Malaria: Rosemary M. Olivero - Elizabeth D. Barnett

2156 SECTION 22 Parasitic Diseases
220 Malaria
Rosemary M. Olivero • Elizabeth D. Barnett
Malaria is a disease of global importance. In 2015 there were an estimated in India, were awarded Nobel prizes. Further work by many investigators
214 million new cases of malaria resulting in 438,000 deaths.122 World- rounded out the current understanding of the life cycle of the malaria
wide, despite declines in malaria cases and deaths, the majority of deaths parasites and the complex interrelationship with vector mosquitoes.
from malaria continue to occur in children.122 Regular transmission of During the 20th century, parallel efforts directed toward vector
malaria occurs in parts of Africa, Asia, the Middle East, Central and control and discovery and development of drugs to treat malaria were
South America, Hispaniola, and Oceania. The infection has been imported undertaken. The development of larvicides and insecticides permitted
by travel to nearly every part of the world. Because of the ubiquity of control of the mosquito vector. The spectacular success of house spraying
the infection and the increasing volume of international travel, recogniz- with dichlorodiphenyltrichloroethane (DDT) was instrumental in
ing the signs and symptoms of malaria and knowing about methods eradicating malaria from most of North America and Europe and in
of prevention and treatment are important for health care professionals decreasing its prevalence significantly in the Mediterranean area, the
wherever they practice.46,55 Middle East, the Far East, and parts of southern Africa.145 The develop-
Malaria usually is transmitted from one person to another through ment of antimalarial drugs, stimulated largely by the need to protect
bites of infected female Anopheles mosquitoes. Disease typically results soldiers during World Wars I and II during shortages of the standard
from infection with one or more of the four species of Plasmodium antimalarial agent quinine, allowed for successful treatment of malaria
(Plasmodium falciparum, P. vivax, P. ovale, or P. malariae) that commonly cases.
infect humans. A fifth species, P. knowlesi, which is a malaria parasite The World Health Organization (WHO) launched a global campaign
of monkeys, has also been identified as causing human malaria by for eradication of malaria in 1957. Early successes, attributable to the
zoonotic transmission.29 These protozoa have complex life cycles involving efficacy of DDT and development of new antimalarial agents, subse-
arthropod and vertebrate hosts. If untreated, P. falciparum can progress quently were hindered by resistance of mosquito vectors to DDT and
to coma, renal failure, pulmonary edema, and death. Asymptomatic resistance of the parasites to antimalarial drugs. In 1969, the WHO
carriage may last decades in the case of infection with P. malariae. philosophy on malaria was altered to emphasize the development of
Relapses are common after infection with P. vivax and P. ovale. Resistance health services and research. The goals of malaria control since then
of the parasites to antimalarial agents and incomplete success in develop- have been refined and broadened to include implementation of selective
ing and maintaining programs to eradicate the mosquito vectors have and sustainable preventive measures, early diagnosis and prompt treat-
contributed to making malaria a persistent worldwide challenge. ment, early detection or prevention of epidemics, and strengthening
of local infrastructures to allow better understanding of the determinants
of local transmission and malaria control.145,164
HISTORY During 2000 through 2010, reductions of more than 50% in malaria
Malaria has been known since antiquity and probably affected prehistoric cases have occurred in almost half (43 of 99) of the countries with
humans. Fossilized mosquitoes have been found in geologic strata 30 ongoing transmission; eight additional countries showed downward
million years old. Descriptions of the signs and symptoms of malaria trends. These successes are likely due to renewed global commitment
have been found in early Hindu and Chinese writing, and Hippocrates to financing of malaria programs, allowing increased access to insecticide-
described seasonal and geographic aspects of the disease.164 Numerous treated mosquito nets (from <2% in 2000 to 55% in 2015 in sub-Saharan
references to malaria occur in literature, ranging from Shakespeare’s Africa), and indoor residual spraying, as well as increased availability
The Tempest to Laura Ingalls Wilder’s Little House on the Prairie. The of rapid diagnostic tests and artemisinin-based combination therapies.122
name is derived from the Italian mal aria (“bad air”) based on recognition Reductions in malaria control have proven most challenging in countries
of the connection between malaria and swamps. One of the first methods with the most intense transmission, such as the Democratic Republic
of malaria control, draining swamps, was based on this association. of Congo and Nigeria.122 Ongoing challenges to global malaria elimination
The first malaria treatment known to Europeans was bark of the include maintaining local control measures; resistance to antimalarial
cinchona tree, which was identified in the early 17th century almost drugs, especially to artemisinin derivatives; changes in climate; and
200 years before the active ingredient (quinine) was isolated. Not until population movement as a result of urbanization, mass displacement
the late 1800s was the vector-borne nature of malaria understood and of populations, and international travel.17,86,92,97,122,146
described; for their roles in this discovery, Laveran, a French military Mortality from malaria, particularly in adults, increased around the
surgeon working in Algeria, and Ross, a British military physician working turn of the 21st century, with increases in malaria deaths from 995,000
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CHAPTER 220 Malaria 2157
in 1980 to a peak of 1,817,000 in 2004. Corresponding to the increases in travelers from the United States, and the need for increased prevention
in malaria cases attributed to financing of global malaria programs, measures in this population.
mortality rates decreased to 1,238,000 in 2010. The majority of malaria
deaths continue to be reported from Africa.107,122
Despite reductions in many areas of the world, in the United States ORGANISM
in 2011 there were 1925 reported cases of malaria; this represents the The life cycle of malaria parasites is complex and requires a suitable
highest number of cases since 1980. The number of reported cases population of Anopheles mosquitoes and infected humans for completion
declined to 1687 in 2012 then increased to 1727 in 2013.32,33 These (Fig. 220.1). To begin the cycle, the female anopheline mosquito injects
figures emphasize the impact of international travel on malaria prevalence sporozoites along with saliva in preparation for taking a blood meal
i = Infective Stage
d = Diagnostic Stage Human liver stages
Liver cell Infected

liver cell
Mosquito stages 2
Ruptured 1 i
12
oocyst A
Mosquito takes
a blood meal Exo-erythrocytic cycle
Release of (injects sporozoites)
11 Oocyst sporozoites
i Ruptured schizont
4 3
Schizont
C
Sporogonic Cycle
Human blood stages
5 Immature
trophozoite
10 Ookinete 8 (ring stage)
Mosquito takes d
a blood meal
(ingests gametocytes)
Macrogametocyte
B
Erythrocytic cycle Mature d
trophozoite
Microgamete entering
macrogamete 9
P.falciparum
6
Exflagellated Ruptured
microgametocyte schizont
7 Schizont d
Gametocytes d 7
Gametocytes
P. vivax
P. ovale
P. malariae
FIG. 220.1 Life cycle of the human malaria parasites. The malaria parasite life cycle involves two
hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into
the human host (1). Sporozoites infect liver cells (2) and mature into schizonts (3), which rupture and
release merozoites (4). (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in
the liver and cause relapses by invading the bloodstream weeks, or even years, later.) After this initial
replication in the liver (exo-erythrocytic schizogony [A]), the parasites undergo asexual multiplication
in the erythrocytes (erythrocytic schizogony [B]). Merozoites infect red blood cells (5). The ring stage
trophozoites mature into schizonts, which rupture, releasing merozoites (6). Some parasites differentiate
into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical
manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogame-
tocytes), are ingested by an Anopheles mosquito during a blood meal (8). The parasites’ multiplication
in the mosquito is known as the sporogonic cycle (C). While in the mosquito’s stomach, the microgametes
penetrate the macrogametes, generating zygotes (9). The zygotes in turn become motile and elongated
(ookinetes) (10) and invade the midgut wall of the mosquito, where they develop into oocysts (11).
The oocysts grow, rupture, and release sporozoites (12), which make their way to the mosquito’s
salivary glands. Inoculation of the sporozoites (1) into a new human host perpetuates the malaria life
cycle. (From Centers for Disease Control and Prevention. About Malaria: Biology; http://www.cdc.gov/
malaria/about/biology/)
from a vertebrate host. Sporozoites, the infective stage of Plasmodium,

