TRAVEL MEDICINE

INVITED ARTICLE

Charles D. Ericsson and Robert Steffen, Section Editors

Diagnosis and Treatment of Malaria in Children

William Stauffer1,2 and Philip R. Fischer3
1
Division of Infectious Disease and International Medicine, Department of Medicine, University of Minnesota, and 2Regions Hospital/HealthPartners,
Center for International Health and International Travel Clinic, St. Paul, and 3Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester

Malaria continues to be a problem for children returning or immigrating to industrialized countries from tropical regions.
Proper diagnosis begins with clinical suspicion. In nonimmune children, malaria typically presents with high fever that
might be accompanied by chills and headache. Symptoms and signs may be more subtle in partially immune children,
and anemia and hepatosplenomegaly may also be present. Children may present with respiratory distress and/or rapidly
progressing cerebral malaria that manifests as altered sensorium and, sometimes, seizures. Thick blood smears help to
determine when infection is present, but a single smear without parasites is not sufficient to rule out malaria. Thin blood
smears aid in identifying the species of parasite. Treatment must include careful supportive care, and intensive care
measures should be available for treating children with complicated Plasmodium falciparum malaria. Medical regimens
can include mefloquine, atovaquone-proguanil, sulfadoxine-pyrimethamine, quinine or quinidine, clindamycin, doxycycline, chloroquine, and primaquine.
Malaria is a devastating infection that annually affects 1300
million people worldwide, resulting in 13000 pediatric deaths
per day [13]. In fact, malaria is the leading cause of mortality
among children !5 years of age in Africa and is the cause of
20% of all-cause mortality in this age group [1]. Despite the
availability of good preventive measures [4], 110,000 cases of
malaria were reported in US civilian travelers during 1985
2001 [5]. Furthermore, an estimated 20% of cases of malaria
imported to the United States and Europe occur in patients
!18 years of age [69]. In areas where malaria is not endemic,
medical practitioners are frequently unfamiliar with the disease,
and delays in diagnosis and treatment are common [1012].
Given the life-threatening potential of this illness, increased
awareness and knowledge of proper management is necessary.
Here, we provide a brief overview of the current approach to
the diagnosis and treatment of malaria, with special attention
to treatment of patients who, after recent travel or migration,
present with malaria in an area where malaria is not endemic.

Received 6 May 2003; accepted 9 July 2003; electronically published 17 October 2003.
Reprints or correspondence: Dr. Philip R. Fischer, Dept. of Pediatric and Adolescent Medicine,
Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (fischer.phil@mayo.edu).
Clinical Infectious Diseases 2003; 37:13408
 2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3710-0010$15.00

1340 CID 2003:37 (15 November) TRAVEL MEDICINE

MALARIA PARASITE LIFE CYCLE

AND EPIDEMIOLOGY
The 4 Plasmodium species that infect humans (Plasmodium
falciparum, vivax, ovale, and malariae) are usually transmitted
by anopheline mosquitoes. Both P. vivax and P. ovale can become dormant in the liver, forming hypnozoites that may
emerge months to years after initial infection to cause disease.
Infection caused by P. falciparum is associated with the greatest
morbidity and mortality. The clinical severity of P. falciparum
malaria is highly dependent on the malaria-specific immune
status of the infected individual.

CLINICAL PRESENTATION
It has been reported that 160% of malaria is misdiagnosed at
initial presentation in areas where malaria is not endemic [11].
Furthermore, up to 80% of malaria-related deaths in the United
States have been deemed preventable and have been attributed
to inappropriate chemoprophylaxis, delay in diagnosis, or inappropriate treatment [7]. Clinicians should routinely obtain
a relevant travel history from the caretakers of any ill child.
Malaria is, however, occasionally transmitted by mosquitoes in
areas where it is not endemic [13], as well as through blood
transfusions [14] or transplacentally [15], and the lack of his-

tory of travel to an area where malaria is endemic does not

exclude the diagnosis.

may have minimal symptoms and malaria blood smears are

frequently falsely negative. Malaria should be considered and
the diagnosis diligently pursued under these circumstances.

