded by sporozoites, but multiplication within the
hepatic cell produces thousands of merozoites from each sporozoite-infected
hepatic cell. The process of liver schizogony lasts from 7 to 10
days for P falciparum, P ovale, and P
vivax and 10 to 14 days for P malariae. P
vivax and P ovale can also produce dormant
liver stages (hypnozoites) that can reactivate weeks or months after
the initial infection and can cause clinical relapse.
++
++
Merozoites released by ruptured hepatic cells invade red blood
cells, where they may asexually multiply or undergo sexual differentiation
into male and female gametocytes. Parasites established in the red
blood cell (trophozoites) that asexually multiply form red blood
cell schizonts. These schizonts eventually rupture the red cells
containing them and release more merozoites, which continue the cycle
of red cell invasion and multiplication.
++
Male and female gametocytes are ingested by mosquitoes with their
human blood meal. In the mosquito, the male gametocyte exflagellates,
releasing a microgamete that fertilizes the female macrogamete,
producing a zygote. The elongated zygote, or ookinete, penetrates
the mosquito’s stomach wall and forms an oocyst behind
it. The oocyst grows and eventually ruptures to release numerous
sporozoites, which migrate throughout the mosquito. Those that enter
the salivary glands can then infect humans the mosquito bites, thus
renewing the cycle of infection.
++
Malaria can also be acquired by direct blood exposure through
blood transfusions. With current blood-screening procedures, such
cases are rare in the United States. Congenital malaria, with passage
of infection from mother to newborn, can also occur, though it is
relatively infrequent in endemic areas. It is seen more frequently
in nonimmune women and in women who have an overt attack of clinical
malaria during pregnancy. In areas where malaria is endemic, infection
during pregnancy, even among semi-immune women, can lead to low
birth weight and an increased risk of perinatal mortality.
+++
Pathophysiology
of Malaria Infection
++
Malarial disease is caused by the blood stages of the parasite.
Rupture of red cells and release of merozoites into the blood leads
to the fever, chills, and malaise seen in all forms of malaria. Plasmodium-infected
erythrocytes, opsonized with antibodies or complement, are less
deformable than uninfected erythrocytes and are consequently trapped
in the spleen, leading to splenomegaly. Anemia and thrombocytopenia
are due primarily to splenic consumption of erythrocytes and platelets,
but autoimmune hemolysis plays a role in the continued destruction
of erythrocytes that can occur for weeks after appropriate treatment. In
addition, bone marrow suppression occurs in severe malarial anemia,
so the anemia seen is due to both erythrocyte destruction (by autoimmune
hemolysis and spleen removal of infected erythrocytes) and impaired
erythropoiesis.
++
The pathogenesis of organ dysfunction in P falciparum malaria
is complex, and precise mechanisms are still being worked out, but
it clearly originates in the interactions between infected red blood
cells (iRBCs) and the endothelial cells lining vascular organ beds.
Cytoadherence of iRBCs in capillaries leads to sequestration of
red cells and parasites in microvascular beds, and the resultant local
tissue ischemia and hypoxia likely contributes to the renal, gastrointestinal,
pulmonary, and central nervous system complications seen in falciparum malaria.
However, several additional factors likely contribute to pathogenesis
of P falciparum complications. Endothelial cell damage
from activation by iRBCs may cause impairment of the blood-brain
barrier (in cerebral malaria) or vascular damage in other organs
and may lead to local release of cytokines and other inflammatory
factors.5 In support of this hypothesis, several cytokines,
notably TNF-α, are present in higher amounts in the
cerebrospinal fluid of children with cerebral malaria than in control
children.6 Animal models also strongly support the role
of proinflammatory cytokines, particularly TNF-α and
IFN-γ, in the pathogenesis of severe malaria.5 Regulatory
polymorphisms of cytokine genes also appear to play a role in the
development of disease.
++
The hypoglycemia seen in acute P falciparum infection
is due to both a depletion of glycogen reserves and an increased
demand for glucose because of increased anaerobic glycolysis in
host tissues and in parasitized erythrocytes. Numerous factors contribute
to lactic acidosis, including increased lactate production in parasitized
erythrocytes, anaerobic glycolysis induced by seizures, increased metabolic
rates caused by fever and anemia, and the decreased oxygen-carrying
capacity of the blood in anemia.
++
Numerous host genetic factors can affect susceptibility to malarial
infection and disease. Protective factors against disease with P
falciparum include hemoglobinopathies (hemoglobin S [sickle
cell trait], hemoglobin C and E, a and b thalassemia, blood
group 0, and G6PD deficiency), and specific HLA class I and class
II alleles; Duffy blood group antigens and hereditary ovalocytosis
have been associated with protection against P vivax. The
best described protective factors are the hemoglobinopathies. Heterozygous
carriers of hemoglobin S (sickle cell trait) have an 80% to
95% protection from severe malarial disease, and the high prevalence
of hemoglobin S in malaria-endemic areas of sub-Saharan Africa is
thought to reflect this protection.7 Other hemoglobinopathies,
including hemoglobin C and E and the α and β thalassemias,
have also been associated with some degree of protection from severe
malarial disease.8 Recently, a strong protective association
of blood group O against severe malaria with P falciparum was
demonstrated in children in Gambia.9 Alterations in erythrocyte
structure or function can be protective against malarial infection
and disease. The Duffy blood group antigens are required for the
invasion of P vivax into erythrocytes, and the
almost universal absence of these antigens in West African individuals convincingly
correlates with their innate resistance to P vivax infection,
in contrast to their susceptibility to the other three species of
human malaria. Some protective effect has also been seen in individuals
who carry the genes for hereditary ovalocytosis and G6PD deficiency.