remain in the circulation for less than 1 hour and then migrate to the EPIDEMIOLOGY
liver, where they invade hepatocytes and multiply asexually. Proliferation Transmission of malaria occurs in large parts of Africa, the Indian
within hepatocytes takes approximately 1 week for P. falciparum and subcontinent, Southeast Asia, the Middle East, Oceania, and Central
P. vivax and approximately 2 weeks for P. malariae. At the end of this and South America (Fig. 220.2). Although indigenous transmission of
period, mature tissue schizonts rupture and release thousands of malaria has been eradicated almost completely from the United States,
merozoites, which then invade red blood cells (RBCs). P. vivax and P. Canada, Europe, most of the Caribbean, parts of South America, Israel,
ovale have a second type of exoerythrocytic form, the hypnozoite, which Turkmenistan, Morocco, the United Arab Emirates, Armenia, Lebanon,
can remain dormant for weeks to years. Dormant hypnozoites may Reunion, Singapore, Hong Kong, Japan, Korea, Taiwan, Brunei, and
develop weeks, months, or years later into merozoites, which then can Australia, many cases of imported malaria occur in these countries
enter RBCs and cause relapse of malaria. The factors that influence each year.122
which exoerythrocytic form develops are not understood. Complete P. falciparum is the major malaria species in sub-Saharan Africa and
details of the erythrocytic phases of P. knowlesi in humans are not yet the island of Hispaniola, with P. malariae assuming a more minor role.
known.82 P. vivax occurs alongside P. falciparum in the Indian subcontinent,
Merozoites released from tissue schizonts invade RBCs, where the Central and South America, Mexico, Southeast Asia, and Oceania.
erythrocytic phase of the life cycle occurs. Two pathways exist in the P. ovale occurs mainly in Africa. P. vivax occurs rarely in sub-Saharan
erythrocytic, or blood, phase: asexual and sexual. In the asexual phase, Africa because most Africans lack the Duffy blood group antigen
development of the parasite begins with the youngest stage, the tro- necessary for parasite invasion.76 P. knowlesi has been isolated only in
phozoite or ring form. The parasite undergoes nuclear division to form Southeast Asia.122
schizonts and then merozoites in the asexual multiplication process,
called erythrocytic schizogony/merogony. Lysis of RBCs releases the TRANSMISSION
merozoites, which invade other RBCs, perpetuating the asexual eryth-
rocytic cycle. The cycle continues until interrupted by treatment or by Epidemiologic Terminology
the host’s immune response. Patterns of transmission of malaria include stable endemic malaria
In the sexual phase, subpopulations of merozoites in the erythrocytic (natural transmission occurring over many years, with a predictable
phase differentiate into gametocytes, or sexual forms, which then are incidence of illness and prevalence of infection) and unstable malaria
available for ingestion by mosquitoes to complete the life cycle within (transmission rates vary from year to year in areas of low immunity,
the mosquito. Female macrogametocytes and male microgametocytes with a greater likelihood of epidemics occurring). The degree of endemic
appear in the circulation within 3 to 15 days of the onset of symptoms. malaria is based on the parasite rate in children 2 to 9 years old. Types
Gametocytes of P. vivax may appear in 4 days, whereas gametocytes of of endemic malaria include hypoendemic (parasite rate of 0–10%),
P. falciparum may require 10 days for development. mesoendemic (parasite rate of 11–50%), hyperendemic (parasite rate
In the stomach (midgut) of the mosquito, male gametocyte nuclei consistently >50%, with a high proportion of adults having enlarged
divide into four to eight nuclei and form motile gametocytes that fertilize spleens), and holoendemic (parasite rate consistently >75%, with a low
the female gametocytes. The zygotes become motile ookinetes that proportion of adults having enlarged spleens).164
migrate through the wall of the midgut, attach to its outer surface, and Autochthonous malaria is acquired locally and may be indigenous
form oocysts. The oocysts rupture 9 to 14 days later and release spo- or introduced. Introduced malaria may occur when migrant populations
rozoites that invade the mosquito salivary glands, where they are ready with asymptomatic infection provide blood meals for feeding anopheline
for inoculation into the next vertebrate host. mosquitoes under conditions that allow for the life cycle to be completed
A B
FIG. 220.2 Malaria-endemic countries in the (A) Western and (B) Eastern Hemispheres, 2016. (From
Centers for Disease Control and Prevention. Health Information for International Travel 2016, http://
wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria.)
in the mosquito, enabling the mosquito to infect others. Imported maternal antibody. The highest incidence of infection with malaria
malaria cases may occur in nonendemic areas but result from infection occurs in infants and young children who are no longer protected by
in an endemic area. Induced malaria is acquired by exposure to infected maternal antibody but who are too young to develop sufficient acquired
blood, such as from blood transfusion, needlestick injury, laboratory immunity. The lack of acquired immunity in infants and young children
accident, or, historically, medical treatments. Cryptic malaria cases are accounts partly for their increased risk for acquiring disease and having
cases for which no explanation can be found and no epidemiologic severe manifestations such as cerebral malaria. Acquired immunity
link to other cases can be identified. diminishes during pregnancy, and pregnant women are at high risk for
development of severe complications of malaria. Individuals in the
Mosquito-borne Transmission population who remain asymptomatic but harbor gametocytes in their
The most typical means of transmission of malaria is through the bite blood are reservoirs of infection when bitten by mosquitoes. With the
of an infected female anopheline mosquito. Although more than 450 exception of P. knowlesi, which infects monkeys, there are no significant
species of Anopheles mosquitos exist, only approximately 60 have been animal reservoirs of malaria.
shown to be effective vectors of malaria.25 A population of infected Clinical manifestations of malaria may be severe in nonimmune
humans is necessary to sustain transmission because of the short life patients. Malaria is the most common life-threatening infection acquired
span of mosquitoes (5–20 days) and the long incubation period required by travelers to malaria-endemic regions. Individuals with acquired
in the mosquito (8 to ≥10 days). immunity who then leave endemic areas for long periods may lose their
immunity and be at risk for severe disease if reexposed.
Bloodborne Transmission Genetic factors determine the risk for acquiring malaria and having
Transmission of malaria via blood transfusion is well documented.106,123 severe infection. Individuals who have a Duffy-negative blood type lack
Transmission also may occur through organ donation or needlestick the most important specific receptors for invasion of the merozoites
injury.32,57 Relapses of malaria cannot occur with bloodborne transmis- of P. vivax, and these individuals have markedly reduced susceptibility
sion, even if the infecting species is P. vivax or P. ovale, because the to infection with this species.76,103 This resistance is the basis for the
infection is produced by the transmission of infected RBCs rather than low incidence of vivax malaria in Africa. Specific human leukocyte
by forms that invade the liver. antigens present in individuals from West Africa may protect against
the development of severe complications of malaria, including cerebral
Congenital Malaria malaria and severe anemia. The best-known example of the relationship
Infants can acquire malaria from their mothers during pregnancy. between malaria and genetics is the association between sickle hemo-
Transplacental transmission of parasites has been proposed as the most globinopathies and protection against severe falciparum malaria. This
likely route of transmission, although breakdown of placental barriers balanced polymorphism is thought to have helped ensure survival of
allowing transmission of maternal blood cells to the infant during labor the gene for hemoglobin S in the population because of the selective
or delivery also has been suggested as a mechanism of transmission.64,94,102 advantage provided on a population basis to those who are heterozygous
P. vivax most often is associated with this phenomenon, but it may for sickle-cell disease. Individuals with sickle hemoglobinopathies still
occur with all species. Congenital malaria is less likely to occur in infants may be infected and manifest signs and symptoms of malaria, although
of semi-immune mothers because of transplacental passage of maternal the risk for acquiring severe malaria or dying of malaria may be 60-fold
antibody during the third trimester. As with transfusion-associated to 70-fold less in children with hemoglobin AS than in children with
malaria, relapses do not occur. An important sequela of infection that hemoglobin AA.168
occurs in pregnancy is fetal growth restriction and increased risk of
morbidity and mortality.169
PATHOPHYSIOLOGY
Cryptic Malaria Pathophysiologic changes in malaria are caused by destruction of RBCs,
The category of cryptic malaria includes cases for which no source of production of cytokines, stimulation of intravascular synthesis of nitric
infection can be identified. Typical cases include confirmed malaria in oxide, and sequestration of infected erythrocytes.
US residents who have never traveled to or resided in malarial areas, Lysis of RBCs leads to anemia, which may be acute and severe, and
who have not received blood transfusions, and who are not linked its attendant hemodynamic consequences. Anemia may develop as a
epidemiologically with other cases.32,81,136 Airport malaria, one kind of result of hemolysis, impaired erythropoiesis, or bone marrow depression
cryptic malaria, occurs in proximity to international airports and is secondary to folic acid deficiency.127 Intravascular hemolysis may be so
thought to occur when mosquitoes arriving with airplanes from endemic severe that it results in pronounced hemoglobinuria (blackwater fever),
areas infect individuals working in or living near airports.75 which may be a precipitating event in the development of renal failure.
This complication has been noted in association with treatment using
quinine. Hematopoiesis is suppressed during acute infection, and such
HOST-PARASITE INTERACTION suppression may not be reversed as readily in iron-deficient individuals,
The intensity of transmission of malaria depends on factors that affect contributing to the development of chronic anemia.
the density of vectors and the extent of vector-human contact. Transmis- Cytokines such as tumor necrosis factor (TNF) and interleukin-1
sion of malaria may be continuous or seasonal, or it may depend on have important roles in the pathogenesis and severity of malaria infec-
local site-specific factors, such as the presence of irrigation projects or tion.14,77,79 Severe disease has been associated with higher concentrations
intermittent flooding. Mosquito vectors differ in their efficiency in of TNF, and TNF polymorphisms may play a role in the development
transmitting malaria; the principal vector in sub-Saharan Africa, of specific complications.99,100 Higher TNF concentrations have been
Anopheles gambiense, is known for being a highly effective vector. observed in those with cerebral malaria and those who have required
Variations in climate may affect the viability of mosquitoes. longer hospitalizations for malaria.77 Parasite factors responsible for
The incidence and severity of malaria are affected by the intensity release of cytokines have not been identified. A possible mechanism
of exposure, the presence of immunity, and genetic factors. Distinction for the role of TNF in malaria pathogenesis is the binding of TNF to
must be made between malaria infection (presence of parasitemia) and its receptors, causing signaling to amplify cytokines of inflammatory
malaria illness. A major puzzle in malaria is why individuals with similar cascades.138 Another possible role of TNF in malaria is to stimulate
degrees of parasitemia may exhibit radically different clinical production of nitric oxide, a short-lived neurotransmitter. Nitric oxide
manifestations. may have a role in cerebral malaria pathogenesis, and its transient nature
Individuals who reside in endemic areas and are exposed continually may provide a partial explanation for the complete recovery noted in
to infected mosquitoes acquire some degree of immunity to malaria some patients with severe cerebral malaria. TNF and nitric oxide have
illness. Adults in these areas continue to become infected, but they have both harmful and beneficial roles in the pathogenesis of malaria; both
lower levels of parasitemia. Infants born to mothers with acquired have been shown to be correlated with clearance of parasites and eventual
immunity may be protected transiently by transplacental passage of recovery and with severity of illness.
Sequestration of infected RBCs has long been thought to contribute take several days to become established, may not occur at all in asyn-
to the clinical manifestations of malaria, particularly that caused by P. chronous infections, or may be modified by previous immunity or
falciparum. Late-stage parasites induce host cells to develop knobs on treatment.
the surface of erythrocytes that facilitate adherence of these cells to In children, fever and headache may be the sole symptoms or
vascular endothelium. The effects of these sequestered RBCs on the gastrointestinal symptoms may predominate. Physical signs of malaria
perfusion, nutrition, and oxygenation of surrounding tissues may be include pallor, jaundice, and hepatosplenomegaly. Rash and lymphade-
responsible for the complications of P. falciparum infection, including nopathy typically are not associated with malaria, although malaria
cerebral malaria, renal failure, and watery diarrhea.109,132 Consumption may precipitate recrudescence of latent herpes infections.
of glucose by metabolically active late-stage parasites contributes to Anemia is the most common laboratory abnormality in malaria.
hypoglycemia and lactic acidosis. Despite these changes, the majority Thrombocytopenia is common and may be the first manifestation in
of histopathologic appearances of tissue is remarkably benign, consistent patients with uncomplicated malaria.168 Leukopenia also may occur,
with the reversible nature of the changes and supportive of the role of and leukocytosis is less common and should provoke investigation for
cytokines and secondary messengers in the pathogenesis of complications other conditions. Liver function test abnormalities may be present and
of cerebral malaria.164,168 Recent postmortem microscopy of brain sections can be mistaken for infectious hepatitis, especially in patients with
from adults who died of malaria confirmed that sequestration of cerebral jaundice and tender hepatosplenomegaly. Hypoglycemia occurs frequently
microvasculature was significantly higher in patients with cerebral malaria with falciparum malaria and may develop before or as a consequence
and was also correlated with deeper levels of premortem coma and of treatment with quinine. When present in children before treatment,
shorter time to death.133 hypoglycemia is associated with a poor prognosis.165 Hyponatremia
may occur as part of the syndrome of inappropriate secretion of
CLINICAL MANIFESTATIONS AND antidiuretic hormone. Serum creatinine and blood urea nitrogen values
may be elevated transiently or may increase significantly with acute
LABORATORY FINDINGS renal failure.
The clinical manifestations of malaria depend on the species causing Malaria stimulates a polyclonal increase in immunoglobulins associ-
the infection, the immune status of the individual, the mode of transmis- ated with rapid production of malaria-specific antibodies and reduced
sion of infection, whether the individual was taking prophylaxis, and complement levels. False-positive tests for syphilis, rheumatoid factor,
host immune factors (Table 220.1). Acute malaria generally is understood heterophil agglutinins, and cold agglutinins may occur.164
to refer to the signs and symptoms associated with disease caused by
infection with malaria parasites. Severe and Complicated Malaria
Recurrent infections are of three types: relapse, recrudescence, and Nonimmune individuals are most susceptible to severe complications
reinfection. Relapses occur as a result of delayed maturation of the of falciparum malaria, which include cerebral malaria, pulmonary failure
dormant liver stages (hypnozoites) of P. vivax or P. ovale. Recrudescence or acute respiratory distress syndrome, renal failure, and severe anemia.90
occurs when parasitemia caused by the same parasite responsible for Hypoglycemia and metabolic acidosis may occur. Falciparum malaria
the initial infection recurs after clearance or a significant reduction in in nonimmune patients should be considered a medical emergency,
the initial parasitemia, and occurs most commonly with P. falciparum and treatment of P. falciparum should be initiated in all ill patients with
because of drug resistance. Reinfection with different parasites and malaria until the species can be confirmed. The highest mortality is
infection with more than one type of Plasmodium occur especially in seen in those who have a combination of severe respiratory distress,
areas with a high intensity of transmission. Persistent infection is noted impaired consciousness, and severe anemia. The Centers for Disease
with P. malariae; hypnozoites have not been identified with P. malariae, Control and Prevention (CDC) and WHO criteria for the diagnosis of
so the organism is thought to persist as a low-level parasitemia that severe malaria are outlined in Table 220.2.
can exist for years without causing symptoms.
A classic description of malaria includes features of the malaria Severe Anemia
paroxysm resulting from lysis of parasitized RBCs and release of Children younger than 1 year old, especially in sub-Saharan Africa, are
merozoites into the circulation at the completion of asexual reproduction. those most likely to experience severe malarial anemia. This complication
The paroxysm is characterized by fever and chills accompanied by is thought to occur most often in areas with year-round transmission.
constitutional symptoms of headache, body ache, fatigue, dizziness, Clinical consequences of anemia are determined by rate of development
and malaise. Gastrointestinal symptoms include nausea and vomiting, and severity of the anemia, with high risk for complications as hemo-
abdominal pain, and diarrhea. Cough and dyspnea may accompany an globin decreases to less than 5 g/dL.112 Hemolysis has been reported as
attack. Although periodicity of the paroxysms in primary attacks is a consequence of treatment with artemisinin derivatives, most commonly
thought to be pathognomonic for malaria species, this periodicity may IV artesunate, approximately 2 weeks after initiation of treatment142; it
TABLE 220.1 Characteristics of the Plasmodium Species Responsible for Human Malaria
SPECIES
Characteristic P. falciparum P. vivax P. ovale P. malariae P. knowlesi
Incubation period in days (range) 12 (8–25) 14 (8–27) 17 (15 to ≥18) 28 (15 to ≥40) 11 (9 to >12)
Periodicity of febrile attacks (hours) None 48 48 72 24
Earliest appearance of gametocytes (days) 10 3 ? ? ?
Relapse No Yes Yes No No
Duration of untreated infection (years) 1–2 1.5–4 1.5–4 3–50 ?
RBC preference Younger cells (but can Reticulocytes Reticulocytes Older cells ?
invade cells of all ages)
Characteristic morphology Ring forms Schüffner dots Schüffner dots Normal-sized cells Ring forms
Multiply infected cells Enlarged RBCs Enlarged RBCs Band or rectangular Occasional multiply
forms of trophozoites infected cells
Banana-shaped Band forms
gametocytes
RBC, Red blood cell.
TABLE 220.2 Manifestations of Severe Malaria Respiratory Complications