GENERAL PRESENTATION
Patients with P. falciparum malaria present with high fever that
may be accompanied by chills, rigors, sweats, and headache.
Other common findings include generalized weakness, backache, myalgias, vomiting, and pallor. In children, these symptoms resemble and are frequently mistaken for a viral syndrome
or acute gastroenteritis. Children who are partially immune
(e.g., newly arrived immigrants or refugees from areas where
malaria is highly endemic) frequently present with signs such
as hepatosplenomegaly, anemia, and jaundice. It is not unusual
for these patients to have very minimal symptoms, such as
anorexia or decreased activity, or even to be asymptomatic. A
recent study of Liberian children immigrating to Minnesota
found that smears of blood from 28 of 43 patients were positive
for malaria parasites. Of children with positive test results, onethird were asymptomatic, and splenomegaly was the only manifestation of disease in one-third [16].
In addition to specific tests for malaria, several other nonspecific laboratory abnormalities are common in patients with
this disease, such as elevated C-reactive protein levels, elevated
procalcitonin levels, thrombocytopenia, neutropenia, and elevated liver enzyme levels. Although it is unusual in the travel
population, the partially immune patient may have additional
laboratory abnormalities on presentation, such as anemia, hypoalbuminemia, and hematuria. Hyponatremia and hypoglycemia deserve special mention, because they are associated with
more-severe morbidity and occur more commonly in children
than in adults [17].
Although P. falciparum generally manifests days to weeks
after initial exposure, P. vivax and P. ovale, which have the
hepatic hypnozoite stage, may present much later. Patients
with P. vivax infection commonly present with paroxysmal
fevers, chills, headaches, and myalgias. In chronically infected
children, anemia and hypersplenism are common. Splenic
rupture is a serious complication in children with hypersplenism. P. malariae and P. ovale generally cause fever but not a
toxic appearance. In some individuals, P. malariae may coexist
as a commensal organism, causing infection but no clinical
disease.
Malaria frequently occurs in patients who have a history of
recent or ongoing use of a malaria chemoprophylactic agent.
This may be attributed to several factors, such as drug resistance, noncompliance with treatment, or inadequate or inappropriate administration (especially in children, because of the
difficulties in administering bitter medications). It may be very
difficult to diagnose malaria in these children, because they

COMPLICATED P. FALCIPARUM MALARIA

Many factors influence a patients risk of developing severe
malaria, particularly the species of malaria parasite and the
patients immune status, which depends on previous exposure
to malaria. As noted, P. falciparum is the most virulent of the
plasmodia. Complications of P. falciparum infection are the
result of cytokine release and of the parasites unique ability to
cause parasitized RBCs to adhere to vascular endothelium and
cause RBC sequestration, altered blood flow, and ischemia. The
patients immune status also greatly affects the manifestations
of malaria. In populations originating from areas of constant,
high-intensity malaria transmission, most mortality occurs
among younger children, as a result of severe anemia. In the
same populations, infected adults and older children may have
minimal symptoms or may be asymptomatic [18].
Conversely, in areas where malaria is less prevalent, partial
immunity may not develop, or it may develop at an older age.
In these cases, as is true for nonimmune travelers, the major
cause of mortality is cerebral malaria. Headache, confusion,
and irritability may precede cerebral malaria, but a nonimmune
childs condition can precipitously decline from normal sensorium to coma within hours [19]. Seizures are common, and
children, as opposed to adults, frequently have increased intracranial pressure [20, 21]. Other typical findings include decorticate or decerebrate posturing, nystagmus, dysconjugate
gaze, papilledema, retinal hemorrhages, and altered respiration
[20]. The findings of examination of CSF are generally unremarkable (WBC count of !20 cells/mL, slightly elevated protein
level, and normal glucose level). Imaging studies may reveal
nonspecific findings that are consistent with cerebral edema or
ischemia. Before a conclusive diagnosis of cerebral malaria can
be made, it is imperative that other causes of neurologic decline
be excluded, even when P. falciparum parasitemia has been
detected [18, 20].
Hypoglycemia, an important complication of severe malaria
in children, results from parasite-induced suppression of gluconeogenesis in the liver and induction of insulin secretion
from the pancreas. The excess secretion of insulin is intensified
by the initiation of quinine treatment and can result in devastating neurologic sequelae. Respiratory distress is another
common complication in children, but, unlike in adults, it is
rarely primarily the result of pulmonary edema or respiratory
distress syndrome and instead usually is a consequence of severe
acidosis. Black water fever (severe hemolysis, hemoglobinuria,

TRAVEL MEDICINE CID 2003:37 (15 November) 1341

and renal failure) and algid malaria (vascular collapse, shock,

and hypothermia) are rare presentations in children.