Finally, specific human leukocyte antigens (HLA) of the major histocompatibility
complex (MHC) can affect susceptibility to malarial disease. Studies
have demonstrated that Gambian children without class I antigen
HLAB53 and one form of class II antigen DR13 were more likely to
have severe malaria than those with these HLA types.10
+++
Development
of Immunity
++
Individuals living in malaria-endemic areas never develop complete
immunity to the illness. However, with repeated exposure to a variety
of different malaria strains over several years, they become relatively
tolerant to infection. These “semi-immune” individuals
often have asymptomatic parasitemia, and when malarial disease does
occur, it is generally much milder than that seen in nonimmune persons.
++
The major factors in acquiring immunity to malarial disease are
repeated and frequent exposure to P falciparum, exposure
to multiple strains of P falciparum, and age. Acquiring
immunity to malarial disease occurs during childhood in malaria-endemic
areas, but the pattern of acquisition differs in areas of differing
endemicity. In areas of low- and midlevel endemicity, children acquire
immunity more slowly than in areas of high-level endemicity. The
primary manifestations of disease also tend to differ in areas of varying
endemicity. In areas with high endemicity, children develop severe
anemia, which is seen most commonly in those ages 6 months to 3
years. In areas with low- or midlevel endemicity, cerebral malaria
is more common and occurs in a broader age range (6 months to 6
years). In malaria-endemic areas, children less than 6 months old,
and especially those less than 3 months old, are protected from malarial
infection and disease by fetal hemoglobin and passively transferred
maternal antibodies.
+++
Clinical Manifestations
++
The clinical presentation of malaria depends on the infected
individual’s age and level of immunity and on the Plasmodium species
causing the illness. In the United States, most children who present
with malaria are nonimmune. More than 90% of those with P
falciparum infection (the most common Plasmodium species
in imported malaria) present within 3 months of travel to or immigration
from a malaria-endemic area,2 while less than 50% of
those with P vivax or P ovale infection
present within 3 months; rarely, P vivax and P
ovale may present more than a year after exposure.
++
Nonimmune individuals, whether children or adults, tend to present
with more severe signs and symptoms than semi-immune individuals
and may develop severe disease with relatively low-level parasitemia.
Prodromal, flulike symptoms occur during the early cycles of erythrocytic
infection and may include fever (with no specific pattern), headache,
malaise, myalgias, arthralgias, abdominal pain, and diarrhea. Children,
especially infants, may not exhibit the classic “febrile
paroxysm” seen in adults. In infants, more nonspecific
symptoms such as fever, lethargy, decreased appetite, and listlessness
may continue to predominate. Vomiting, loose stools, and abdominal
pain are very common complaints in both infants and children. Many
infants and older children will also have intermittent fevers without
a clear pattern, rather than the 48-hour (P vivax,P
ovale,P falciparum) or 72-hour (P
malariae) fever patterns classically described with these
infections. Children with P falciparum in particular
may exhibit very irregular fever patterns. Up to 10% of
children with malarial disease may not have documented fever during
the illness. Seizures are common in severe malaria. Nonimmune adults
frequently exhibit the classic febrile paroxysm, which consists
of three phases: a brief “cold” phase, with chills
and sometimes rigors; a hot phase, with high fever, dry, flushed
skin, tachypnea, and thirst; and a sweating stage, with defervescence
accompanied by diaphoresis and a feeling of great relief but also
great weakness. The paroxysms coincide with the rupture of infected erythrocytes
and the release of merozoites, pigment, and cell debris into the
circulation.
++
The physical signs most frequently seen in malaria are hepatomegaly
and splenomegaly, which occur in about half of all children with acute
malarial disease. In areas where malaria is highly endemic, a large
percentage of children develop palpable splenomegaly over time,
and the prevalence of splenomegaly in children ages 2 to 9 years
has been used to define an area’s malaria-endemicity pattern.
In areas of unstable transmission and in nonimmune individuals,
it is less common.11 Although malaria often leads to some
degree of anemia, particularly when not treated immediately, pallor
is seen in only 25% of children with malaria in endemic
areas and jaundice in only 10% to 15% of children.
Scleral icterus may be seen in children. Jaundice is more common
in nonimmune adults. Other physical exam findings relate to complications
of malaria, such as coma or posturing in children with cerebral
malaria or chest indrawing and respiratory distress in children
with lactic acidosis.
+++
Complications
from P Falciparum Malaria
++
Nonimmune children with P falciparum malaria
often develop complications from the disease. The World Health Organization
(WHO) lists 10 defining criteria for severe malaria, as listed in Table 352-1.12 The most common of
these complications in children are severe malarial anemia, respiratory
distress, and impaired consciousness. Each of these complications
can contribute to and exacerbate the others, and mortality increases
as the number of malarial complications increases.