Centers for Disease Control World Health Pulmonary edema typically develops late in the course of severe malaria
and Prevention Definitiona Organization Definition162 when other complications are already present, and it may occur when
parasitemia has resolved and the patient appears to be improving
Cerebral malaria Prostration, impaired clinically. Pulmonary edema occurs more commonly in adults than in
Severe anemia consciousness, coma children, and the pathogenesis is consistent with capillary leak syndrome.
Acute renal failure (cerebral malaria) or multiple Supplemental oxygen or mechanical ventilation with positive end-
Hemoglobinuria convulsions expiratory pressure may be necessary to manage respiratory complica-
Hypoglycemia Severe anemia tions. A well-characterized pulmonary inflammatory response driven
Metabolic acidosis Renal impairment by alveolar macrophages can lead to respiratory distress in severe
Hypotension caused by Hemoglobinuria malaria.118 Respiratory distress is the most dangerous presentation of
cardiovascular collapse Hypoglycemia (<40 mg/dL) severe malaria, especially in combination with severe anemia and cerebral
Acute respiratory distress syndrome Acidosis or hyperlactatemia malaria.52
Coagulopathy Circulatory collapse or shock
Hyperparasitemia (>5% infected Respiratory distress or Cerebral Malaria
RBCs) pulmonary edema Cerebral malaria is the most common complication of falciparum malaria
Abnormal bleeding in children and occurs most often in children 3 to 6 years old.66,128 It
Hyperparasitemia (>2% infected presents as alteration of consciousness and diffuse encephalopathy with
RBCs in low-transmission prolonged multiple seizures in a patient with no other explanation.
areas or >5% in high- Patients may be comatose without response to stimuli and may assume
transmission areas) an opisthotonic posture. Generalized convulsions may occur, and focal
Jaundice findings are uncommon. Serial electroencephalographic monitoring of
Failure to feed 65 Kenyan children uncovered a large range of clinical and electrographic
RBCs, Red blood cells. seizures with diffuse background slow-wave activity, which are nonspecific
a
From www.cdc.gov/malaria/about/disease/html#severe. features; electrical seizure activity consistently arose from the posterior
temporoparietal region.30 Intracranial pressure often is increased in
children with cerebral malaria, and the presence of increased intracranial
pressure was recently found to be associated with increased mortality.152
is unclear whether this hemolysis is a complication of artemisinin Factors associated with neurologic sequelae include prolonged coma,
treatment rather than the severity of malaria in these cases. severe anemia, and multiple seizures. Mortality rates range from 15%
to 30% of affected children; most survivors recover completely, though
Hypoglycemia approximately 10% may have neurologic sequelae. The most common
Hypoglycemia (blood glucose <40 mg/dL) may be present on initial neurologic sequelae in children noted in a study in the Gambia were
evaluation in 20% of children with severe malaria and is associated hemiplegia, cortical blindness, aphasia, and ataxia.19
with a poor prognosis. The etiology of pretreatment hypoglycemia is Many factors, including hypoglycemia, anemia, microvascular
thought to be a combination of parasite consumption of glucose and obstruction, acidosis, and elaboration of inflammatory mediators,
inadequate gluconeogenesis in the liver. Hypoglycemia also can occur contribute to the syndrome of cerebral malaria. Histopathologic
as a result of treatment, most typically with quinine. Intravenous or features are minor, with occasional hemorrhages and perivascular
oral administration of quinine may lead to hypoglycemia by stimulating infiltrates.
insulin secretion. Pregnant women seem to be especially susceptible to Malarial retinopathy is a more recently described phenomenon in
this complication. children with falciparum cerebral malaria. The retinal changes seen in
malarial retinopathy include retinal whitening, vessel discoloration,
Acid-Base Changes retinal hemorrhages, and papilledema, and the severity of retinal findings
Metabolic acidosis is a marker of malaria illness severity and clinically has been found to have prognostic value in predicting risk of death
may manifest as hyperpnea. Acidosis often is associated with hypoglycemia. and length of coma in survivors of severe malaria.12
Fluid resuscitation and treatment with antimalarial drugs often result
in rapid resolution of acidosis, although persistence of acidosis may Hyperreactive Malarial Syndrome (Tropical Splenomegaly
occur in patients who eventually die of malaria. Syndrome, Hyperreactive Malarial Splenomegaly)
Hyperreactive malarial syndrome is characterized by massive spleno-
Renal Complications megaly, high concentrations of total serum IgM and malarial antibodies
Acute renal failure is a potentially life-threatening consequence of acute of multiple immunoglobulin classes, and clinical and immunologic
malaria that occurs more commonly in adults than in children. It typically response to antimalarial agents.84,183 Hyperreactive malarial syndrome
is oliguric and often is reversible if the patient can be supported is correlated with malaria endemicity, with an incidence ranging from
by dialysis through the oliguric phase. Acute renal failure is a rare 0.5% to 80% of the adult population. The pathogenesis is unknown
development in residents of endemic areas and long has been thought but seems to involve chronic exposure to malaria, resulting in chronic
to occur more frequently in patients treated with quinine or quinidine stimulation of the immune system and genetic factors. Findings on
(blackwater fever). The histologic changes resemble those of acute tubular physical examination include a huge spleen (>10 cm below the costal
necrosis. margin) and an enlarged liver. Laboratory findings include anemia and
Nephrotic syndrome and chronic renal failure occur more frequently an increased reticulocyte count, elevated IgM (>2 standard deviations
in areas where malaria is endemic and usually are associated with infection above the mean), and high antibody levels of antimalarial antibodies.157
with P. malariae. Symptoms occur in individuals younger than 15 years Some patients have thrombocytopenia or neutropenia. Patients may
old in approximately half of cases, with gradual progression to renal have an increased risk for acquiring bacterial infections, and some
failure over 3 to 5 years. Most patients have asymptomatic proteinuria researchers have suggested that hyperreactive malarial syndrome is a
and the gradual development of hypertension and deterioration in premalignant condition.10 Lifelong treatment with antimalarial agents
renal function. Adults more commonly have hematuria and azotemia; is the treatment of choice for patients who reside in endemic areas.84
adults and children may have hematuria. The disease does not respond Treatment of patients who have left endemic areas has not been standard-
to antimalarial agents. Treatment with corticosteroids, cyclophosphamide, ized; several case reports show success with a single short (≤7 days)
and azathioprine has had variable results, with remission occurring treatment course of antimalarial agents followed by close monitoring
only in patients with mild changes on renal biopsy.164 of the size of the spleen.84,157
because of fetal tachycardia and distress secondary to maternal fever;

