You are on page 1of 12

Protozoan Diseases: Malaria Clinical Features, Management, and Prevention 371

(rodent burrows for P. papatasi and P. duboscqi). Antiadult Desjeux P (2004) Leishmaniasis: Current situation and new
perspectives. Comparative Immunology, Microbiology and Infectious
measures consist of insecticide spraying. Malaria control Diseases 27: 305318.
programs, based on indoor residual insecticide spraying, Garnham PCC (1965) The Leishmanias, with special reference of the
have had a side benefit for leishmaniasis incidence in role of animal reservoirs. American Zoologist 5: 141151.
Laveran A and Mesnil F (1903) Sur un protozoaire nouveau, Piroplasma
several countries where a resurgence of leishmaniasis donovani Lav. et Mesn, parasite dune fievre de lInde. Comptes
was observed after the ending of these campaigns: India, rendus de l Academie des Sciences 137: 957961.
Italy, Greece, the Middle East, and Peru. Rioux JA, Lanotte G, Serres E, et al. (1990) Taxonomy of Leishmania:
Use of isoenzymes; Suggestions for a new classification. Annales de
In practice, control programs include several integrated Parasitologie humaine et comparee 65: 111125.
measures targeted not only at the reservoir host and/or World Health Organization (1990) Control of the leishmaniases.
vector but also at associated environmental changes. Technical Report Series 793. Geneva, Switzerland: WHO.
Health education campaigns can considerably improve
the efficiency of control programs. National leishmaniasis
control programs have been developed in various countries
Further Reading
to face endemics or epidemics (India, China, and Brazil
for VL; Central Asian republics of the former USSR and
Chang KP and Bray RS (1985) Leishmaniasis. Amsterdam, the
Tunisia for CL). Netherlands: Elsevier.
In conclusion, the leishmaniases are widely distributed Dedet JP and Pratlong F (2003) Leishmaniasis. In: Cook GC and
Zumla AA (eds.) Mansons Tropical Diseases, 21st edn., pp.
and are an important public health problem in various
13391371. London: Saunders.
countries. Despite progress in understanding of most facets Farrell JP (2002) Leishmania, Vol. 4: World Class Parasites. Boston, MA:
of their epidemiology, control of leishmaniasis remains Kluwer Academic Publishers.
Killick-Kendrick R (1990) Phlebotomine vectors of the leishmaniases:
unsatisfactory. There is much still to be done.
A review. Medical and Veterinary Entomology 4: 124.
Molyneux DH and Ashford RW (1983) The Biology of Trypanosoma
See also: Land Use / Land Change and Health; Re- and Leishmania, Parasites of Man and Domestic Animals. London:
Taylor and Francis.
emerging Diseases: Overview; Skin Diseases (Non-
Murray HW, Berman JD, Davies CR, and Saravia NG (2005) Advances in
Cancerous). leishmaniasis. Lancet 366: 15611577.
Peters W and Killick-Kendrick R (1987) The Leishmaniases in Biology
and Medicine, 2 vols. London: Academic Press.


Alvar J (1994) Leishmaniasis and AIDS co-infection: The Spanish Relevant Websites
example. Parasitology Today 10: 160163.
Alvar J and Jimenez M (1994) Could infected drug users be potential
Leishmania infantum reservoirs? AIDS 8: 854. CDC, Division
Basset D, Faraut F, Marty P, et al. (2005) Visceral leishmaniasis in organ of Parasitic Diseases, Leishmania Infection.
transplant recipients: 11 new cases and review of literature. eMedicine from
Microbes and Infection 7: 13701375. WebMD, Leishmaniasis.
Desjeux P (1999) Global control and Leishmania/HIV co-infection. Vetstream, The Canine Leishmaniasis
Clinics in Dermatology 17: 317325. Website.
Desjeux P (2001) The increase in risk factors for leishmaniasis Wikipedia, Leishmaniasis.
worldwide. Transactions of the Royal Society of Tropical Medicine World Health Organization,
and Hygiene 95: 239243. Leishmaniasis: Background Information.