DIAGNOSIS
Diagnostic techniques. Diagnostic tests for malaria include
standard thick and thin blood smears, rapid antigen detection
tests, PCR, and antibody tests. Thick and thin blood smears
remain the most widely available and used tests, particularly
in the United States. Thick blood smears test for the presence
or absence of parasites, and thin blood smears allow speciation
and quantification. The sensitivity and specificity of blood
smears vary greatly and are influenced by many factors, such
as laboratory skill, timing and quality of smear collection, and
level of parasitemia [22, 23]. Most skilled laboratory personnel
can detect parasite levels as low as 50 parasites/mL of blood.
One set of negative thick and thin blood smears is never sufficient to exclude malaria, even when prepared by the most
skilled hands, but 3 sets of negative blood smears are generally
considered sufficient, although additional smears may be necessary in some cases.
Many rapid antigen tests are available outside the United
States. Most of these tests will differentiate between P. falciparum
and nonfalciparum infections through the detection of histidinerich proteins and/or parasite lactate dehydrogenase. These tests
have shown mixed results in multiple trials, but several seem to
compare favorably with blood smears when performed by trained
personnel under laboratory conditions [24, 25].
PCR tests are felt to be at least as sensitive and specific as
the traditional blood smear [2629] and can detect parasite
levels of 1 parasite/mL. In the United States, the use of PCR
is clinically limited, because the tests generally are only available
from specialized, government-sponsored laboratories. In addition, PCR results may continue to be positive for 11 week
after treatment because of persistence of antigen in the serum.
Currently, PCR is used mainly to confirm positive blood smears
and is valuable in identification of malaria species, particularly
when the results of smears are not definitive or there is a mixed
infection.
The detection of antibodies is not useful in the diagnosis of
acute malaria, and in the United States, such a test may only
be obtained from the US Centers for Disease Control and Prevention under special circumstances. This test is used in 2
common scenarios. First, antibody detection is used when the
patient is a newly arrived immigrant or refugee with tropical
splenomegaly (hyperactive malarial splenomegaly). Tropical
splenomegaly is a term that has traditionally been used to
describe individuals who have a large spleen, are suspected of
having chronic malaria, and have multiple blood smears that
are negative for malaria parasites. In this cohort, antibody
(IgM) levels are markedly elevated, and IgM levels and spleno1342 CID 2003:37 (15 November) TRAVEL MEDICINE

megaly decrease after presumptive antimalarial treatment. Second, antibody detection is used when the patient is a returned
traveler with a history of malaria diagnosis and treatment during recent travels and serologic confirmation is desired. It is
interesting to note that evidence suggests that travelers who
have received a diagnosis of malaria while in the tropics frequently were given an incorrect diagnosis [30].
Diagnostic approach to the patient. When evaluating a
nontoxic child with suspected malaria, the clinician must answer 2 questions. First, was the patient in an area where P.
falciparum malaria is endemic? A nontoxic-appearing child who
is exposed only to nonfalciparum malaria may receive outpatient evaluation if no other serious infection is suspected. Second, if the patient has been exposed to falciparum malaria, is
he or she partially immune? For clinical purposes, children may
be considered to be partially immune if they are 16 years of
age, have a history of malaria, and have recently resided in an
area where malaria is highly endemic. Such children generally
are new immigrants or refugees. Prompt and thorough evaluation is necessary, but outpatient evaluation and treatment
may be sufficient if caregivers are deemed to be reliable and
the child does not appear toxic. A nonimmune, febrile child
who may have been exposed to P. falciparum represents a medical emergency; an aggressive inpatient evaluation should be
performed, regardless of the childs appearance (figure 1).
A toxic-appearing child with a history of malaria exposure
should be admitted to an intensive care unit, and aggressive
diagnosis and treatment should be pursued. Appropriate laboratory work must be performed, including blood smears for
malaria parasites, and empirical parenteral antimalarial therapy
must be initiated. If no parasites are seen on initial smears,
follow-up smears should be obtained every 8 h if there is continued concern about malaria. A child who emigrates from a
holoendemic malarious area has a significant chance of having
a positive blood smear, and the presence of malaria parasitemia
does not preclude the possibility of other, coexisting illnesses.

TREATMENT
Treatment for malaria must be selected on the basis of the
infecting Plasmodium species, the severity of disease, the drug
susceptibility of the infecting parasites, and the availability of
medications and resources. The severity of illness will influence
the drug selected and the route of administration (figure 2).
Treatment of P. falciparum Malaria

P. falciparum malaria may be classified as uncomplicated or

complicated. Complicated malaria may be suspected when a
patient at risk of malaria presents with altered mental status,
respiratory distress, signs or symptoms of shock, seizures, gross
hematuria, or severe laboratory abnormalities, including aci-

Figure 1. Clinical approach to patients with suspected malaria. *A patient should be considered to be partially immune if he or she is 16 years
of age, has a history of malaria infection, and has recently (!2 years before presentation) resided in an area where malaria is highly endemic. **A
rapid test may become a useful addition to diagnosis. ICU, intensive care unit.

demia, profound anemia, signs of disseminated intravascular

coagulation, or hyperparasitemia (on the basis of the percentage
of RBCs that are infected: 12% in nonimmune children and
110% in partially immune children). Caution must be exercised, particularly in the United States, when a clinician is notified of hyperparasitemia in an apparently well-appearing

child. Although this finding may occur in partially immune

children, it is more frequently the result of a laboratory error.
Managing uncomplicated P. falciparum malaria. Oral
quinine (or quinidine, if quinidine is more readily available)
plus sulfadoxine-pyrimethamine has been suggested as the first
line of therapy for uncomplicated chloroquine-resistant P. fal-

Figure 2. Treatment approach to patients with laboratory-confirmed malaria. *In children 17 years of age. **If Plasmodium vivax is acquired in
an area of high chloroquine resistance (e.g., New Guinea), alternative therapy may be necessary. G6PD, glucose-6-dehydrogenase; ICU, intensive care
unit; ID, infectious diseases; SP, sulfadoxine-pyrimethamine.
TRAVEL MEDICINE CID 2003:37 (15 November) 1343

Table 1.