Malaria in Special Populations disruption of maternal-fetal blood flow and exchange of metabolic
Malaria in Children substrates by malaria parasites trapped in the placenta; and the potential
The signs and symptoms of malaria in children range from asymptomatic for reduction in fetal glucose supply, which may be exacerbated by
infection to life-threatening illness. Severe anemia is most likely to treatment with quinine, a drug that is able to stimulate the release of
develop in children younger than 2 years old, whereas cerebral malaria insulin.88 Heavy infection of the placenta interferes with transfer of
is most likely to occur in older children (mean age, 3.5 years). The tetanus antibodies from the mother to the fetus, but the effect on other
greatest burden of disease is borne by infants and young children, antibodies is unknown.18 Prompt treatment of pregnant women with
although the impact of disease on adolescents has not been studied malaria is critical to survival of the mother and the fetus, as fetal growth
extensively. Malaria in pregnant adolescents may be of particular restriction and low birth weight are associated with high infant mortality
concern.80 and morbidity rates.15,169
In endemic areas, lack of diagnostic facilities, limited resources, and
encroaching drug resistance complicate the ability to make a rapid,
accurate diagnosis and provide expedient treatment to children with DIAGNOSIS
malaria. Malaria often is difficult to distinguish from other common The most important first step in establishing the diagnosis of malaria
illnesses such as pneumonia. Clinical algorithms that can distinguish is to consider the diagnosis in all individuals with febrile illness, especially
children with malaria from children with pneumonia or other illnesses febrile individuals with a history of travel to endemic areas. Having a
have been developed and studied but do not eliminate completely the high index of suspicion for the diagnosis of malaria cannot be over-
overlap with conditions having similar clinical manifestations.139,140,148 emphasized. Failure to diagnose and treat malaria promptly contributed
Risk factors for a fatal outcome in children with malaria were studied to fatal outcomes in US civilians who died of malaria between 1963
in Kenya; the presence of coma or respiratory distress, or both, at initial and 2001.111 In one series of fatal falciparum malaria cases in the United
evaluation identified children at high risk for dying.52,96 States, 40% of patients were not recognized as having malaria during
Imported malaria occurs in children in many nonendemic countries. their initial contact with a physician.50 Manifestations of the disease
The diagnosis often is delayed because of lack of consideration of malaria are most classic in nonimmune individuals or in individuals in areas
as a cause of illness and unfamiliarity with the disease. In children with where malaria transmission is seasonal. Signs and symptoms of disease
acquired immunity, the signs and symptoms of disease may be subtle may be nonspecific in semi-immune individuals, those who have received
and nonspecific, but fever or a history of fever is universal.40,89 Other malaria prophylaxis, or individuals who have been partially treated.
symptoms include anorexia, vomiting, diarrhea, headache, lethargy, and In nonendemic areas, a history of travel to an endemic area should
abdominal pain. Laboratory findings include anemia, thrombocytopenia, suggest the diagnosis in all individuals with a febrile illness, regardless
and leukopenia. The diagnosis of malaria should be considered in every of the accompanying signs and symptoms.179 Common diagnoses
child with fever or a history of recent fever who has visited an area mistakenly assigned to patients ultimately determined to have malaria
where malaria occurs. include gastroenteritis and viral syndrome. The course of disease may
be modified by exposure to antimalarial drugs, such as agents that may
Congenital Malaria have been used for prophylaxis, and the incubation period may be
P. falciparum, P. malariae, P. vivax, and P. ovale can be transmitted prolonged after the administration of antimalarial chemoprophylaxis.
congenitally, but the disease most often is associated with P. vivax. Because malaria may be transmitted by blood transfusion or an organ
Congenital malaria has not been reported with P. knowlesi. That congenital transplant, may be congenitally acquired, and, rarely, occurs cryptically,
malaria is not seen more frequently is due partly to the effective barrier the diagnosis also should be considered in patients with compatible
function of the placenta. Congenital malaria develops in infants of signs and symptoms of malaria, anemia, or thrombocytopenia and no
approximately 0.1% of immune mothers and 10% of nonimmune other explanation for their illness.
mothers in endemic areas, although placental infection occurs in one Microscopy is the technique traditionally used for establishing the
third of pregnant women.70 In endemic areas, distinguishing malaria diagnosis of malaria. Rapid diagnostic tests to detect parasite antigens
acquired congenitally from malaria acquired by transmission from are important tools in centers lacking around-the-clock expertise in
mosquitoes is difficult. In non–malaria-endemic countries, congenital malaria diagnostic microscopy. Other alternatives to microscopic
malaria is very rare; only five cases have been reported in the United diagnostic techniques for malaria include tests using fluorescent
States since 2000.27 microscopy, DNA probes, polymerase chain reaction (PCR), antibody
The onset of symptoms is insidious and usually occurs at 2 to 8 detection, and flow cytometry. Only a few of these methods meet the
weeks of age. The typical malaria paroxysm is absent, with the infant requirements of low cost, high reliability and reproducibility, and rapid
instead having poor feeding, fever, vomiting, diarrhea, irritability, and turnaround time. Some of them are suitable for use in field conditions,
hepatosplenomegaly on physical examination.64 The most common however, and have been used in endemic areas and for self-diagnosis.
laboratory finding is anemia, but thrombocytopenia and hyperbiliru- Diagnosis of cerebral malaria is largely clinical. Patients with cerebral
binemia also occur. Therapy for the infecting species of malaria is malaria typically do not have marked cerebrospinal fluid (CSF) pleo-
curative, and the infant does not need treatment of the exoerythrocytic cytosis, differentiating this entity from bacterial meningitis. In comparing
stages of the parasite (although the mother does). CSF parameters in children with cerebral malaria to those with viral
encephalitis, those with cerebral malaria have a lower CSF glucose level
Malaria in Pregnancy and higher protein and lactate dehydrogenase (LDH) levels, CSF-to-blood
The effects of malaria on the mother depend on the degree of immunity LDH ratio, and CSF-to-serum adenosine deaminase ratio.68 The clinical
that she has attained and her parity.102 Relapses and recrudescence of finding of malarial retinopathy shows promise in aiding in the diagnosis
malaria are common during pregnancy, as acquired immunity diminishes of severe falciparum malaria complicated by coma,12 but use of this
with the pregnant state. Malaria can exacerbate the anemia occurring finding is limited to settings where indirect ophthalmoscopy is
during pregnancy, and hypoglycemia and renal insufficiency may available.
complicate falciparum malaria during pregnancy.51
Placental infection during pregnancy is associated with delivering Microscopy
low-birth-weight infants, particularly in primigravidas. Fetal growth Microscopy is the gold standard for establishing the diagnosis of malaria.
restriction begins early in gestation and can occur even in asymptomatic Identification of typical parasite forms by an experienced microscopist
parasitemia.144 An in vitro study showed that placental falciparum malaria is the mainstay of diagnosis worldwide (Figs. 220.3 through 220.7).
results in inhibition of transplacental amino acid transport and that There are many advantages of using light microscopy: it can be performed
this is a plausible mechanism of fetal growth restriction.15 Vivax malaria at low cost, it can be done rapidly, it typically allows identification of
has been linked to maternal anemia and low birth weight in multigravidas the infecting species and estimation of parasite load, and it can be
and primigravidas.113 Severe falciparum malaria is harmful to the fetus Text continued on p. 2167
A B C
D E F
G H I
FIG. 220.3 Plasmodium vivax. (A–B) Ring trophozoites. (C–E) Trophozoites. (F–G) Schizonts. (H)
Macrogametocyte. (I) Ookinete. (From Centers for Disease Control and Prevention, DPDx: Laboratory
Identification of Parasitic Diseases of Public Health Concern: Malaria. www.cdc.gov/dpdx/malaria/
gallery.html.)
A B C
D E F
G H I
J
FIG. 220.4 Plasmodium ovale. (A–B) Ring trophozoites. (C–E) Trophozoites. (F–G) Schizonts. (H–I)
Macrogametocytes. (J) Microgametocyte. (From Centers for Disease Control and Prevention, DPDx:
Laboratory Identification of Parasitic Diseases of Public Health Concern: Malaria. www.cdc.gov/dpdx/
malaria/gallery.html.)
A B C
D E F
G H I
FIG. 220.5 Plasmodium falciparum. (A–C) Ring trophozoites. (D–E) Trophozoites. (F–G) Schizonts. (H–I)
Gametocytes. (From Centers for Disease Control and Prevention, DPDx: Laboratory Identification of
Parasitic Diseases of Public Health Concern: Malaria. www.cdc.gov/dpdx/malaria/gallery.html.)
A B C
D E F
G H I
J K
FIG. 220.6 Plasmodium malariae. (A–B) Ring trophozoites. (C–F) Trophozoites. (G–I) Schizonts. (J–K)
Macrogametocytes. (From Centers for Disease Control and Prevention, DPDx: Laboratory Identification
of Parasitic Diseases of Public Health Concern: Malaria. www.cdc.gov/dpdx/malaria/gallery.html.)
A B C
D E F
G
FIG. 220.7 Plasmodium knowlesi. (A–B) Ring trophozoites. (C) Trophozoites. (D–F) Schizonts. (G)
Gametocyte. (From Centers for Disease Control and Prevention, DPDx: Laboratory Identification of
Parasitic Diseases of Public Health Concern: Malaria. www.cdc.gov/dpdx/malaria/gallery.html.)
performed with a small sample of blood. The major disadvantage of may be missed when using high-dry (×440) magnification. The micros-
microscopy is the need for an experienced microscopist. In settings copist begins by looking at the thin edge of the blood film farthest from
where malaria is not endemic, the need for specialists to review micro- where the drop of blood was placed. Giemsa stain is preferred to Wright
scope slides may lead to a delay in establishing the diagnosis. stain when available because it preserves details such as Schüffner dots
Thin smears are the most useful in diagnosing malaria. They are in P. vivax and P. ovale infections. When individual RBCs can be seen
easy to prepare, with only a single drop of blood required. The drop at low magnification (×100), switching to oil immersion allows examina-
of blood is placed at one end of the slide, and the edge of a second tion for parasites within the cells. The major disadvantage of thin films
slide is placed at the edge of the blood smear and drawn across the is low sensitivity. With low parasite loads (<100 to 300/µL), the amount
slide.119 RBC morphology is preserved by methanol fixation, so invasion of blood on the smear may be too small to allow detection of the
of large RBCs by the parasites can be identified and speciation of the parasites.
organism is possible (see Table 220.1). Oil-immersion magnification Thick smears have greater sensitivity than thin smears as a result of
(×1000) should be used for viewing the slide because many young the larger quantity of blood used. Because the RBCs are lysed during
asexual intraerythrocytic parasites are only 2 to 3 µm in diameter and preparation of the slide, the types of cells containing parasites cannot
be identified. To make a thick smear, a drop of blood is placed on the diagnosis of vivax malaria, although this assay has a higher sensitivity
slide and spread in a circle. The slide is stained without using methanol for detection of malaria than the HRP-2 assays.26,67,105 A limitation of
fixation so that RBCs lyse. HRP-2-based assays is that they remain positive after therapy because
Estimating parasite density is useful for assessing degree of parasitemia HRP persists in the blood after acute infection. LDH-based assays are
and for evaluating response to therapy. The density of parasites can be able to distinguish between P. falciparum and other malaria species,
determined on thick or thin smears.168 When thin smears are used, the although the test is unreliable in detecting P. vivax in the presence of
proportion of RBCs infected is counted while the smear is viewed under P. falciparum.137 An advantage of LDH-based assays is the ability to
an oil-immersion lens. distinguish between viable and nonviable parasites, rendering the test
useful for monitoring response to therapy.23,28,67,105,125
Fluorescent Microscopy The target antigens, malaria species detected, sensitivity, and specificity
The quantitative buffy-coat test relies on identification of parasitized of the four most commonly used RDTs in the United States are sum-
RBCs stained with acridine orange in the RBC layer of centrifuged marized in Table 220.3. The Binax Now test is the only RDT licensed
blood.161 Experienced personnel can perform the test rapidly, but the in the United States.44 Although RDTs including Binax Now offer timely
reagents are costly when compared with those needed for microscopy, results without the use of microscopy, false-negative results are possible
and the species of parasite cannot be identified. If a fluorescent micro- and can be problematic when there is low parasitemia. For this reason,
scope is available, identification of parasitized RBCs can be accomplished many centers in the United States will perform diagnostic microscopy
by staining a thick smear with acridine orange and examining it under as a follow-up to a negative RDT; this approach reduces the risk of
fluorescent light. missing the diagnosis of malaria and should be performed when an
experienced microscopist is available. Because RDTs do not allow for
Detection of Parasite Antigen quantification of parasitemia, diagnostic microscopy should be pursued
Rapid diagnostic tests (RDTs) for diagnosis of malaria have been where available when a diagnosis of severe malaria is entertained, so
developed. These tests are immunochromatographic assays using that response to therapy can be monitored closely.
monoclonal antibodies directed against target malaria antigens and Dipstick tests may have a role in cost-effective diagnosis of malaria
require only 5 to 15 µL of blood, with results obtained in 5 to 20 in situations in which laboratory services are inadequate, in mobile
minutes.180 Depending on the combinations of target antigens used, clinics or sites lacking electricity,180 in locations where levels of malaria
certain RDTs detect only P. falciparum antigens, whereas others can transmission are low and drug resistance is high, when the cost of
distinguish P. falciparum from P. vivax, P. ovale, and P. malariae. Assays treatment exceeds the cost of the dipstick test, and when blood smears
detecting histidine-rich protein 2 (HRP-2) are specific for P. falciparum, are negative and determining the diagnosis is critical. In developed
whereas assays based on parasite LDH or HRP-2 and aldolase can identify countries, dipstick assays can benefit laboratories with less experienced
four species of Plasmodium.37,91,105 microscopists by helping them establish a rapid diagnosis, confirm a
Compared with PCR, HRP-2 assays performed well, with sensitivity diagnosis made by microscopy, or determine the infecting species. Current
of 88% to 95% and specificity of 95% to 97%; when the HRP-2 assays limitations of the tests are decreased sensitivity compared with expert
were compared with microscopy, sensitivity ranged from 80% to 95% microscopy, especially at low levels of parasite density, cost, and lack
and specificity ranged from 85% to 100%.119 The tests also performed of approval by the US Food and Drug Administration (FDA) of most
well when used in nonimmune travelers; a meta-analysis of 21 studies of the tests.
identified sensitivity of 88% to 98% and specificity of 95% to 100% Dipstick malaria tests have been proposed for use by travelers for
for detection of P. falciparum.98 The HRP-2/aldolase-based assays can self-diagnosis of malaria and have been tested for this purpose. The
detect four species of malaria, but they have a lower sensitivity for accuracy of both test performance and interpretation of results by
TABLE 220.3 Malaria Rapid Diagnostic Tests Available in the United Statesa
Malaria Antigen Malaria Species
RDT Name Target Detected Sensitivity Comment
Binax Now HRP-2 and aldolase P. falciparum, P. vivax, 94% for P. falciparum Sensitivity increased to 96% for pure P.
P. malariae, and 84% for non-P. falciparum falciparum infection
P. ovale 87% for pure P. vivax infections Overall specificity of 99%44
62% for pure P. ovale and FDA approved for use in the United States
P. malariae infections
Parasight F HRP-2 P. falciparum 96.5–100 in Kenya when >60 Antigen persists for 6–7 days 6 in 11.9–20%
parasites/µL, lower with less of subjects whose blood smears had
parasitemia11 cleared11,65
40% in travelers when <50 Not FDA approved for use in the United States
parasites/µL, >93% when
>100 parasites/ µL65
ICT Malaria HRP-2 and aldolase P. falciparum and 97% for P. falciparum Specificity of 90% for P. falciparum
Pf/Pv P. vivax 44% for P. vivax Specificity of 100% for P. vivax131
Not FDA approved for use in the United States
OptiMAL-IT LDH P. falciparum, P. vivax, 85-95%; decreased with lower Specificity of 100% P. falciparum, 75–85% for
P. malariae, and parasite density63 P. vivax
P. ovale Not FDA approved for use in the United States
Clearview LDH P. falciparum, P. vivax, 93% specificity of 100%, with Specificity of 100% for P. falciparum, 99% for
P. malariae, and sensitivities of 99%, 90.0%, P. vivax, 90% for P. malariae, and 60% for
P. ovale 86%, and 60%, respectively, P. ovale63
for P. falciparum, P. vivax, Not FDA approved for use in the United States
P. malariae, and P. ovale63
a
Direct microscopy should be performed where available with a negative RDT given higher false-negative rates with low parasitemia, and when severe malaria is suspected.
HRP-2, Histidine-rich protein-2; RDT, rapid diagnostic test.
travelers has not been demonstrated as high enough to recommend in the United States are listed in Table 220.4. Drugs used for the preven-
this strategy routinely for travelers. Most experts suggest using the test tion of malaria are discussed in a subsequent section.
to guide initial treatment while the traveler is heading to a source of The choice of agent to treat symptomatic malaria depends on the
health care for more definitive diagnosis and treatment.69,117 presence of resistance to chloroquine and other antimalarial drugs, the
availability of drugs in the local area, and the age of the patient. Local
DNA Probe and national guidelines for the treatment of malaria differ, and prac-
Specific DNA probes for identification of P. falciparum have been titioners treating patients with malaria should consult local resources
developed and tested in field conditions in Thailand.8 The technique and experts. Country-specific information on the local areas with malaria,
compared favorably with microscopy and could be used to test large the estimated risk for malaria, whether there is chloroquine-resistant
numbers of samples at a time, but it had the disadvantage of needing malaria, and which malaria species are present is available in the United
a radiolabeled probe. Nonisotope probes have been used in other field States from the CDC (www.cdc.gov/malaria/travelers/country_
trials in Madagascar, where an enzyme-linked probe was compared table/a.html) and outside the United States from local and national
with microscopy for diagnosis of falciparum malaria. Results were health organizations and the WHO (www.who.int/malaria/diagnosisand
comparable to examination of thick smears by microscopy for P. falci- treatment.html).
parum infection, but the assay could not identify infection with P. vivax, In malaria-endemic areas, strategies such as intermittent treatment
P. ovale, or P. malariae alone.101 of infants and pregnant women are being employed in combination
with use of insecticides and treated bed nets to prevent and treat
Polymerase Chain Reaction malaria.150 A full discussion of these programs is beyond the scope of
PCR-based techniques used for establishing the diagnosis of malaria this chapter.
are highly sensitive and now are able to detect mixed infections. Compared
with thick and thin smears, sensitivity and specificity are nearly 100%. Antimalarial Agents Available for Use in the United States
PCR techniques can be useful for determining the species of an infection Chloroquine
when microscopy is equivocal. Early detection of resistance to antimalarial Chloroquine is the drug of choice for chloroquine-susceptible malaria
drugs is another benefit of PCR-based techniques, which have been caused by P. falciparum and P. vivax and for all infections with P. ovale
used to detect a mutation of P. falciparum associated with resistance and P. malariae. Chloroquine is a 4-aminoquinoline with rapid schi-
to chloroquine.43,72 Currently, PCR is the only definite and validated zonticidal activity. It is not effective against exoerythrocytic forms of
means of diagnosing P. knowlesi, because this species may be confused the parasite, and patients treated with chloroquine after acquiring P.
with P. malariae on microscopy.82 vivax or P. ovale infection need to have additional treatment to eliminate
Major disadvantages of the PCR assay include the need for expensive these forms. Chloroquine is most active against late ring stages and
equipment, reagents, and significant technical expertise and the mature trophozoites. Response to treatment is rapid, with disappearance
length of time required to perform the testing. At this time, the PCR of parasitemia within 48 to 72 hours after initiation of treatment when
assay may be better suited for use in large-scale epidemiologic surveys, the parasite is susceptible.
rather than for establishing the diagnosis of acute malaria in the clinical Chloroquine is available as an oral preparation and, outside the
setting. United States, as intramuscular and intravenous formulations. Oral
absorption is excellent, and the drug is safe and effective when given
Flow Cytometry by nasogastric or orogastric tube in comatose children.177 Intramuscular
Automated blood cell analyzers based on flow cytometry have been and intravenous administration may be associated with an increased
shown to display cells containing malaria pigment as a population of risk for cardiac arrhythmias, hypotension, and circulatory failure, and
cells distinct from other blood components. To date, this discovery has its use is discouraged by experts. There is a current prolonged shortage
been serendipitous in patients not suspected to have malaria and the of chloroquine in the United States, and alternate medications for the
diagnosis must be confirmed by conventional methods.55,73 A future treatment of malaria should be pursued without delay until this shortage
application of this technology could be to modify automated blood is resolved.
cell analyzers to flag specimens that need to be examined further by Adverse reactions to chloroquine rarely occur at the doses used
thin or thick smears (or both).73 for prevention or treatment of malaria. Side effects include gastro-
intestinal symptoms such as nausea, vomiting, and diarrhea; dizziness;
Antibody Detection headache; and fatigue. Pruritus may be a troubling adverse event,
Malaria antibodies develop rapidly after infection and remain present especially in black patients. Chloroquine has no known teratogenic
for years; they are of limited value in diagnosing malaria in individual effects, and it may be used in pregnant and lactating women. The
patients. Occasionally, antibody tests might prove useful in the diagnosis drug is not contraindicated in glucose-6-phosphate dehydrogenase
of nonimmune individuals with cryptic febrile illnesses or on a popula- (G6PD)-deficient individuals. Psychotic symptoms occur rarely with
tion basis to assess the degree of community-wide immunity. Measure- chloroquine.48 Oral doses are absorbed rapidly. The lethal dose of
ment of antibody may have a role in the diagnosis of hyperreactive chloroquine is 1 g in children and 4 g in adults. Cumulative doses
malarial syndrome.183 exceeding 100 g are associated with an increased risk for development
of retinopathy. Dose reduction is required for patients with severe
renal impairment, and chloroquine should be used with caution in
TREATMENT patients with hepatic impairment, alcoholism, or concurrent use of
Treatment of malaria depends on identification of the species of hepatotoxic drugs.
Plasmodium causing infection, knowledge of the presence of resistance
to chloroquine and other drugs in the area in which malaria was Artemether-Lumefantrine
contracted, and therapeutic goals (treatment of acute illness versus Artemisinin (qinghaosu) is a sesquiterpene lactone that, along with its
eradication of the exoerythrocytic phase of malaria). Drugs and classes derivatives (artemether, artesunate, arteether, and others), has antimalarial
of drugs currently in use for treating malaria include 4-aminoquinolines activity thought to be due to the ability to cause free radical damage
and related compounds (chloroquine, mefloquine [Lariam], amodia- in parasite membrane systems.59 These compounds are unique in their
quine); primaquine; sulfadoxine-pyrimethamine (Fansidar); halofantrine; ability to cure malaria more rapidly than other agents, with rare adverse
atovaquone-proguanil (Malarone); artemisinin (qinghaosu) and other events. Significant hemolysis has been reported 13 to 15 days after
artemisinins (artemether, artesunate) and artemisinin drugs in combina- treatment with artemisinin derivatives; this has occurred most frequently
tion with other agents; cinchona alkaloids (quinine, quinidine); and after treatment of patients with high parasite loads with parenteral
the antimicrobial agents doxycycline, tetracycline, and clindamycin. artesunates.142 There is no consensus on the mechanisms through which
Investigational compounds and combination drugs are in various stages artemisinin derivatives kill malaria parasites. Lumefantrine, a dichlo-
of development. Drugs that may be used for the treatment of malaria robenzylidine derivative, also has an unclear mechanism of action. The
2170
SECTION 22 Parasitic Diseases
TABLE 220.4 Guidelines for Treatment of Malaria in the United Statesa