++
++
By WHO definition, cerebral malaria is present in a patient who
(1) cannot localize a painful stimulus, (2) has peripheral asexual P
falciparum parasitemia, and (3) has no other causes of
an encephalopathy. The pathophysiology of impaired consciousness
in a child with severe malaria is likely the same as that of coma.
Recurrent convulsions are a frequent antecedent to subsequent impaired
consciousness and coma: according to strict WHO criteria, 50% to
80% of African children with cerebral malaria have a prior history
of convulsions.13
++
Cerebral malaria often develops rapidly. Parents typically give
a history of 2 to 3 days of fever, followed by abrupt onset of convulsions
or severely impaired consciousness. Children with cerebral malaria
may progress from a normal sensorium to coma within hours. Focal
seizures are occasionally seen, but focal neurological deficits
are rare. Meningeal signs are usually absent. Abnormal posturing,
pupillary changes, absent corneal reflexes, Cheyne-Stokes or Kussmaul
respirations, and gaze abnormalities may be seen. “Malaria
retinopathy” consists of four main components: retinal
whitening, vessel changes, retinal hemorrhages, and papilledema.
Retinal whitening and the vessel color changes are specific to malaria
and are not seen in other ocular or systemic conditions.14 Retinal
hemorrhages have been noted in 6% to 36% of African children
on admission and papilledema in 2% to 12%. Retinal
hemorrhages generally resolve without residual visual defects, but
papilledema is an independent indicator of poor outcome. Malaria
retinopathy appears to distinguish children with cerebral malaria
from those with coma due to other causes15 but must be
assessed with indirect ophthalmoscopy. Increased intracranial pressure
(ICP), generally not seen in adults with cerebral malaria, is a
feature of cerebral malaria in children; children with severely
increased ICP (ICP > 40 mmHg) have a very high risk of death or
severe neurological sequelae. It is unclear, however, whether severely
increased intracranial pressure reflects a primary disease process
due to P falciparum or to a terminal event.
++
The mortality rate for strictly defined cerebral malaria in African
children is 16% to 20%. Concurrent respiratory
distress, lactic acidosis, or severe malarial anemia increase the
mortality rate. Given the severity of cerebral malaria, it is remarkable
that only approximately 4% to 6% of children who
survive cerebral malaria have long-term neurological deficits.13,16 Retrospective
studies suggested that cerebral malaria is associated with cognitive
impairment, and recent prospective studies have documented that
approximately one in four children with cerebral malaria will have
cognitive impairment 2 years after the illness.17
++
Nonimmune adults can develop neurological sequelae after severe malaria,
even without cerebral malaria. Neurological sequelae seen in nonimmune
adults may also be seen in nonimmune older children and may include
cranial nerve defects, mononeuritis multiplex, polyneuropathy, and
cerebellar dysfunction.
+++
Severe Malarial
Anemia
++
Malaria is the leading cause of anemia requiring hospital admission
in the African child (eFig. 352.1). Severe
anemia is seen most often in children less than 4 years old and
is more frequent in areas of very high P falciparum transmission.
Many children with malaria in endemic areas are already anemic from
iron deficiency and hookworm infection, and the sudden worsening
of anemia caused by P falciparum can lead to congestive
heart failure, with subsequent respiratory distress and lactic acidosis.
++
+++
Metabolic Dysfunction
++
Hypoglycemia (a blood glucose level of ⩽ 2.2 mmol/L)
and lactic acidosis (a plasma lactate of ⩾ 5 mmol/L) are
seen frequently in children with P falciparum malaria,
often together, and are independent predictors of mortality.18 Children
are more likely to be hypoglycemic on presentation with P
falciparum malaria than are adults. Quinine induces hyperinsulinemia
in patients with acute malaria, but peripheral insulin resistance increases
in acute infection and counters the hypoglycemic effects of elevated
insulin levels. Late-onset hypoglycemia may be seen when acute infection
has resolved but quinine treatment continues. The signs of hypoglycemia
(depressed consciousness, dilated pupils, seizures) may also be
seen in cerebral malaria, so checking the blood glucose level is
imperative in any severely ill child with malaria. Prolonged lactic
acidosis is a strong predictor of mortality. Respiratory distress,
another frequent complication of P falciparum malaria
in children, is most often attributable to underlying metabolic
acidosis rather than a primary pulmonary or cardiac process. The
pulmonary edema seen in adults is rarely seen in children, and pneumonia
is also uncommon in children with severe malaria.
++
Prostration (conscious but unable to sit, drink, or eat) is a
common complication of malaria.11,19 The exact pathophysiology
of this clinical phenomenon is not clear, but it can be associated
with mortality as high as 8% even in the absence of other
complications.19 Children with P falciparum malaria
may have an elevated blood urea nitrogen and creatinine values on
admission, but this is most often due to hypovolemia and corrects
with fluid administration. Renal failure from glomerulonephritis
or massive intravascular hemolysis (blackwater fever) is rarely
seen in children in endemic areas, but it appears to be more common
in adults. It may occasionally be seen in nonimmune children. Circulatory
collapse may be due to concurrent bacterial meningitis or sepsis, which
should be ruled out in children with severe malaria. Abnormal bleeding
is also an infrequent clinical problem in children with severe malaria.