Drugs used for the treatment of malaria.

Pathogen, drug

Pediatric dosage

Chloroquine-sensitive Plasmodium falciparum

Adult dosage

First choice: chloroquine

10 mg of base/kg (maximum, 600 mg of base), then 1 g (600 mg of base), then 500 mg (300 mg of base)
5 mg of base/kg 6 h later, then 5 mg of base/kg at
6 h later, then 500 mg (300 mg of base) at 24 and
24 and 48 h
48 h

Alternative: atovaquone-proguanil

1120 kg: 250/100 mg (1 adult tablet) qd for 3 days

1 g/400 mg (4 adult tablets) qd for 3 days

2130 kg: 500/200 mg (2 adult tablets) qd for 3 days

3140 kg: 750/300 mg (3 adult tablets) qd for 3 days
140 kg: 1 g/400 mg (4 adult tablets) qd for 3 days

Chloroquine-resistant P. falciparum
First choice: atovaquone-proguanil
Common alternative: quinine sulfate
1344

Plus sulfadoxine-pyrimethamine

Same dose as for chloroquine-sensitive P. falciparum

c

25 mg/kg/day in 3 doses for 37 days

Same dose as for chloroquine-sensitive P. falciparum

650 mg q8h for 37 daysc

!1 year of age: 1/4 tablet once on last day of quinine 3 tablets at once on last day of quinine

13 years of age: 1/2 tablet

48 years of age: 1 tablet
914 years of age: 2 tablets
114 years of age: 3 tablets

Or plus clindamycin

2040 mg/kg/day in 3 doses for 5 days

900 mg t.i.d. for 5 days

Or plus doxycyclined

2 mg/kg/day for 7 days

100 mg b.i.d. for 7 days

Other alternatives
Mefloquinee

!45 kg: 15 mg/kg, then 10 mg/kg 12 h later

750 mg, then 500 mg 12 h later

Halofantrine

!40 kg: 8 mg/kg q6h for 3 doses; repeat in 1 week

500 mg q6h for 3 doses; repeat in 1 week

Artesunateg

4 mg/kg/day for 3 days

4 mg/kg/day for 3 days

Artesunate plus mefloquine

Same dosages as above

Same dosages as above

Same as for chloroquine-sensitive P. falciparum/0.3

mg of base/kg/day po for 14 days

Same as for chloroquine-sensitive P. falciparum/

15 mg of base/day (26.3 mg of salt/1 tablet) po
for 14 days

Mefloquine followed by primaquine

Same as for chloroquine-resistant P. falciparum

Same as for chloroquine-resistant P. falciparum

Quinine sulfate plus doxycycline followed by primaquine

Same as for chloroquine-resistant P. falciparum

Same as for chloroquine-resistant P. falciparum

Quinine sulfate plus sulfadoxine-pyrimethamine followed

by primaquine

Same as for chloroquine-resistant P. falciparum

Same as for chloroquine-resistant P. falciparum

Plasmodium ovale and chloroquine-sensitive Plasmodium vivax:

chloroquine followed by primaquineh
Chloroquine-resistant P. vivaxi
First choice

Plasmodium malariae: chloroquine

Same as for chloroquine-sensitive P. falciparum

Same as for chloroquine-sensitive P. falciparum

All Plasmodium species: parenteral therapy

First choice
Quinidine gluconatej,k

10 mg/kg loading dose iv (maximum, 600 mg) in nor- 10 mg/kg loading dose iv (maximum, 600 mg) in normal saline, administered slowly over the course of
mal saline, adminstered slowly over the course of
12 h, followed by continuous infusion of 0.02 mg/
12 h, followed by continuous infusion of 0.02 mg/
kg/min until oral therapy can be initiated
kg/min until oral therapy can be initiated

Quinine dihydrochlorideg,k

20 mg/kg loading dose iv in 5% dextrose, administered over the course of 4 h, followed by 10 mg/
kg administered over the course of 24 h q8h
(maximum, 1800 mg/day) until oral therapy can be
initiated

20 mg/kg loading dose iv in 5% dextrose, administered over the course of 4 h, followed by 10 mg/
kg administered over the course of 24 h q8h
(maximum, 1800 mg/day) until oral therapy can be
initiated

3.2 mg/kg im, then 1.6 mg/kg/day

3.2 mg/kg im, then 1.6 mg/kg/day

Rarely recommended

Rarely recommended

Alternatives
Artemetherl
m

Chloroquine
NOTE.
a

Adapted from Stauffer and Kamat [7], with permission.