Clinical Diagnosis and Recommended Drug and Pediatric Doseb
Plasmodium spp. Region Infection Acquired Recommended Drug and Adult Doseb Pediatric dose should NEVER exceed adult dose
Uncomplicated malaria: Chloroquine-resistant or A. Atovaquone-proguanil (Malarone)d A. Atovaquone-proguanil (Malarone)d
P. falciparum or unknown resistancec (All Adult tab = 250 mg atovaquone/100 mg proguanil: 4 adult tabs PO Adult tab = 250 mg atovaquone/100 mg proguanil
species not identified malarious regions except those daily × 3 days Pediatric tab = 62.5 mg atovaquone/25 mg proguanil
If “species not identified” is specified as chloroquine- 5–8 kg: 2 pediatric tabs PO daily × 3 days
subsequently diagnosed as sensitive listed below.) 9–10 kg: 3 pediatric tabs PO daily × 3 days
P. vivax or P. ovale: see P. 11–20 kg: 1 adult tab PO daily × 3 days
vivax and P. ovale (below) 21–30 kg: 2 adult tabs PO daily × 3 days
for treatment with 31–40 kg: 3 adult tabs PO daily × 3 days
primaquine. >40 kg: 4 adult tabs PO daily × 3 days
B. Artemether-lumefantrine (Coartem)d
1 tablet = 20 mg artemether and 120 mg lumefantrine
A 3-day treatment schedule with a total of 6 oral doses is recommended for both adult and pediatric patients based on weight. The patient
should receive the initial dose, followed by the second dose 8 h later, then 1 dose PO twice daily for the following 2 days.
5–15 kg: 1 tablet/dose
15–25 kg: 2 tablets/dose
25–35 kg: 3 tablets/dose
≥35 kg: 4 tablets/dose
C. Quinine sulfate plus one of the following: doxycycline C. Quinine sulfatee plus one of the following: doxycycline,g
tetracycline, or clindamycin tetracycline,g or clindamycin
e
Quinine sulfate: 542 mg base (= 650 mg salt) PO 3 times a day × Quinine sulfate: 8.3 mg base/kg (= 10 mg salt/kg) PO × 3 or 7 daysf
3 or 7 daysf Doxycycline: 2.2 mg/kg PO q12h × 7 days
Doxycycline: 100 mg PO twice daily × 7 days Tetracycline: 25 mg/kg/day PO divided 4 times a day × 7 days
Tetracycline: 250 mg PO 4 times a day × 7 days Clindamycin: 20 mg base/kg/day PO divided 3 times a day × 7 days
Clindamycin: 20 mg base/kg/day PO divided 3 times a day × 7 days
D. Mefloquine (Lariam and generics)h D. Mefloquine (Lariam and generics)h
684 mg base (= 750 mg salt) PO as initial dose, followed by 456 mg 13.7 mg base/kg (= 15 mg salt/kg) PO as initial dose, followed by
base (= 500 mg salt) PO given 6–12 h after initial dose 9.1 mg base/kg (= 10 mg salt/kg) PO given 6–12 h after initial dose.
Total dose = 1250 mg salt Total dose = 25 mg salt/kg
Uncomplicated malaria: Chloroquine-sensitive (Central Chloroquine phosphate (Aralen and generics)i Chloroquine phosphate (Aralen and generics)i
P. falciparum or America west of Panama 600 mg base (= 1000 mg salt) PO immediately, followed by 300 mg 10 mg base/kg PO immediately, followed by 5 mg base/kg PO at 6,
species not identified Canal; Haiti; the Dominican base (= 500 mg salt) PO at 6, 24, and 48 h 24, and 48 h
Republic; and most of the Total dose: 1500 mg base (= 2500 mg salt) Total dose: 25 mg base/kg
Middle East) or or
Hydroxychloroquine (Plaquenil and generics) Hydroxychloroquine (Plaquenil and generics)
620 mg base (= 800 mg salt) PO immediately, followed by 310 mg 10 mg base/kg PO immediately, followed by 5 mg base/kg PO at 6,
base (= 400 mg salt) PO at 6, 24, and 48 h 24, and 48 h
Total dose: 1550 mg base (= 2000 mg salt) Total dose: 25 mg base/kg
Uncomplicated malaria: All regions Chloroquine phosphatei: treatment as above Chloroquine phosphatei: treatment as above
P. malariae or P. or or
knowlesi Hydroxychloroquine: treatment as above Hydroxychloroquine: treatment as above
Uncomplicated malaria: All regions Chloroquine phosphatei plus primaquine phosphatej Chloroquine phosphatei plus primaquine phosphatej
P. vivax or P. ovale For suspected chloroquine- Chloroquine phosphate: treatment as above Chloroquine phosphate: treatment as above
resistant P. vivax, see below. Primaquine phosphate: 30 mg base PO daily × 14 days Primaquine: 0.5 mg base/kg PO daily × 14 days
or or
Hydroxychloroquine plus primaquine phosphatej Hydroxychloroquine plus primaquine phosphatej
Hydroxychloroquine: treatment as above Hydroxychloroquine: treatment as above
Primaquine phosphate: 30 mg base PO daily × 14 days Primaquine phosphate: 0.5 mg base/kg PO daily × 14 days
Uncomplicated malaria: Chloroquine-resistantk (Papua A. Quinine sulfate plus either doxycycline or tetracycline plus A. Quinine sulfate plus either doxycyclineg or tetracyclineg
P. vivax New Guinea and Indonesia) primaquine phosphatej plus primaquine phosphatej
Quinine sulfate: treatment as above Quinine sulfate: treatment as above
Doxycycline or tetracycline: treatment as above Doxycycline or tetracycline: treatment as above
Primaquine phosphate: treatment as above Primaquine phosphate: treatment as above
B. Atovaquone-proguanil plus primaquine phosphatej B. Atovaquone-proguanil plus primaquine phosphatej
Atovaquone-proguanil: treatment as above Atovaquone-proguanil: treatment as above
C. Mefloquine plus primaquine phosphatej C. Mefloquine plus primaquine phosphatej
Mefloquine: treatment as above Mefloquine: treatment as above
Continued
CHAPTER 220 Malaria
2171
2172
TABLE 220.4 Guidelines for Treatment of Malaria in the United Statesa—cont’d