Thrombocytopenia is frequently seen in children with P falciparum malaria,
but bleeding problems are rare. Mild hyponatremia and hypokalemia
are common in P falciparum malaria, but adverse
outcomes due to either abnormality are rare.
++
Tropical splenomegaly syndrome is a chronic complication of P
falciparum malaria in which splenomegaly persists after
the acute infection is treated. Massive splenomegaly, hepatomegaly,
anemia, and an elevated IgM level are the classic features of this
disorder, which is thought to be due to an impaired immune response
to P falciparum antigens. The only effective therapy
for this disorder is lifelong antimalarial prophylaxis. With this treatment,
spleen size gradually regresses but increases again if prophylaxis
is stopped.
+++
Complications
from Non-Falciparum Malaria
++
In malaria due to P vivax and P ovale, complications
other than anemia (which is seldom as severe as that caused by P
falciparum) are uncommon. Nonetheless, nonimmune children
with P vivax and P ovale malaria
may be acutely ill and profoundly fatigued during recovery from
their illness. Death can occur from P vivax or P
ovale infection. Very rarely, splenic rupture may occur
after trauma. Children and adults with chronic P malariae infection
may develop nephrotic syndrome, caused by immune complex deposition
on glomerular walls. The nephrotic syndrome caused by P
malariae is poorly responsive to steroids. Because of its
rapid life cycle, P knowlesi malaria can cause
high-level parasitemia and severe seizures, and can rapidly lead
to death.20 Since P knowlesi can be mistaken
for P malariae on microscopy, it should be considered
in any severely ill patient who acquires malaria in Southeast Asia,
particularly in patients who are thought to have P malariae infection
on microscopy but have high-level parasitemia, as high-level parasitemia
with P malariae infection is unusual.
++
Malaria is often misdiagnosed in the United States, and many
of the deaths caused by malaria in this country are due to a delay
in diagnosis. Every febrile child who has been in a malaria-endemic
area within the year before presentation should be evaluated for
malaria. Febrile newborns whose mothers were in malaria-endemic
areas within 2 years of presentation should be assessed for congenital malaria.
++
In the nonimmune child returning from a malaria-endemic area,
malaria is most likely to be confused with typhoid—which
may also present with fever, abdominal pain, vomiting, diarrhea,
and malaise—or dengue. The fevers of typhoid are unremitting
and generally unaccompanied by chills, rigors, or diaphoresis, and the
splenomegaly of typhoid is typically less marked than that of malaria.
The classic typhoid “rose spot” exanthem is not
seen in malaria, but it is often missing in cases of typhoid as
well. In its prodromal phase, malaria can also be confused with
viral or bacterial gastroenteritis, including hepatitis A, influenza,
enteroviral infection, and other viral illnesses. Cerebral malaria
may be confused with bacterial or viral meningitis or encephalitis.
If blood smears are repeatedly negative for malaria parasites and
if antimalarial treatment does not improve symptoms, the differential
diagnosis should include tuberculosis, endocarditis, brucellosis,
leptospirosis, trypanosomiasis, kala-azar, histoplasmosis, and noninfectious
diseases such as rheumatologic or neoplastic disease.
++
Examination of Giemsa-stained thick and thin blood smears remains
the primary method of diagnosing malaria. Thick smears are more
sensitive in detecting parasites, but thin smears are necessary for
identifying Plasmodium species and allow estimation
of the degree of peripheral blood parasitemia. It is most important
to distinguish P falciparum from the other three
human malaria species. P falciparum malaria is
suggested by parasitemia that exceeds 2% of red cells,
red cells that contain multiple parasites, the almost exclusive presence
of ring forms of the parasite, ring forms with a double chromatin
dot, and the presence of parasites in all ages of red cells (eFig. 352.2a). The banana-shaped gametocyte is
pathognomonic for P falciparum malaria (eFig. 352.2b). P malariae is
characterized by low-level parasitemia and a characteristic band trophozoite
(eFig. 352.2c; band trophozoite in center). Schuffner’s
stippling is characteristic of P vivax (eFig. 352.2d) and P ovale,
though it may be more subtle in P ovale infections. P
ovale–infected cells often have an oval shape
in addition to the stippling (eFig. 352.2e).
++
++
Asymptomatic parasitemia is common in highly endemic areas, so
in these places, a positive blood smear for malaria does not necessarily
implicate malaria as the cause of the patient’s disease.
In these locations, it is sometimes difficult to distinguish acute
malarial disease from other infectious diseases that cause similar
symptoms.