Protozoan Diseases: Malaria Clinical Features,

Management, and Prevention
A K Boggild and K C Kain, University of Toronto, Toronto, ONT, Canada
2008 Elsevier Inc. All rights reserved.

Clinical Features disease include infection with P. falciparum and high para-
site burden, age <2 in a P. falciparum-endemic region, and
The clinical features of malaria are largely dependent inadequate or ineffective chemoprophylaxis in nonimmune
upon host immune status, intercurrent use of antimalarial travelers to risk areas. Symptoms of P. falciparum infection
drugs, and causative organism. Risk factors for severe generally manifest within 8 weeks of exposure, while those
372 Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

caused by other species may take several months to become few days of symptom onset. Spontaneous, nontraumatic
apparent. In long-term residents of endemic areas, malaria splenic rupture has been documented in ~20 cases
infection may be completely asymptomatic. of acute malaria, though this phenomenon may be under-
reported. Rupture is most likely to occur in the context of
P. vivax infection and in nonimmune adults, as opposed
Uncomplicated Malaria
to in residents of endemic regions where gradual splenic
Malaria is the most frequent cause of systemic febrile enlargement occurs over time, following repeated episodes
illness without localizing findings among ill travelers of malaria. Increased intraabdominal pressure due to vomit-
returning from the developing world. Fever (or a history ing, rigors, or aggressive palpation on clinical exam
of fever) is present in >90% of people who present are thought to increase the risk of splenic rupture during
to medical attention with malaria following international acute malaria. In those with chronic splenomegaly second-
travel. Classic history is that of paroxysmal fevers occur- ary to multiple attacks of malaria, frank trauma is generally
ring every 2472 h, punctuated by fever-free intervals, implicated in splenic rupture. Abdominal pain with
and accompanied by chills, rigors, and sweats. These left upper quadrant tenderness, hypotension with orthosta-
paroxysms reflect the periodicity of the malarial parasite: sis, left-sided pleural effusion, and signs of intraabdominal
synchronous maturation of schizonts and lysis of parasi- hemorrhage such as periumbilical ecchymoses should
tized erythrocytes leads to synchronous liberation of alert the clinician to the possibility of splenic rupture.
pyrogenic cytokines and inflammatory mediators, hence, Acute malaria is further accompanied by defects in
the periodicity of fever. P. malariae, which causes quartan coagulation, characterized by enhanced intrinsic coagula-
malaria, has a 72-h life cycle, while P. vivax and ovale tion cascade activity and fibrinogen turnover, leading to
cause tertian malaria, with paroxysms occurring every increased concentration of fibrin degradation products.
48 h. P. falciparum, the species that causes the most severe Hypoglycemia is a common complication of acute malaria,
disease and can lead to death, is associated with more and arises in the context of reduced oral intake, increased
frequent, daily paroxysms. These patterns can vary catabolism due to fever, reduced hepatic gluconeogenesis
widely, and rarely demonstrate these classic periodici- and glycogenolysis, and parasite utilization of glucose as
ties. Factors such as host immune status and intercurrent its major energy source. Cinchona alkaloids used in the
use of antimalarial drugs can greatly influence the management of malaria can further exacerbate this hypo-
presence or absence and periodicity of fever, as well glycemia by stimulating b-islet cell insulin secretion;
as other presenting symptoms. Headache, nausea, vomit- therefore, vigilant monitoring is indicated.
ing, and mild delirium are frequent accompaniments
of febrile paroxysms. While paroxysmal fever is more
Severe and Cerebral Malaria
commonly reported with malaria, unremitting fever has
also been described. Vague symptoms such as abdominal Key events in the pathogenesis of malaria include (1)
discomfort, myalgia, and fatigue antedate the onset of fever invasion of host erythrocytes by the malarial parasite, (2)
by 12 days. In semi-immune adult residents of endemic adherence of parasitized erythrocytes to cell surface
areas, low-grade fever may be the only sign to betray molecules expressed in the vasculature of vital organs
infection; thus, a high index of suspicion is warranted in (sequestration), and (3) induction of proinflammatory
any febrile patient with risk exposure. Rash, if present, mediators in response to infection. Severe complications
should alert the clinician to an alternate diagnosis. arise due to each of these mechanisms and the hosts
In addition to fever, anemia is a hallmark of malaria immune response to them. The similarity of early-stage
infection, whether uncomplicated or complicated. Hemo- malaria to many systemic viral illnesses can lead to diag-
globin level is often normal at presentation, possibly due nostic and therapeutic delay, which enables the parasite
to hemoconcentration, but falls over time. Contributors burden to increase and the pathogenesis of severe malaria
to malarial anemia are manifold, but include de facto lysis to ensue. Severe and cerebral malaria are almost univer-
of parasitized erythrocytes, increased destruction of non- sally caused by P. falciparum, and carry mortality rates
parasitized erythrocytes, and generalized bone marrow of 1030%, even in the setting of appropriate parenteral
suppression in the acute stage of disease, due in part antimalarial drug therapy. While deaths due to the other
to reduced iron supply, and reduced marrow vascularity three species infecting humans have been reported, these
secondary to parasite sequestration. The anemia of cases are extremely rare. However, infection with P. vivax
uncomplicated disease tends to be worse in children, has been reported to cause severe manifestations such as
and in those with protracted infection. acute renal failure (ARF), severe thrombocytopenia,
Splenomegaly with thrombocytopenia (due to increased shock, acute respiratory distress syndrome (ARDS), and
splenic clearance) are robust clinical predictors of those encephalopathy, though these sequelae are much less
with acute malaria. Between 5090% of patients with likely to occur with P. vivax than with P. falciparum infec-
malaria will have nontender splenomegaly within a tion. The clinical features of severe malaria differ between
Protozoan Diseases: Malaria Clinical Features, Management, and Prevention 373