Clinical Diagnosis and Recommended Drug and Pediatric Doseb
SECTION 22 Parasitic Diseases
Plasmodium spp. Region Infection Acquired Recommended Drug and Adult Doseb Pediatric dose should NEVER exceed adult dose
Uncomplicated malaria: Chloroquine-sensitive (see Chloroquine phosphate: treatment as above Not applicable
alternatives for uncomplicated malaria sections or
pregnant womenl,m,n above for chloroquine-sensitive Hydroxychloroquine: treatment as above
species by region)
Chloroquine-resistant (see Quinine sulfate plus clindamycin Not applicable
sections above for regions with Quinine sulfate: treatment as above
chloroquine-resistant P. Clindamycin: treatment as above
falciparum and P. vivax) or
Mefloquine: treatment as above
Severe malariao,p,q All regions Quinidine gluconateo plus one of the following: doxycycline,e Quinidine gluconateo plus one of the following: doxycycline,e
tetracycline,e or clindamycin tetracycline,e or clindamycin
Quinidine gluconate: 6.25 mg base/kg (= 10 mg salt/kg) loading Quinidine gluconate: same mg/kg dosing and recommendations as
dose IV over 1–2 h, then 0.0125 mg base/kg/min (= 0.02 mg salt/ for adults.
kg/min) continuous infusion for at least 24 h. Doxycycline: treatment as above. If patient not able to take oral
An alternative regimen is 15 mg base/kg (= 24 mg salt/kg) loading medication, may give IV. For children <45 kg, give 2.2 mg/kg IV
dose IV infused over 4 h, followed by 7.5 mg base/kg (= 12 mg q12h and then switch to oral doxycycline (dose as above) as soon
salt/kg) infused over 4 h q8h, starting 8 h after the loading dose as patient can take oral medication. For children >45 kg, use same
(see package insert). Once parasite density <1% and patient can dosing as for adults. For IV use, avoid rapid administration.
take oral medication, complete treatment with oral quinine, dose Treatment course = 7 days.
as above. Quinidine/quinine course = 7 days in Southeast Asia; = Tetracycline: treatment as above
3 days in Africa or South America. Clindamycin: treatment as above. If patient not able to take oral
Doxycycline: treatment as above. If patient not able to take oral medication, give 10 mg base/kg loading dose IV followed by 5 mg
medication, give 100 mg IV q12h and then switch to oral base/kg IV q8h. Switch to oral clindamycin (oral dose as above) as
doxycycline (as above) as soon as patient can take oral medication. soon as patient can take oral medication. For IV use, avoid rapid
For IV use, avoid rapid administration. Treatment course = 7 days. administration. Treatment course = 7 days.
Tetracycline: treatment as above Investigational new drug (contact CDC for information):
Clindamycin: treatment as above. If patient not able to take oral artesunate followed by one of the following: atovaquone-
medication, give 10 mg base/kg loading dose IV followed by 5 mg proguanil (Malarone), clindamycin, or mefloquine
base/kg IV q8h. Switch to oral clindamycin (oral dose as above) as
soon as patient can take oral medication. For IV use, avoid rapid
administration. Treatment course = 7 days.
Investigational new drug (contact CDC for information):
artesunate followed by one of the following: atovaquone-
proguanil (Malarone), doxycycline (clindamycin in pregnant
women), or mefloquine
a
Based on drugs currently available for use in the United States. If outside the United States, contact national authorities about current recommendations.
CDC, Centers for Disease Control and Prevention; G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous; PO, by mouth.
b
If a person develops malaria despite taking chemoprophylaxis, that particular medicine should not be used as part of their treatment regimen. Use one of the other options instead.
c
Three options (A, B, C, or D) are available for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum. Options A, B, and C are equally recommended. Because of a higher rate of severe neuropsychiatric reactions seen at
treatment doses, we do not recommend option D (mefloquine) unless the other options cannot be used. For option C, because there are more data on the efficacy of quinine in combination with doxycycline or tetracycline, these treatment combinations
are generally preferred to quinine in combination with clindamycin.
d
Take with food or whole milk. If patient vomits within 30 minutes of taking a dose, they should repeat the dose.
e
US manufactured quinine sulfate capsule is in a 324 mg dosage; therefore 2 capsules should be sufficient for adult dosing. Pediatric dosing may be difficult due to unavailability of noncapsule forms of quinidine.
f
For infections acquired in Southeast Asia, quinine treatment should continue for 7 days. For infections acquired elsewhere, quinine treatment should continue for 3 days.
g
Doxycycline and tetracycline are not indicated for use in children age <8 years. For children age <8 years with chloroquine-resistant P. falciparum, atovaquone-proguanil and artemether-lumefantrine are recommended treatment options; mefloquine can
be considered if no other options are available. For children age <8 years with chloroquine-resistant P. vivax, mefloquine is the recommended treatment; if it is not available or is not being tolerated and if the treatment benefits outweigh the risks,
atovaquone-proguanil or artemether-lumefantrine should be used.
h
Treatment with mefloquine is not recommended in persons who have acquired infections from Southeast Asia due to drug resistance.
i
When treating chloroquine-sensitive infections, chloroquine and hydroxychloroquine are recommended options. However, regimens used to treat chloroquine-resistant infections may also be used if available, more convenient, or preferred.
j
Primaquine is used to eradicate any hypnozoite forms that may remain dormant in the liver and thus prevents relapses in P. vivax and P. ovale infections. Because primaquine can cause hemolytic anemia in G6PD-deficient persons, G6PD screening must
occur prior to starting treatment with primaquine. For persons with borderline G6PD deficiency or as an alternate to the above regimen, primaquine may be given 45 mg orally one time per week for 8 weeks; consultation with an expert in infectious
disease and/or tropical medicine is advised if this alternative regimen is considered in G6PD-deficient persons. Primaquine must not be used during pregnancy.
k
Three options (A, B, or C) are available for treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax. High treatment failure rates due to chloroquine-resistant P. vivax have been well documented in Papua New Guinea and Indonesia.
Rare case reports of chloroquine-resistant P. vivax malaria have also been documented in Myanmar (Burma), India, and Central and South America. Persons acquiring P. vivax infections outside Papua New Guinea or Indonesia should be started on
chloroquine. If the patient does not respond, the treatment should be changed to a chloroquine-resistant P. vivax regimen and CDC should be notified. For treatment of chloroquine-resistant P. vivax infections, options A, B, and C are equally
recommended.
l
For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum or chloroquine-resistant P. vivax, treatment with doxycycline or tetracycline is generally not indicated. However, doxycycline or tetracycline may
be used in combination with quinine (as recommended for nonpregnant adults) if other treatment options are not available or are not being tolerated, and if the benefit is judged to outweigh the risks.
m
Atovaquone-proguanil and artemether-lumefantrine are generally not recommended for use in pregnant women, particularly in the first trimester due to lack of sufficiency safety data. For pregnant women diagnosed with uncomplicated malaria caused
by chloroquine-resistant P. falciparum, atovaquone-proguanil or artemether-lumefantrine may be used if other treatment options are not available or are not being tolerated and if the potential benefit is judged to outweigh the potential risks.
n
For P. vivax and P. ovale infections, primaquine phosphate for radical treatment of hypnozoites should not be given during pregnancy. Pregnant patients with P. vivax and P. ovale infections should be maintained on chloroquine prophylaxis for the
duration of their pregnancy. The chemoprophylactic dose of chloroquine phosphate is 300 mg base (= 500 mg salt) orally once per week. After delivery, pregnant patients who do not have G6PD deficiency should be treated with primaquine.
o
Persons with a positive blood smear or history of recent possible exposure and no other recognized pathology who have one or more of the following clinical criteria (impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary
edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of >5%) are considered to have
manifestations of more severe disease. Severe malaria is most often caused by P. falciparum.
p
Patients diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy. Treatment with IV quinidine should be initiated as soon as possible after the diagnosis has been made. Patients with severe malaria should be
given an intravenous loading dose of quinidine unless they have received more than 40 mg/kg of quinine in the preceding 48 hours or if they have received mefloquine within the preceding 12 hours. Consultation with a cardiologist and a physician with
experience in treating malaria is advised when treating malaria patients with quinidine. During administration of quinidine, blood pressure monitoring (for hypotension) and cardiac monitoring (for widening of the QRS complex and/or lengthening of the
QTc interval) should be done continuously and blood glucose (for hypoglycemia) should be monitored periodically.
q
Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy.Modified from Centers for Disease Control and Prevention. Guidelines for Malaria Treatment in the United States. www.cdc.gov/
malaria/resources/pdf/treatmenttable.pdf.
CHAPTER 220 Malaria
2173
fixed dose combination of artemether (20 mg) and lumefantrine (120 mg) drug is needed to treat the remaining parasites. Drugs that may be used
(Coartem) is available in the United States, is FDA approved, and is with quinine include doxycycline, tetracycline, and clindamycin.
considered a first-line agent for treatment of uncomplicated falciparum Quinidine is a related drug that may be given intravenously; in
malaria in countries where it is available. Artemether-lumefantrine is countries where intravenous quinine is unavailable, it is a treatment
well tolerated and effective against multidrug-resistant falciparum option for severe malaria. The mechanisms of action and adverse events
malaria.141 A six-dose regimen compared favorably with other agents are similar, although cardiac arrhythmias occur more commonly with
in African children and adults with uncomplicated falciparum quinidine and cardiac monitoring is advised.176
malaria.108,130 Its side effect profile along with rapid parasite clearance
and high cure rate for uncomplicated falciparum malaria in African Primaquine
infants and children make this regimen favorable.42 Bioavailability of Primaquine, an 8-aminoquinoline derivative that is effective against
lumefantrine is enhanced when it is taken with food.41 exoerythrocytic hypnozoites, is used primarily to prevent relapses of
Artemether-lumefantrine is not approved for use in treatment of infections with P. vivax and P. ovale, although it may not be completely
infection with P. vivax, P. ovale, or P. malariae because there are few effective against some strains of P. vivax. Despite adequate treatment
data on its efficacy for infection with these species. There may be a role with primaquine, relapses of infections with P. vivax and P. ovale do
for the use of artemether-lumefantrine in treating chloroquine-resistant occur16; in some instances this may be due to inadequate dosing. It is
vivax malaria, because this drug combination produces rapid clearance not an effective blood schizonticide but is an active gametocidal and
of the blood stage. The short half-life of lumefantrine may, however, sporontocidal drug for the four main species of Plasmodium that cause
allow for a shorter time to relapse by dormant hypnozoites.9,182 human malaria. Primaquine can cause intravascular hemolysis in individu-
als with G6PD deficiency, and patients should be confirmed to have
Atovaquone-Proguanil normal G6PD activity before using primaquine. Other adverse events
A fixed-dose combination (available in adult and pediatric formulations) include gastrointestinal symptoms such as nausea, epigastric pain, anorexia,
of atovaquone and proguanil hydrochloride is available for treatment and abdominal cramps. Rare side effects include methemoglobinemia,
of malaria caused by P. falciparum for individuals who were not taking hemoglobinuria, and bone marrow suppression. Safety in pregnancy
this agent for prophylaxis. The combination is significantly more effective has not been established, and the drug should not be used by pregnant
than either drug alone and is effective for treatment of malaria strains women. After delivery, women with P. vivax or P. ovale infections and
resistant to other antimalarial drugs. It has fewer reported adverse events without G6PD deficiency may be treated with primaquine.
than quinine-based regimens. The combination also is likely to be active
against the blood stages of P. vivax, P. ovale, and P. malariae, but the Tetracycline and Doxycycline
regimen does not have activity against the hypnozoites of P. vivax. Tetracycline, doxycycline, and the related drug minocycline have very
Atovaquone-proguanil is significantly more effective than mefloquine, slow activity against malarial schizonts.164 Doxycycline and minocycline
chloroquine, amodiaquine, or pyrimethamine-sulfadoxine in locations may be given once daily. They are active against chloroquine-resistant
where parasites are resistant to these drugs.87 and pyrimethamine-sulfadoxine-resistant P. falciparum. Resistance to
tetracycline has not been shown. Because of their slow activity, these
Mefloquine agents should be given in combination with a rapidly acting drug such
The development of mefloquine was a major advance in the treatment as quinine. These drugs should not be used in children younger than
of chloroquine-resistant malaria, although resistance has developed 8 years old or by pregnant or nursing women.
rapidly in some parts of the world where it is used widely. Mefloquine
is a 4-quinolone-carbinolamine whose exact mechanism of action is
unknown. Its main target is early trophozoites. Similar to chloroquine, Antimalarial Agents Not Currently Available or
it is not active against exoerythrocytic phases. Mefloquine has been Recommended for Treatment of Malaria in the United States
associated with neurologic and psychiatric side effects when used for Other Artemisinin Derivatives
treatment or prophylaxis,164 and in 2013 the US FDA updated their Aside from artemether-lumefantrine, the only artemisinin derivative
warnings regarding these potentially serious side effects. Vomiting occurs available in the United States is parenteral artesunate, which is available
commonly when mefloquine is given to children younger than 5 years on an emergency basis only from the CDC. Further study of late hemolysis
old and may decrease its efficacy.159 Mefloquine should not be admin- especially after use of parenteral artesunate in high levels of parasitemia
istered concurrently with quinine, quinidine, or halofantrine due to is needed.142 Other artemisinin derivatives are available in other parts of
increased risk of developing arrhythmias. Pregnancy is not a contraindica- the world. When used alone, recrudescence rates are high, and the drug
tion to treatment in any trimester, although with the development of class has limited potential for prophylaxis. Oral preparations, suppositories,
other well-tolerated medications, mefloquine is no longer the first choice and oil-based preparations for intramuscular injection are available,
for treatment of malaria in pregnancy. although standardization of preparations is lacking.141 Combinations
including artemisinins are the preferred antimalarial agents worldwide121
Quinine and Quinidine and have shown major utility in areas of multidrug-resistant P. falciparum.1,59
Quinine has been used for the treatment of malaria for centuries.164 It In clinical trials in the Gambia, artemether was as effective as quinine and
is active against the mature asexual erythrocytic forms of all four species chloroquine for treatment of cerebral malaria in children.172,178 When used
of human malaria and against the gametes of all species except P. fal- in sequence with mefloquine, the combination was effective and tolerated
ciparum, where it has activity only against immature gametes. It is not well by patients with acute, uncomplicated falciparum malaria in Thailand,
effective against exoerythrocytic forms. It may be given orally, intrave- an area with multidrug resistance.76 Later studies showed that the use of
nously, or intramuscularly. Quinine crosses the placenta easily and may this combination may have helped halt the progressions of mefloquine
be used in the treatment of pregnant women, although close monitoring resistance in the region.116 Artemisinin-based combination treatments of
for hypoglycemia is warranted.88 falciparum malaria have been shown to be better tolerated and more
Adverse reactions to quinine include tinnitus, headache, nausea, effective than quinine and non-artemisinin combination therapies.20 The
visual and hearing disturbances, and tremors, a constellation of symptoms use of artemisinin-based combination therapies has contributed to sig-
called cinchonism. Symptoms may appear during the first 1 to 3 days nificant reductions in malaria burden in many parts of the world. There
of therapy and stop when treatment is terminated. Hypoglycemia may is, however, reduced susceptibility of P. falciparum to artemisinin derivatives
occur, particularly when the drug is used to treat pregnant women. in the Cambodia-Thailand border region, likely owing to use of the
Severe adverse events are rare but may occur idiosyncratically. Blackwater artemisinins as single-drug therapy as opposed to combination therapy,
fever (hemoglobinuria) seems to occur after treatment with quinine, leading to a WHO-led program to contain artemisinin resistance in this
but the causal mechanism is unknown. region.39 Emerging resistance to artemisinin derivatives in Southeast Asia
Recrudescence rates may be high when quinine is used alone because has been documented; longer courses of artemisinin-based combination
of the presence of quinine-resistant strains of P. falciparum, and a second therapy may be required in these areas to achieve cure.7
Pyrimethamine-Sulfadoxine its long half-life, activity against liver-stage malaria parasites, and favorable
The combination pyrimethamine-sulfadoxine, a sulfonamide plus a therapeutic and safety profile.83,110,154 As with primaquine, G6PD activity
dihydrofolate reductase inhibitor, exhibits synergy in its action against must be measured prior to its use.
malaria parasites; the combination is active even against strains resistant Adjunctive therapies that have been shown to be beneficial include
to the individual drug components. Although pyrimethamine-sulfadoxine antipyretic and anticonvulsant drugs. Exchange transfusion remains a
has been used for presumptive treatment of malaria in travelers who controversial option168,176 largely owing to the lack of sufficient random-
are taking other drugs for prophylaxis in areas where chloroquine ized controlled trials. Exchange transfusion may decrease parasite
resistance occurs, widespread resistance to the drug combination and clearance times compared with quinine alone,171 but there is a lack of
its slow action limits its use in nonimmune individuals with falciparum clear survival benefit with exchange transfusion.143 Adjunctive therapies
malaria. The CDC no longer recommends pyrimethamine-sulfadoxine that would modify or prevent the deleterious effects of inflammatory
for treatment of malaria. Although safety has not been established in mediators, oxidative stress, iron overload, acidosis, and hypercoagulability
pregnancy, the drug has been used widely and effectively for intermittent in severe and cerebral malaria have been proposed, but limited clinical
presumptive treatment of pregnant women in endemic areas to decrease studies have not shown significant benefit.71 A randomized study of
the risk for severe anemia and placental malaria.36,156,158 inhaled nitric oxide in severe malaria is ongoing.56 Some therapies, such
as high-dose corticosteroids for cerebral malaria or heparin, have been
Amodiaquine shown to be harmful.176,181 The search for effective adjunctive therapy
Amodiaquine, similar to chloroquine, is a 4-aminoquinolone. It has for severe and complicated malaria continues.
similar efficacy but may have increased activity compared with chlo-
roquine for the treatment of strains of P. falciparum resistant to
chloroquine.120 It is available in an oral preparation and is more palatable PREVENTION
than chloroquine. Significant adverse events, including agranulocytosis, Prevention of malaria can be accomplished by reducing the mosquito
hepatotoxicity, and death, when used as a prophylactic agent have limited population, using personal protection methods to prevent mosquito
its use as a first-line agent. It is not licensed or marketed in the United bites, and using chemoprophylaxis. Reduction of mosquito vectors is
States, though its use is increasing outside the United States. most successful when locally controlled programs are developed and
maintained.78 Strategies that combine personal protective measures with
Halofantrine community-based control measures, such as distribution of insecticide-
Halofantrine is a 9-phenanthrene-methanol that has been used to treat treated mosquito nets and indoor residual spraying, are most likely to
malaria caused by chloroquine-resistant P. falciparum. Its major side be successful.122 Most programs in endemic areas require a combination
effect is dose-related prolongation of the QT interval, and it has been of preventive strategies and effective treatment modalities. Many
associated with cardiac arrhythmias and sudden death, especially in nonendemic countries have developed recommendations for prevention
individuals taking mefloquine prophylaxis.115,163 Its major use was in of malaria in travelers.
uncomplicated malaria in areas of multidrug resistance, but cardiac
toxicity at the doses required to be effective and mounting resistance Personal Protective Measures
limit its widespread use.166 It is contraindicated in pregnant and lactating A significant reduction in the incidence of malaria in children in com-
women because of embryotoxic effects. Travelers who are taking munities where bed nets, especially when impregnated with insecticide,
mefloquine for prophylaxis should be cautioned against accepting are used consistently has been reported from many countries.34,49,160 In
treatment with halofantrine if they are diagnosed with malaria during northern Ghana, community-wide use of bed nets was associated with
their travels. Halofantrine is unavailable in the United States. a reduction in all-cause child mortality in young children.14 Use of bed
nets, especially those impregnated with insecticide, is recommended
Supportive Therapy for travelers to malarial areas. Other personal protective measures include
Malaria is a potentially fatal illness even in patients who may using mosquito repellents and insecticide-impregnated clothing or gear;
have developed partial immunity. Children and those without prior wearing clothing that covers areas likely to be bitten; and residing in
immunity with falciparum malaria should have immediate treatment air-conditioned or well-screened areas during times when mosquitoes
and generally should be admitted to the hospital, especially in nonen- are biting. Diethyltoluamide (DEET)-containing repellents are recom-
demic countries such as the United States. Patients with severe malaria mended most commonly for prevention of mosquito bites and are
should be managed in intensive care units, and experts in treatment of highly effective.45 Other agents, such as picaridin, oil of lemon eucalyptus,
malaria and its complications should be consulted. Blood smears should and IR3535, are available. Picaridin is available in a 20% formulation,
be examined at least every 12 to 24 hours (and every 4 to 6 hours for which may be used as an alternative to DEET.129 Other agents have not
severe malaria) until parasitemia is less than 1%. Patients with uncom- been studied extensively against Anopheles mosquitoes.
plicated malaria can be treated with oral medication, although patients
should be switched promptly to parenteral medication if oral medication Chemoprophylaxis
is not tolerated. CDC (www.cdc.gov/malaria/pdf/treatmenttable.pdf) Country-specific information regarding recommendations for the use
and WHO (www.who.int/malaria/diagnosisandtreatment.html) guidelines of antimalarial drugs may differ, and readers are urged to seek recom-
for treatment of malaria, including management of severe malaria, mendations from national or local authorities. In the United States,
are available. these recommendations are available widely in publications from the
Goals of supportive therapy are to maintain oxygenation and treat CDC134 or national health information sources. Many excellent sources
acidosis and hypoglycemia. Treatment with dextrose infusion, oxygen, of health information for travelers include discussions of malaria preven-
and blood transfusion may be necessary. Mechanical ventilation with tion.21,22,24,95,149,155,162 The Infectious Diseases Society of America has
positive-pressure ventilation may be needed to manage acidosis and acute published detailed pre-travel guidelines that include recommendations
respiratory distress syndrome. In some cases, hemodialysis may be needed. for malaria prevention.60 A list of drugs available for malaria prevention
A high index of suspicion should be maintained for other concomitant is presented in Table 220.5. Prevention of malaria for travelers is best
or nosocomial infections, such as meningitis or septicemia. discussed in the context of providing complete pre-travel services, advice,
and information.
Investigational Drugs and Adjunctive Therapy
Targets for new antimalarial drugs include malaria proteases and protein
kinases, which play a crucial role in malaria pathogenesis.38,147 These Antimalarial Agents Available in the United States for
drugs are largely in the development phase. Prevention of Malaria
A novel primaquine analogue, tafenoquine, is currently under Chloroquine and Hydroxychloroquine
investigation for use in prophylaxis and treatment of P. falciparum and A major determinant of appropriate chemoprophylaxis is whether a
P. vivax malaria in African countries. The advantages of this drug are patient is to travel to an area of chloroquine resistance. In areas of the
TABLE 220.5 Drug Regimens Used for Prevention of Malaria