++
In semi-immune individuals living in an area endemic for P
falciparum malaria, the level of parasitemia often does
not correlate with severity of disease, although there is a general
correlation on a population level. In nonimmune individuals, the
level of parasitemia generally does correlate with severity of disease,
and high-level parasitemia (> 5%) in a nonimmune individual
is frequently accompanied by complications of malaria. However,
in nonimmune patients, even low-level parasitemia may be accompanied
by severe illness. This may be in part because peripheral blood
parasitemia is an imperfect indicator of sequestered parasite load,
and persons with a high level of sequestered parasites in end-organ microvasculature
may have low-level peripheral blood parasitemia. In a severely ill
nonimmune child, malaria blood smears should be repeated every 8
to 12 hours, and at least three smears over a 48- to 72-hour period
should be obtained before malaria is excluded as a diagnosis. Children
have sometimes received treatment with antimalarial medication prior
to seeing a physician, and this may lead to a negative blood smear
for malaria parasites. If the clinical picture in these individuals
is consistent with malaria, and no alternative diagnosis can be
made, empirical treatment for malaria may be necessary. Testing
with a rapid diagnostic test such as the Binax NOW (see below) is
indicated in these children, because the test may remain positive
up to 48 hours after treatment begins.
++
The Binax test is now FDA approved for rapid diagnosis of malaria.
This immunochromatographic test for P falciparum histidine
rich protein (HRP2) and aldolase is approved for testing for P
falciparum and P vivax, and should also
be able to detect P ovale and P malariae,
though sensitivity and specificity for these organisms has not been assessed. Aldolase
is present in all four of these species, and though the test would
be read as positive for P vivax, the infection
could be due to P ovale or P malariae. The
test is simple to perform and can be done in the field or lab in
10 minutes. Other rapid tests for P falciparum also
show high sensitivity and specificity but are not currently approved
by the FDA. Parasite mRNA or DNA polymerase chain reaction (PCR)
testing has been performed in research settings. It is much more
sensitive than the traditional blood smear and allows parasite species
and strain identification, but at present it remains a research
tool. Of note, PCR testing at a reference lab is currently the only
way to identify P knowlesi infection.
++
No other laboratory tests are diagnostic for malaria. Lab findings that
support the diagnosis include a normocytic, normochromic anemia
and thrombocytopenia. However, in children with concurrent hookworm
infection or iron deficiency, microcytosis and hypochromia may be
seen. Hypoglycemia and metabolic acidosis may occur with severe
malaria. Elevation of indirect bilirubin and a mild elevation of transaminases
may also be seen. The cerebrospinal fluid (CSF) in children with
cerebral malaria is generally unremarkable, with less than five
white blood cells per ml, no red blood cells, normal or mildly elevated
protein, and a normal glucose relative to serum glucose. When elevated
CSF lactate levels are seen, they are an independent predictor of
mortality.
++
Treatment of malaria can be complex. Physicians without experience
in malaria treatment may call the CDC malaria hotline for expert advice
(770-488-7788 Mon-Fri 8-4:30 Eastern US time; or 777-488-7100 at
all other times). Four questions must be urgently answered in the
evaluation of a child with malaria or suspected malaria: (1) Is the
child semi-immune or nonimmune? (2) Does the child have P
falciparum malaria? (3) Was the child exposed to malaria
in an area with chloroquine-resistant or chloroquine-sensitive malaria
parasites? (4) Does the child have any evidence of complications
from malarial disease by history, exam, or lab findings?
++
All ill-appearing children should be considered nonimmune. Children
less than 5 years old, children traveling to malaria-endemic areas but
originally from a nonendemic area, and children who have been away
from an endemic area for more than 6 months should be considered
nonimmune. In many malaria-endemic countries, there are large cities
where little or no malaria transmission occurs, and individuals
from these cities are essentially nonimmune. A well-appearing child
over 5 years of age who has arrived within 6 months from a malaria-endemic
area but who has Plasmodium species infection on
blood smear may be considered semi-immune. If there are no significant
physical exam or laboratory findings of concern, and compliance
with treatment and good follow-up are certain, such children may
be considered for outpatient therapy.
++
P falciparum malaria can be a life-threatening emergency,
especially in the nonimmune individual. Any child from a malaria-endemic
area with signs and symptoms of severe malaria should be treated
for P falciparum malaria while awaiting blood smear
confirmation. Nonimmune children with documented P falciparum malaria
should be hospitalized, because clinical decompensation can occur
rapidly, even in children with a relatively benign initial presentation.
Nonimmune children with P vivax,P ovale, or P
malariae infection generally don’t develop severe
complications, but they can appear quite ill with the initial paroxysm
and also usually require hospitalization.
++
Decisions about antimalarial therapy are based on the chloroquine
resistance pattern in the area malaria was acquired. The physician should
search carefully for evidence of complications from malarial infection
(as outlined in the “Diagnosis” section), because
early treatment of these complications may ameliorate the disease
process. In children, evidence of hypoglycemia, lactic acidosis,
and severe anemia must be sought so that if present, they can be corrected
appropriately.
+++
Severe P
Falciparum Malaria
++
In the United States, intravenous quinidine has been the drug
of choice for all children with P falciparum malaria
who require hospitalization. In malaria-endemic countries, intravenous
or intramuscular quinine, artesunate, or artemether are the drugs
of choice for severe chloroquine-resistant P falciparum malaria. Quinidine
gluconate has become less available in United States hospitals with
the advent of newer antiarrythmic drugs. Artensunate is recommended
by the World Health Organization (WHO) in preference to quinidine
for the treatment of severe malaria and has been used worldwide
for many years and can now be obtained on a protocol through the
CDC (see Table 352-2). Treating P
falciparum infection with quinine, quinidine, artesunate,
or artemether alone has been associated with significant recrudescence
rates, which are decreased with the addition of doxycycline, sulfadoxine-pyrimethamine,
or clindamycin (Table 352-2). High-level
quinine resistance, though reported, remains uncommon.