1345

Assume that malaria parasites are sensitive to chloroquine if exposure occurred in Central America, west of the Panama Canal; Mexico; Haiti; the Dominican Republic; or the Middle East, except Yemen,
Oman, and Iran.
b
If chloroquine is not available, hydroxychloroquine sulfate is effective: 400 mg of hydroxychloroquine sulfate is equivalent to 500 mg of chloroquine phosphate.
c
In Southeast Asia, relative resistance to quinine has increased, and the treatment should be continued for 7 days.
d
Not approved for use in children !8 years of age.
e
Pediatric dose not approved by the US Food and Drug Administration. Mefloquine should not be given in combination with quinine, quinidine, or halofantrine. It should not be used in areas of reported
mefloquine resistance, such as the Thai-Myanmar and Thai-Cambodia borders. Common adverse effects include nausea, vomiting, diarrhea, and dizziness. Toxic psychosis and seizures are less common
adverse effects.
f
May be effective against multidrug-resistant P. falciparum, but treatment failures and resistance have been reported. May lengthen PR and corrected QT intervals, and cardiac arrhythmias have been
reported. Its use is not recommended when other medications known to prolong PR or corrected QT intervals are being administered or when mefloquine has been used for chemoprophylaxis. Cardiac
monitoring is suggested during dosing. Should not be taken within 1 h before and 2 h after a meal.
g
Not available in the United States.
h
Should not be used to treat patients with abnormal glucose-6-dehydrogenase levels, and status should be checked in all patients before use.
i
Chloroquine-resistant P. vivax is a significant problem in PapuaNew Guinea and Indonesia. Resistance has been reported in Myanmar, India, Irian Jaya, Thailand, the Solomon Islands, Vanuatu, Guyana,
Brazil, and Peru.
j
Continuous electrocardiographic monitoring and blood pressure and glucose monitoring are recommended.
k
Quinidine may have greater antimalarial activity then quinine. The loading dose should be decreased or omitted for patients who have received quinine or mefloquine. If 148 h of parenteral treatment
is required, the quinine dose should be reduced by one-third to one-half.
l
Not available in the United States. Also available in rectal suppository formulation.
m
Extreme caution must be exercised in administering parenteral chloroquine, because there is a very narrow therapeutic window and overdose may result in death.

Table 2.

Formulations of medications for malaria available in the United States.

Medication
CQ

Formulations

Comments

Tablets (salt/base): 250/150 mg and 500/300 mg

May pulverize tablet. The generic form is

more easily pulverized.

MQ

Tablets (salt/base): 250/228 mg

May pulverize tablet.

Atovaquone-proguanil

Tablets: 250/500 mg (adult tablet) and 62.5/

25 mg (pediatric tablet)

May pulverize tablet. Slightly less bitter in

taste than CQ and MQ. Approved for use
in patients weighing 111 kg.

Sulfadoxinepyrimethamine

Tablets: 500/25 mg

May pulverize tablet.

Clindamycin

Capsules, 75, 150, and 300 mg; oral liquid, 75

mg/5 mL; iv formulation, 150 mg/5 mL
(contains 9.45 mg/mL benzyl alcohol)

Doxycycline

Tablets, 50 and 100 mg; syrup, 50 mg/5 mL;

suspension, 25 mg/5 mL

Approved for use in children 17 years of age.

Quinidine

As gluconate (62% quinidine): slow-release

tablets, 324 mg; iv formulation, 80 mg/mL

Also available as sulfate (83% quinidine) and

polygalacturonate (80% quinidine). May
obtain iv formulation from Eli Lilly.

Primaquine

Tablet as phosphate (base): 26.3 mg (15 mg)

May pulverize tablet. Do not use in infants.