Drug Adult Dosage Pediatric Dosage Comments
Chloroquine-Sensitive Areas
Chloroquine phosphate 500 mg salt (300 mg base) 8.3 mg/kg salt (5 mg/kg base) Begin 1–2 wk before exposure, continue during
(drug of choice) orally once/wk once/wk, up to adult dose of exposure, and continue for 4 wk after exposure
300 mg base May be used in pregnant women
Hydroxychloroquine 400 mg salt (310 mg base) 6.5 mg/kg salt (5 mg/kg base) Begin 1–2 wk before exposure, continue during
sulfate orally once/wk orally once/wk exposure, and continue for 4 wk after exposure
An alternative to chloroquine for use only in areas
with chloroquine-sensitive malaria
Chloroquine-Resistant Areas
Atovaquone-proguanil 250 mg/100 mg (1 tablet) 5–8 kg: 12 pediatric tablet daily Begin 1–2 days before exposure, continue during
daily 9–10 kg: 3 4 pediatric tablet daily exposure, and continue for 7 days after exposure
11-20 kg: 1 pediatric tablet daily Pediatric tablets contain 62.5 mg atovaquone and
21-30 kg: 2 pediatric tablets daily 25 mg proguanil hydrochloride
31-40 kg: 3 pediatric tablets daily See text for contraindications
>40 kg: 1 adult tablet daily
Mefloquine 250 mg salt (228 mg base) ≤9 kg: 5 mg/kg salt (4.6 mg/kg Begin 1–2 wk before exposure, continue during
orally once/wk base) orally once/wk exposure, and continue for 4 wk after exposure
10-19 kg: 14 tablet orally once/wk See text for contraindications
20-30 kg: 12 tablet orally once/wk
31–45 kg: 3 4 tablet orally once/wk
>45 kg: 1 tablet orally once/wk
Or
Doxycycline 100 mg daily 2.2 mg/kg/day up to 100 mg/day Begin 1–2 days before exposure, continue during
exposure, and for 4 wk after exposure; not to be
used in children >8 yr or pregnant women
Or
Alternative
Primaquine 52.6 mg salt (30 mg base) 0.8 mg/kg salt (0.5 mg/kg base) Begin 1–2 days before exposure, continue during
orally daily up to adult dose orally daily exposure, and continue for 7 days after exposure
Contraindicated in people with G6PD deficiency, in
pregnancy, and during lactation
Prophylaxis to areas principally with P. vivax
world that have no resistance to chloroquine, the drug of choice for have occurred when these regimens have been used.93 The choice of
prevention of malaria is chloroquine or hydroxychloroquine. This drug regimen depends on the type of drug resistance, length of stay, age of
class is tolerated well and may be given to children and adults of all the traveler, and individual medical history. Drugs currently available
ages, including infants. Dosing of chloroquine and hydroxychloroquine in the United States include mefloquine, doxycycline, atovaquone-
in children is based on the child’s weight and can be found in proguanil, and primaquine.
Table 220.4. In the United States, chloroquine is available only in tablets
that have a very bitter taste. Pharmacies can also prepare appropriate Atovaquone-Proguanil
doses in capsules, and the contents of the capsule can be mixed with a Atovaquone-proguanil is the most common choices for malaria che-
small amount of liquid or semisolid food for administration. Although moprophylaxis because of the favorable side effect profile and the need
liquid preparations are widely available overseas and are stable for long to take the medication once daily for only 1 to 2 days before and 7 days
periods,104 many US pharmacies are reluctant to prepare them. If patients after leaving the area of risk for malaria. Once-weekly dosing of
are considering purchasing liquid preparations overseas, the family atovaquone-proguanil for prophylaxis may be possible, but larger field
should be given information with the child’s medication dose calculated trials are needed before this can be recommended.35 The drug is effective
as the base and the salt because concentrations of liquid preparations against most P. falciparum, including resistant strains. It is available in
may vary. Families also should be cautioned about the greater incidence adult and pediatric dosing formulations and is administered daily.
of ineffective or counterfeit medications available in some areas. In Adverse events most commonly reported with atovaquone-proguanil
2015, the US FDA issued a drug shortage alert for chloroquine, and are abdominal pain, nausea, vomiting, and headache. Some of these
this has yet to be resolved, limiting its current use. Hydroxychloroquine adverse events can be mitigated by taking the drug with food; absorption
was recently on shortage, but the shortage has since been resolved. is also better when taken with a fatty meal. It is not recommended at
Adverse events caused by chloroquine are uncommon when the this time for prophylaxis of infants weighing less than 5 kg, for mothers
medication is used at doses needed for malaria prophylaxis. Minor side nursing such infants, or for pregnant women.
effects include gastrointestinal upset, headache, dizziness, blurred vision,
and pruritus. Adverse events rarely require discontinuation of medication. Mefloquine
Chloroquine may be taken during pregnancy and is not contraindicated Mefloquine generally is well tolerated in children and can be given to
in children with G6PD deficiency. infants. Dosing is based on weight, and no liquid preparation is available.
The choice of antimalarial agents in locations where drug-resistant Doses for older children can be supplied by breaking tablets; when
parasites have been identified is more challenging. Chloroquine- small fractions of tablets are needed, pharmacists can provide individual
containing regimens are not recommended for travel to areas with doses in capsules. The medication has a pasty consistency but does not
known chloroquine-resistant P. falciparum, and deaths from malaria taste as bitter as chloroquine. Infants tend to swallow doses better when
given liquids or semisolid foods after the medication. Adverse events 25,000 users) resulted in withdrawal of the indication for using this
with mefloquine are self-limited in most cases and include gastrointestinal drug for malaria prophylaxis.
disturbance, insomnia, and dizziness.85 Withdrawal rates in adults,
presumably caused by the incidence of these adverse events, may impair Standby Emergency Self-Treatment
the efficacy of mefloquine.31 Rarely, serious adverse events, such as Standby emergency treatment (SBET) is the self-administration of
psychosis or seizures, have occurred after prophylactic doses of meflo- antimalarial drugs when malaria is expected and prompt medical
quine, prompting an updated warning from the US FDA in 2013. This attention is unavailable within 24 hours of the onset of symptoms. The
black box warning requires that providers review an information sheet goal of SBET is to prevent death or severe malaria. This strategy is
and read the details of the warning prior to prescribing mefloquine intended for emergency use only and is considered when the risks of
and has decreased the use of mefloquine for malaria prophylaxis. toxicity from chemoprophylactic drugs outweigh the benefit of avoided
Mefloquine should not be used in individuals who have seizures or infection. SBET should not be recommended for travelers to high-risk
neuropsychiatric disorders or in individuals who have had previous P. falciparum-endemic areas, where chemoprophylaxis is the preferred
adverse events with mefloquine. Mefloquine also is contraindicated in strategy. SBET is an option for clearly defined situations, and its use
patients with cardiac conduction abnormalities, although it may be must be weighed carefully with the traveler’s ability to use SBET as
used in individuals concurrently taking β-blockers for indications other directed.124,135
than arrhythmias.
Mefloquine must be taken weekly, beginning 1 to 2 weeks before Intermittent Preventive Treatment
travel (with some experts recommending initiation up to 4 weeks before Intermittent preventive treatment in infants (IPTi) and children (IPTc)
travel) and continued for 4 weeks after leaving the malarial area. Families is a strategy entertained in sub-Saharan Africa to reduce malaria disease
may be counseled to choose a day of the week to take the medicine burden especially in children who are at higher risk of fatal disease.
and to take their first dose or doses on that day of the week 1 to 2 weeks The impact of IPTi and IPTc on the development of immunity, transmis-
before departure. Mefloquine may be used by pregnant women in any sion of malaria parasites and the development of antimalarial resistance
trimester of pregnancy.114,173 are yet to be defined in the field3 but are areas of current study.
Doxycycline Vaccine
Doxycycline is an effective antimalarial drug in parts of the world where Vaccination against malaria has been a subject of active research for
chloroquine resistance is present. It also has been shown to be effective several decades, but a licensed vaccine is not yet available. Development
in areas where mefloquine-resistant P. falciparum exists, such as portions of a vaccine is challenging because of the complexity of the parasite
of Cambodia, Myanmar (Burma), Vietnam, and Thailand. Limitations life cycle, heterogeneity of the host immune response, lack of animal
in the use of this drug include that it is contraindicated in children models, and absence of surrogate markers of protection. Testing of
younger than 8 years, need for daily dosing, and photosensitivity. In vaccines is difficult because vaccine efficacy depends on conditions of
women, daily use of doxycycline may be associated with an increased transmission and the degree of immunity present in the population
risk for Candida vulvovaginitis. Gastrointestinal side effects, including being studied.167 Targets for development of a vaccine include the
nausea and vomiting, can be limited by taking the medication with sporozoite (prevention of infection), the merozoite (prevention of disease
meals and by avoiding bedtime dosing. Doxycycline must not be used manifestations by preventing invasion of RBCs), and the gametocyte
by pregnant or lactating women. Prophylaxis with doxycycline needs (prevention of transmission by interfering with development of the
to begin 1 to 2 days before travel and should be continued daily for 4 parasite within the mosquito). Hundreds of candidate vaccine antigens
weeks after leaving the malarial area. have been identified by the P. falciparum genome project; choosing the
most promising ones is challenging.53
Primaquine The first malaria vaccines were directed against circumsporozoite
Primaquine is used most often to eradicate exoerythrocytic stages of antigen, an antigen present over most of the surface of the sporozoite.
P. vivax and P. ovale. The CDC recommends primaquine for chemo- Development of these vaccines was based on the concept that sporozoites
prophylaxis primarily in regions with predominantly vivax malaria. should be susceptible to antibody-mediated destruction in the extracel-
Individuals must be tested and shown not to be deficient in G6PD lular space. Results of early studies with these vaccines were disappointing,
before they take this drug. Efficacy of primaquine compared favorably with inadequate protection provided against sporozoite challenge,
with that of mefloquine, doxycycline, and chloroquine plus proguanil inconsistent relationships between antibody response and clinical efficacy,
in children in the holoendemic area of western Kenya.47,151,175 It cannot and numerous local side effects.58,61 More recently, the candidate vaccines
be used in pregnant women. RTS,S/AS02A and RTS,S/ASOIE have shown promise in trials in
Mozambique5 and Kenya.13 The candidate vaccine RTS,S/AS01, currently
being studied in a phase III trial in seven African countries, has shown
Antimalarial Agents Not Available or Recommended in the vaccine efficacy of 50.4% against malaria, with efficacy against severe
United States for Prevention of Malaria malaria of 45.1%.2 Recent phase II data in African children have shown
Tafenoquine that anti-circumsporozoite protein IgG avidity is similar after second
Tafenoquine is an investigational long-acting primaquine analogue that and third doses of RTS,S/ASO1 vaccines, and further study relating the
kills parasites in the liver and in blood. It is thought to be more effective IgG avidity to vaccine efficacy is needed.4 Merozoite surface proteins
and less toxic than primaquine, but it cannot be used by individuals are another group of antigens that have been studied in connection
with G6PD deficiency or by pregnant women. No dosing regimen has with the development of a blood-stage, or asexual, malaria vaccine.126
been established, and it is not licensed for use,54,153,174 but it may be The SPf66 vaccine, derived from three merozoite proteins linked to a
available in the future.62,74,153 4-amino acid from a P. falciparum circumsporozoite protein, has been
tested in clinical trials in Colombia, Tanzania, and the Gambia.6,34,170
Proguanil Although initial studies in countries in South America with low malaria
Proguanil has been used in combination with chloroquine to prevent endemicity showed promise, investigations in African countries with
chloroquine-resistant P. falciparum, but it is less effective than mefloquine high endemicity have been disappointing, with protective efficacy ranging
and is not recommended or available as a single agent in the United from 31% (95% confidence interval [CI], 0–52%) in Tanzania to 8%
States. (95% CI, 18–29%) for first or only clinical episodes and 3% (95% CI,
−24% to 24%) in overall incidence of clinical episodes in the Gambia.
Pyrimethamine-Sulfadoxine Vaccines that block transmission from humans to mosquitoes would
Pyrimethamine-sulfadoxine has been used for prevention of malaria reduce the reservoir of infected mosquitoes and reduce transmission
in areas of chloroquine-resistant P. falciparum. An unacceptably high on a population level. The poor immunogenicity and diversity of
incidence of Stevens-Johnson reactions (fatalities in one in 11,000 to gametocyte antigens have proved challenging to this approach to the
development of a vaccine, and no vaccines of this type have been used 77. Kinra P, Dutta V. Serum TNA alpha levels: a prognostic marker for assessment
yet in clinical trials. Future vaccines are likely to use a combination of severity of malaria. Trop Biomed. 2013;30(4):645-653.
approach that incorporates target antigens from all three stages of the 82. Lee KS, Cox-Singh J, Singh B. Morphological features and differential counts of
Plasmodium knowlesi parasites in naturally acquired human infections. Malar J.
parasite. To have a significant impact on decreasing worldwide burden
2009;8:73.
of malaria, vaccines ultimately may need to be combined with other 83. Lell B, Faucher JF, Missinou MA, et al. Malaria chemoprophylaxis with tafenoquine:
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Malaria: Rosemary M. Olivero - Elizabeth D. Barnett