++
++
The potential cardiac toxicity of quinidine necessitates that
patients receive it as an intravenous infusion, never
as a bolus, while on continuous electrocardiographic
monitoring. Infusion rates should be reduced if the QT interval
is prolonged by more than 25% of the baseline value. Both quinine
and quinidine can induce hyperinsulinemic hypoglycemia, which may
cause lethargy or unresponsiveness that is confused with cerebral
malaria; therefore, glucose levels should be followed in severely
ill patients who are on these medications. Long-term side effects
from either medication are uncommon, and the cinchonism (nausea,
dysphoria, tinnitus, and high-tone deafness) seen with quinine resolves
with cessation of quinine therapy. When children are ready for oral
therapy, they can complete treatment with the oral forms of quinine
or artemsinin.
++
Several studies have investigated intrarectal administration
of quinine and artesunate in children with severe P falciparum malaria
with promising results,21,22 but standardized formulations
and dosing for this route of administration have not yet been agreed
upon.
+++
Uncomplicated P
Falciparum Malaria
+++
Chloroquine-Resistant
++
In the United States, more than 90% of cases of clinical
malaria reported to the CDC were acquired in Africa, Asia, or South
America, all of which have high-level P falciparum chloroquine
resistance.23
++
In the United States, a fixed combination of atovaquone and proguanil
(marketed under the trade name Malarone by Glaxo Wellcome) is the
preferred alternative to quinine treatment for uncomplicated chloroquine-resistant P
falciparum malaria (Table 352-3).
Atovaquone-proguanil has proven highly effective for treating chloroquine-resistant P
falciparum malaria in both semi-immune and nonimmune individuals.25,26 Side
effects (abdominal pain, vomiting, nausea, and headache) are infrequent
and usually mild and self-limited. In some studies, an elevation
of transaminases was seen with atovaquone-proguanil treatment, but
transaminase elevations have not been associated with untoward clinical
events.25 Atovaquone-proguanil should be taken with food
or a milky drink. If vomiting occurs within 1 hour of dosing, a
repeat dose should be given. All doses for treatment should be taken
as a single daily dose.
++
++
Artemisinin derivatives are not available in the United States
but are the primary alternative to quinine in many malaria-endemic countries.
They have been used successfully for severe and uncomplicated malaria
in Asia and Africa, and several large clinical trials have demonstrated
that they are at least as effective as quinine and are well tolerated.27-29 Artemisinin-based
therapies were superior to quinine for treating severe malaria in
adolescents and adults in a large study in Southeast Asia, and artesunate
is now considered standard treatment of severe malaria in Southeast
Asia. In many countries in sub-Saharan Africa, the fixed combination
of artemether/lumefantrine (Coartem) has now become the
preferred treatment for uncomplicated malaria.
++
Oral quinine is the first-line medication in the United States
for the child with chloroquine-resistant P falciparum infection
who does not require hospitalization. Most authorities recommend
concurrent treatment with doxycycline or sulfadoxine-pyrimethamine,
because combined treatment permits a 3-day course of quinine and
decreases the risk of recrudescence24 (Table
352-3). Children who acquire P falciparum infection
in border areas of Thailand (where low-level quinine resistance
is endemic), who have persistent parasitemia greater than 1%,
or who receive clindamycin as their adjunctive therapy should receive
a full 7-day course of quinine treatment.
++
Children frequently vomit after receiving quinine, especially
if they are febrile when receiving the drug. Acetaminophen and sponge
bathing prior to administration of oral quinine may decrease the
likelihood of vomiting. If vomiting occurs within an hour, the full
dose of quinine should be repeated. If vomiting occurs after 1 hour,
no repeat quinine dosing is necessary. Other side effects of quinine
are as noted above. In situations where urgent treatment is required
and intravenous medications cannot be given, intrarectal or intramuscular
quinine has been used successfully.
++
Mefloquine can be used to treat chloroquine-resistant malaria,
but increasing mefloquine resistance (particularly in Southeast
Asia) and significant central nervous system side effects with treatment
dosages make it an inferior choice, to be used only when quinine
or atovaquone/proguanil or an artemisinin-based therapy
is not an option. Mefloquine should not be used if the child took
mefloquine as prophylaxis, and it should not be used in conjunction
with quinine or quinidine, as it may potentiate the cardiac side effects
of these medications.
++
Increasing P falciparum sulfadoxine-pyrimethamine resistance
in many malaria-endemic countries has led to extensive testing of
drug combinations as potential new first-line therapies for P
falciparum malaria. Combination therapies tested include
sulfadoxine-pyrimethamine plus amodiaquine, chloroquine, or artesunate;
artesunate plus mefloquine, lumefantrine, or amodiaquine; and dapsone
plus proguanil. None of these combinations is currently available
in the United States, but they may be viable alternatives for uncomplicated
chloroquine-resistant P falciparum infection in
malaria-endemic countries.