NOTE. All antimalarial drugs are very bitter in taste. To administer in oral form to a child, it is suggested that the pulverized tablet be
placed in a very sweet food item, such as chocolate syrup, sweetened condensed milk, jam, jelly, or a creme-filled cookie. CQ, chloroquine;
MQ, mefloquine.

ciparum malaria in children (tables 1 and 2) [31]. Oral quinine

plus clindamycin, or, in older children (17 years of age), quinine/quinidine plus doxycycline, is a reasonable alternative
[32]. Atovaquone-proguanil has been shown to be effective,
safe, and well tolerated as a single agent in children weighing
111 kg who have uncomplicated chloroquine-resistant P. falciparum malaria. Recently, the results of 2 clinical trials have
demonstrated that atovaquone-proguanil is also effective and
safe in children weighing 511 kg [33, 34]. When atovaquoneproguanil is available, it could now be considered the drug of
choice for uncomplicated chloroquine-resistant P. falciparum
malaria because of its relatively simple dosing, effectiveness,
tolerability, and wide therapeutic window and the lack of resistance to this drug. Although either atovaquone or proguanil
alone induces rapid resistance, it was hoped that the combination would forestall the emergence of drug resistance. Unfortunately, within a couple of years of widespread use, several
case reports of resistance have emerged [35, 36].
Other alternatives include mefloquine, lumefantrine, halofantrine, and the artemisinin compounds. Mefloquine continues to be an effective single agent, although it can cause
significant gastrointestinal and neurologic side effects. Halofantrine demands intensive monitoring of the patient, because it
is associated with potentially severe cardiac adverse effects, including prolongation of the QT interval, and it should never
be used in a patient who has recently received mefloquine,
because the combination may precipitate severe arrhythmias.
Although the artemisinin derivatives are unavailable in many
areas, they are extremely effective and inexpensive antimalarial

1346 CID 2003:37 (15 November) TRAVEL MEDICINE

drugs. However, they must be used in combination with a longacting agent to prevent recrudescence of disease.
Chloroquine-sensitive P. falciparum is now rarely encountered, except in Haiti. Chloroquine sensitivity may be assumed
and treatment considered if the patient was exposed to P. falciparum in Central America, west of the Panama Canal; Argentina; Egypt; Haiti; the Dominican Republic; and some Middle Eastern countries.
Managing complicated P. falciparum malaria. Patients
with complicated malaria need immediate parenteral antimalarial drugs and aggressive supportive therapy. Quinidine is the
parenteral antimalarial of choice in the United States, and quinine and the artemisinin compounds are available outside the
United States. A cardiac monitor should be used and frequent
blood pressure measurements should be made when the patient
is receiving quinine derivatives. These agents must be administered as a gradual intravenous infusion to avoid acute cardiovascular complications, particularly hypotension. Infusion
rates should be reduced if the QT interval is prolonged by 125%
from its baseline value. Quinidine is becoming increasingly rare
in United States hospital pharmacy formularies but may be
acquired directly from the manufacturer, Eli Lilly. If quinidine
acquisition is delayed, parenteral clindamycin may be initiated
until quinidine is available. Oral therapy is initiated as soon as
it can be tolerated by the patient. It should be noted that a
second agent (i.e., sulfadoxine-pyrimethamine or doxycycline)
must be used in conjunction with quinine, quinidine, or, especially, the artemisinin compounds, because when these agents
are used alone, excessive rates of recrudescence are seen.

Table 3. Poor prognostic criteria for patients with severe

Plasmodium falciparum malaria.
Clinical feature
Impaired level of consciousnessa
Respiratory distressa
a

Jaundice

Repeated convulsions
Shock
Laboratory feature
a

Hypoglycemia (whole-blood glucose level !40 mg/dL)

Elevated bilirubin levela (total, 12.5 mg/dL)
Acidosis (plasma bicarbonate level !15 mmol/L)
Lactic acidosis (serum lactate level 145 mg/dL)
Elevated aminotransferase levels (13 times normal)
Renal insufficiency (serum creatinine level 13 mg/dL)
a

Particularly poor prognostic factor in children (especially the combination of respiratory distress and impaired level of consciousness) [38].

Close monitoring and supportive therapy are imperative for

good outcome. Initial hypoglycemia should be treated with a
rapid infusion of 25% (for infants and small children) or 50%
dextrose. To prevent and monitor for hyperinsulinemic hypoglycemia, administration of a 5% or 10% dextrose solution
should be started when treatment with quinine derivatives is
initiated, and blood glucose levels should be tested frequently.
(Quinine-induced hypoglycemia may develop several days after
the beginning of treatment [19].) Hypovolemia and lactic acidosis must be managed with intravenous crystalloids or colloids, and vasopressors and bicarbonate occasionally are necessary. Severe anemia may necessitate blood transfusion.
Seizures may be acutely treated with benzodiazepines, and other
anticonvulsants may be administered when seizures occur repeatedly or are prolonged. Renal failure may develop; in a such
a circumstance, adjustment of drug doses is necessary.
Multiple smears with parasite quantification should be done
to monitor therapeutic success. Very high levels of parasitemia
or failure to respond to treatment may indicate primary drug
failure/resistance, and therapy should be adjusted and exchange
transfusion considered. Because of the lack of objective data,
to what extent exchange transfusion is effective and safe has
been debated, and the exact criteria for initiating therapy are
unclear. Some authorities have suggested that exchange transfusion may be beneficial for any severely ill patient with parasitemia of 115% or for any patient with parasitemia of 5%
15% who has signs of poor prognosis (table 3) [37, 38]. Clinical
trials do not demonstrate efficacy for other ancillary treatments,
including anticytokine agents, chelation agents, corticosteroids,
mannitol, dextran, heparin, and malaria hyperimmunoglobulin
[18, 19]. When managing a severe case of malaria, an experienced infectious diseases or tropical medicine specialist should

be consulted, and additional support may be obtained through

the Centers for Disease Control and Prevention malaria hotline
(770-488-7788).
Treatment of Nonfalciparum Malaria