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2156 SECTION 22 Parasitic Diseases

Rosemary M. Olivero • Elizabeth D. Barnett

Liver cell Infected

from a vertebrate host. Sporozoites, the infective stage of Plasmodium,

TABLE 220.2 Manifestations of Severe Malaria Respiratory Complications

because of fetal tachycardia and distress secondary to maternal fever;

TABLE 220.4 Guidelines for Treatment of Malaria in the United Statesa

TABLE 220.4 Guidelines for Treatment of Malaria in the United Statesa—cont’d

TABLE 220.5 Drug Regimens Used for Prevention of Malaria

30. Crawley J, Smith S, Muthinji P, et al. Electroencephalographic and clinical features

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Malaria: Rosemary M. Olivero - Elizabeth D. Barnett

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Malaria: Rosemary M. Olivero - Elizabeth D. Barnett

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2156 SECTION 22 Parasitic Diseases

Rosemary M. Olivero • Elizabeth D. Barnett

Liver cell Infected

from a vertebrate host. Sporozoites, the infective stage of Plasmodium,

TABLE 220.2 Manifestations of Severe Malaria Respiratory Complications

because of fetal tachycardia and distress secondary to maternal fever;

TABLE 220.4 Guidelines for Treatment of Malaria in the United Statesa

TABLE 220.4 Guidelines for Treatment of Malaria in the United Statesa—cont’d

TABLE 220.5 Drug Regimens Used for Prevention of Malaria

30. Crawley J, Smith S, Muthinji P, et al. Electroencephalographic and clinical features

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30. Crawley J, Smith S, Muthinji P, et al. Electroencephalographic and clinical features