+++
Chloroquine-Sensitive
++
At the time of publication, chloroquine-sensitive P falciparum still
exists in the Middle East, eastern Europe, Central America north
of the Panama Canal, Haiti, and the Dominican Republic, but this
may change. The CDC Web site (www.cdc.gov) and the malaria
hotline (770-488-7788) have up-to-date information on malaria drug
resistance in every country. Chloroquine remains the drug of choice
for chloroquine-sensitive P falciparum malaria.
It is inexpensive, generally well tolerated, and easy to administer.
Side effects include pruritus in dark-skinned patients (which is
fairly common), and, in treatment doses, nausea, dysphoria, and
rarely a transient neuropsychiatric syndrome or cerebellar dysfunction.
If there is any doubt as to whether chloroquine resistance is present
in the area malaria was acquired, quinine should be used. Quinine
or quinidine is the preferred drug for parenteral treatment of chloroquine-sensitive
malaria.
+++
Malaria Due
to P Vivax, P Ovale, P
Malariae, or P Knowlesi
++
Severe illness or complications due to P vivax, P
ovale, or P malariae are uncommon, though
the high fevers, malaise, and anemia caused by P vivax may
occasionally be severe enough to warrant hospitalization. Coinfection
with P falciparum may be missed on blood smear
if the slide reader is inexperienced or if the infection inoculum
is low. Children hospitalized with non-falciparum malaria
should be given the same drug treatment regimen as children hospitalized
for falciparum malaria (Table
352-2).
++
Most guidelines still recommend chloroquine treatment for malaria
due to P vivax,P ovale, and P
malariae. High-grade P vivax resistance
to chloroquine has been reported in Oceania and India and less commonly
in other areas of Asia, Africa, and South America, but testing of
drug alternatives to chloroquine for treating P vivax infection
has been very limited. Quinine, artemisinin derivatives, and atovaquone-proguanil
are effective in vitro and have shown efficacy in small clinical
studies.30-32 In the absence of good data on drug alternatives
to chloroquine for P vivax, and in light of the
low risk of complications in P vivax malaria, chloroquine
remains the initial drug of choice for P vivax infection.
Indications for using alternative therapy are worsening or new symptoms,
persistent P vivax parasitemia after 72 hours,
and possibly acquisition of infection in Oceania or India.
++
Treatment with medications other than chloroquine should be done in
consultation with the CDC or a clinician experienced in treating malaria.
Although scattered reports of P ovale and P
malariae chloroquine resistance exist, resistance is not
widespread and chloroquine remains first-line therapy for these parasites.
Patients with P vivax and P ovale malaria
should also receive a 2-week course of primaquine to eradicate dormant
liver stages of these parasites. Prior to treatment with primaquine,
all patients should be screened for glucose-6-phosphatase-dehydrogenase (G6PD)
deficiency. Individuals with the severe form of G6PD deficiency
may experience an oxidant hemolysis and methemoglobinemia with primaquine
administration and should not receive primaquine. There are currently
no effective alternatives to primaquine for liver-stage parasite eradication.
Based on limited evidence, chloroquine plus sulfadoxine-pyrimethamine should
be used to treat P knowlesi infections4,20;
quinine is an alternative in severely ill patients.
++
For those traveling to endemic areas, avoiding mosquitoes and
using barrier protection from mosquitoes are important ways to prevent
malaria . The Anopheles mosquito feeds from dusk
to dawn. During these hours, travelers should remain in well-screened areas,
wear clothing that covers most of the body, stay in air-conditioned
areas where possible, sleep under a bednet (ideally one impregnated
with permethrin), and use insect repellants with N-N-diethyl-m-toluamide
(DEET). Repellants with low DEET concentrations (< 20%)
are effective for only a short period of time. Rare instances of
toxic encephalopathy have been reported in young children exposured
to high concentrations of DEET, but using repellent with no more
than 40% DEET and avoiding repeated applications minimizes
the risk of this complication. Concentrations of 25% to
35% DEET, to be applied every 6 to 8 hours as needed, are
recommended for children.33 A newer insect repellant called
picaridin (5–10%) is odorless and does not leave
a sticky residue like DEET, but it last for only 1 to 2 hours.34 Spraying
clothing with permethrin, a synthetic pyrethroid, is a safe and
effective method of reducing insect bites in children. Permethrin-sprayed clothes
remain effective for at least 2 weeks, even with laundering.
++
Chemoprophylaxis is the cornerstone of malaria prevention for nonimmune
children and adults who travel to malaria-endemic areas (Table 352-4). Weekly mefloquine is the drug of
choice for malaria chemoprophylaxis in children and adults traveling
to areas with chloroquine-resistant P falciparum.
The FDA does not approve mefloquine for children who weigh less
than 15 kilograms, but since the risks of acquiring severe malaria
outweigh the risks of potential mefloquine toxicity in these children,
the CDC recommends that mefloquine prophylaxis be used for all children.