P. vivax and P. ovale are usually susceptible to chloroquine.

Recent exceptions to this rule have been documented in P. vivax
from South America and Oceania, particularly New Guinea. In
patients for whom the likelihood of chloroquine-resistant P.
vivax is high, mefloquine or quinine/quinidine plus doxycycline
(for patients 17 years of age) may be used [28, 30]. In patients
with P. vivax or P. ovale malaria, the initial treatment regimen
should be followed by treatment with primaquine (radical
cure). Primaquine is effective against the exoerythrocytic liver
phase and is administered to prevent relapse, but occasional
relapses may still occur, despite administration of appropriate
therapy. Glucose-6-dehydrogenase levels should be measured
in all patients who receive primaquine before initiation of therapy, because severe hemolytic anemia may occur in patients
with a deficiency of this enzyme. For patients with glucose-6dehydrogenase deficiency, primaquine should not be used, and
each subsequent relapse should be treated with chloroquine or
an acceptable alternative. Primaquine should not be used to
treat newborn infants. Children who acquired malaria transplacentally or via a transfusion do not have hypnozoite forms
of malaria and need not be treated with primaquine.
P. malariae is susceptible to chloroquine, which is the drug
of choice. This parasite does not have the ability to form a
hypnozoite in the liver, and, therefore, radical cure with primaquine is not needed.
CONCLUSION
Malaria parasites continues to infect children around the world.
With appropriate attention to the possibility of malaria and
appropriate use of laboratory tests, delayed diagnosis can be
avoided. As new diagnostic and therapeutic tools and techniques become increasingly available, there is ever-greater potential for avoiding the severe morbidity and mortality associated with malaria. Ultimately, an effective and safe vaccine is
needed to prevent the tremendous suffering and premature
deaths of millions of children every year that are associated
with this disease.

References
1. World Health Organization (WHO). The global malaria situation: current tools for prevention and control. 55th World Health Assembly.
Global Fund to Fight AIDS, Tuberculosis and Malaria. WHO document
no. A55/INF.DOC./6. Available at: http://www.who.int/gb/EB_WHA/
PDF/WHA55/ea55id6.pdf. Accessed 7 July 2003.
2. Greenwood B, Mutabingwa T. Malaria in 2002. Nature 2002; 415:6702.

TRAVEL MEDICINE CID 2003:37 (15 November) 1347

3. Morrison P, Morrison P. Roll back malaria. Sci Am 2000; 282:1045.

4. Fischer PA, Bialek R. Prevention of malaria in children. Clin Infect Dis
2002; 34:4938.
5. Centers for Disease Control and Prevention. Health information for
international travel 20032004. Atlanta: US Department of Health and
Human Services, Public Health Service, 2003.
6. Holtz TH, Kachur SP, MacArthur JR, et al. Malaria surveillance
United States, 1998. MMWR Morb Mortal Wkly Rep 2001; 50(SS-05):
120.
7. Stauffer WM, Kamat D. Special challenges in the prevention and treatment of malaria in children. Curr Infect Dis Rep 2003; 5:4352.
8. Brabin BJ, Ganley Y. Imported malaria in children in the UK. Arch
Dis Child 1997; 77:7681.
9. Minodier P, Lanza-Silhol F, Piarroux R, Garnier JM, Dumon H, Unal
D. Le paludisme pediatrique dimportation a Marseille. Arch Pediatr
1999; 6:93543.
10. Svenson JE, MacLean JD, Gyorkos TW, Keystone J. Imported malaria:
clinical presentation and examination of symptomatic travelers. Arch
Intern Med 1995; 155:8618.
11. Kain KC, Harrington MA, Tennyson S, Keystone JS. Imported malaria:
prospective analysis of problems in diagnosis and management. Clin
Infect Dis 1998; 27:1429.
12. Viani RM, Bromberg K. Pediatric imported malaria in New York: delayed diagnosis. Clin Pediatr 1999; 38:3337.
13. Centers for Disease Control and Prevention. Local transmission of
Plasmodium vivax malariaVirginia 2002. JAMA 2002; 288:21134.
14. Mungai M, Tegtmeier G, Chamberland M, Parise M. Transfusiontransmitted malaria in the United States from 1963 through 1999.
N Engl J Med 2001; 344:19738.
15. Fischer PR. Malaria and newborns. J Trop Pediatr 2003; 49:1324.
16. Maroushek SR, Aguilar E. Asymptomatic malaria in Liberian children.
Pediatr Res 2002; 51:193A.
17. English MC, Waruiru C, Lightowler C, Murphy SA, Kirigha G, Marsh
K. Hyponatraemia and dehydration in severe malaria. Arch Dis Child
1996; 74:2015.
18. World Health Organization. Severe falciparum malaria. Trans R Soc
Trop Med Hyg 2000; 94(Suppl 1):S190.
19. Warrell DA. Management of severe malaria. Parassitologia 1999; 41:
28794.
20. Chandy JC, Idro RI. Parasitic diseases: cerebral malaria in children.
Infect Med 2003; 20:538.
21. Newton CR, Crawley J, Sowumni A, et al. Intracranial hypertension
in Africans with cerebral malaria. Arch Dis Child 1997; 76:21926.
22. Ohrt C, Purnomo, Sutamihardja MA, Tang D, Kain KC. Impact of
microscopy error on estimates of protective efficacy in malariaprevention trials. J Infect Dis 2002; 186:5406.
23. Coleman RE, Maneechai N, Rachaphaew N, et al. Comparison of field
and expert laboratory microscopy for active surveillance for asymp-

1348 CID 2003:37 (15 November) TRAVEL MEDICINE

24.
25.

26.

27.

28.
29.

30.

31.
32.

33.

34.

35.

36.

37.
38.

tomatic Plasmodium falciparum and Plasmodium vivax in western Thailand. Am J Trop Med Hyg 2002; 67:1414.
Moody A. Rapid diagnostic tests for malaria parasites. Clin Microbiol
Rev 2002; 15:6678.
Craig MH, Bredenkamp BL, Williams CH, et al. Field and laboratory
comparative evaluation of ten rapid malaria diagnostic tests. Trans R
Soc Trop Med Hyg 2002; 96:25865.
Zalis MG, Ferreira-da-Cruz MF, Balthazar-Guedes HC, et al. Malaria
diagnosis: standardization of a polymerase chain reaction for the detection of Plasmodium falciparum parasites in individuals with lowgrade parasitemia. Parasitol Res 1996; 82:6126.
Gaye O, Diouf M, Diallo S. A comparison of thick smears, QBC malaria, PCR and PATH falciparum malaria test in Plasmodium falciparum
diagnosis. Parasite 1999; 6:2735.
Hanscheid T, Grobusch M. How useful is PCR in the diagnosis of
malaria? Trends Parasitol 2002; 18:3958.
Morassin B, Fabre R, Berry A, Magnaval JF. One years experience with
the polymerase chain reaction as a routine method for the diagnosis
of imported malaria. Am J Trop Med Hyg 2002; 66:5038.
Schwartz E, Paul F, Pener H, et al. Malaria antibodies and mefloquine
levels among United Nations troops in Angola. J Travel Med 2001; 8:
1136.
Gilbert DN, Moellering RC, Sande MA, eds. The Sanford guide to
antimicrobial therapy. Hyde Park, VT: Antimicrobial Therapy, 2002.
Krogstad DJ. Malaria. In: Guerrant RL, Walker DH, Weller PF, eds.
Tropical infectious diseases: principles, pathogens and practice. Philadelphia: Churchill Livingstone, 1999:73666.
Looareesuwan S, Chulay JD, Canfield CJ, et al. Malarone (atovaquone
and proguanil hydrochloride): a review of its clinical development for
treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop
Med Hyg 1999; 60:53341.
Borrmann S, Faucher JF, Binder RK, Miller GB, Lell B, Kremsner PG.
Atovaquone and proguanil versus amodiaquine in the treatment of
uncomplicated Plasmodium falciparum malaria in children weighing
5 and !11 kg in Gabon [poster 813]. In: Program and abstracts of
the 50th annual meeting of the American Society of Tropical Medicine
and Hygiene (Atlanta). Northbrook, IL: American Society of Tropical
Medicine and Hygiene, 2001:432.
Fivelman QL, Butcher GA, Adagu IS, Warhurst DC, Pasvol G. Malarone
treatment failure and in vitro confirmation of resistance of Plasmodium
falciparum isolate from Lagos, Nigeria. Malar J 2002; 1:1.
Farnert A, Lindberg J, Gil P, et al. Evidence of Plasmodium falciparum
malaria resistant to atovaquone and proguanil hydrochloride: case reports. BMJ 2003; 326:6289.
White NJ. The treatment of malaria. N Engl J Med 1996; 335:8006.
Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening
malaria in African children. N Engl J Med 1995; 332:1399404.