The lack of a liquid or suspension formulation sometimes makes mefloquine
administration difficult, and potential side effects include nausea
and vomiting. Mefloquine is better tolerated by children if it is
disguised in other foods. Adults have 10% to 25% incidence
of sleep disturbances and dysphoria with mefloquine, but these side
effects appear to be less common in children. A reasonable alternative
to mefloquine is the fixed combination of atovaquone and proguanil
(trade name Malarone), which was recently approved by the FDA for the
treatment and prophylaxis of chloroquine-resistant P falciparum malaria
in adults and children. Clinical trials in areas endemic for chloroquine-resistant P
falciparum have shown atovaquone/proguanil prophylaxis
effective against P falciparum infection in both
adults and children, with minimal side effects (abdominal pain,
vomiting, and headache) that rarely resulted in discontinuation
of the medication.
++
++
Atovaquone/proguanil is approved for children weighing
more than 11 kilograms. The major disadvantage of atovaquone/proguanil prophylaxis
is that it must be taken every day, so it may be better suited for
prophylaxis during short exposure periods. Doxycycline is another
alternative for prophylaxis, but it cannot be used in children less
than 8 years old, and it must be taken every day. Photosensitivity
is a common side effect, and vaginal candidiasis may occur in women
on doxycycline prophylaxis. Chloroquine, chloroquine-proguanil,
and azithromycin do not provide adequate protection for children
traveling to a chloroquine-resistant malaria-endemic area. Daily
primaquine has been used successfully as malaria prophylaxis in
adults and children in areas endemic for chloroquine-resistant P
falciparum; however, it has not yet been studied extensively
enough in nonimmune children to be recommended as routine chemoprophylaxis
for these areas. In locations where malaria remains chloroquine-sensitive,
chloroquine is the drug of choice for prophylaxis. The CDC Web site
(www.cdc.gov) and hotline number (770-488-7788) are useful
resources for determining the current malaria prophylaxis guidelines
for specific countries. No prophylaxis is completely effective,
and travelers may develop malaria despite taking the recommended
malaria chemoprophylaxis.
++
On leaving an area endemic for P vivax or P
ovale after a prolonged visit (> 3 months), children may
require “terminal prophylaxis” with primaquine
(0.6 mg/kg base or 1.0 mg/kg salt daily, up to
a maximum dose of 30 mg base or 52.6 mg salt, for 14 days) to eliminate
extraerythrocytic forms of P vivax and P
ovale and to prevent relapses. Primaquine can cause severe
hemolysis in G6PD-deficient individuals, so it is mandatory to rule
out G6PD deficiency by lab testing before primaquine is prescribed.
++
Small amounts of antimalarial drugs are secreted into the breast milk
of lactating women. The amounts of transferred drug are not considered
harmful but do not provide adequate prophylaxis against malaria.
Breast-feeding children should take standard doses of malaria chemoprophylaxis. Lactating
women should avoid using doxycycline, as prolonged infant exposure
to doxycycline via breast milk could be harmful.
++
In malaria-endemic areas of Africa, studies have demonstrated
that insecticide-treated bednets (ITNs) can reduce all-cause mortality
in children by 17% to 63%. Large-scale distribution
of long-lasting ITNs has been supported by several funding agencies and
the World Health Organization and is now occurring in many countries
in sub-Saharan Africa. There is early evidence from several countries
of a significant reduction in mortality and morbidity following
large-scale ITN distribution.35 Questions remain as to
whether these interventions are sustainable and whether the protection
from infection caused by using bednets will decrease malarial immunity
in the children protected and thereby shift malarial morbidity and
mortality to an older age in these children, but the evidence to
date has not shown a shift in morbidity or mortality.36 In
areas of lower transmission, indoor residual spraying with long-lasting
pyrethroid insecticides also appears to be an effective way to decrease
malaria transmission.
++
The formulation of a malaria vaccine has been a complex problem
because of the many antigens present in both pre-erythrocytic and erythrocytic
phases of the parasite, polymorphisms in the parasite, polymorphisms
in the human host, and the lack of sustained immunity from natural
infection. Numerous malaria vaccine trials are in progress, using components
of pre-erythrocytic and erythrocytic malarial antigens. The RTS.S
vaccine, a vaccine based on the pre-erythrocytic antigen circumsporozoite
protein (CSP), is the first vaccine to show significant efficacy
in African children with a protective efficacy of 35% against
clinical malaria in children ages 1 to 4 years.37 Several
additional trials of different age groups and dosing regimens are currently
under way.
++
Finally, artemisinin combination therapies as first-line treatment
for malaria in areas of increasing drug resistance may also help
limit transmission by reducing gametocytes, as gametocytes are the
form of parasite required for transmission to and development in
the Anopheles mosquito. A multistrategy approach
using some combination of insecticide-treated bednets or indoor
residual spraying, artemisinin combination therapy, and a partially
effective vaccine may be the most effective way to reduce malaria
transmission. Malaria eradication, first proposed in the 1950s but
unsuccessful at that time, is now being proposed again. The likelihood
of success in malaria eradication will depend on many factors, including
the long-term commitment by funding agencies and national governments
to this goal; the extent to which effective interventions can be
successfully implemented, particularly in difficult-to-reach or
politically troubled areas; the development of drug and insecticide
resistance; and the continuation of careful malaria surveillance
and follow-up after case numbers decrease.