Table 1 Criteria for severe disease the latter of which can persist for weeks. Acute tubular
Criteria for severe Plasmodium falciparum malaria (WHO, 2000) necrosis secondary to glomerular filtration of hemoglobin
Asexual forms of Plasmodium falciparum on blood smear or liberated from lysed red cells is the underlying pathogene-
compatible history sis of the oliguric ARF seen in severe malaria. Blackwater
plus fever refers to the voiding of cola-colored urine in the
Any one or more of the following features:
. Impaired consciousness or unrousable coma with GCS <10
setting of significant intravascular hemolysis due to anti-
. Prostration with extreme weakness malarial drug hapten formation, and while this condition
. Severe normocytic anemia (hemoglobin <50 g/L) in and of itself creates a massive hemoglobin load for
. Acute renal failure with urine output <400 ml/24 h and serum the kidney to process, it is rarely accompanied by ARF.
creatinine >265 mmol/L Thrombocytopenia coupled with prolonged prothrombin
. Pulmonary edema or acute respiratory distress syndrome
. Hypoglycemia (plasma glucose <2.2 mmol/L)
(PT) and partial thromboplastin (PTT) at times leads to
. Shock with systolic blood pressure <80 mmHg stigmata of bleeding, including gastrointestinal hemor-
. Spontaneous bleeding/disseminated intravascular rhage. Disseminated intravascular coagulation is the most
coagulation severe on the spectrum of malaria-related coagulopathies.
. Repeated generalized convulsions (>2 within 24 h) Lactic acidosis, while less common than jaundice, ARF,
. Acidemia/acidosis (arterial pH <7.25 or plasma bicarbonates
and severe thrombocytopenia at presentation, is a major
<15 mmol/L or venous lactate >15 mmol/L)
. Macroscopic hemoglobinuria not associated with oxidant predictor of poor outcome in severe malaria. Hypovole-
drugs and red blood cell enzyme defects mia, anemia, microvascular obstruction due to sequestra-
. Jaundice detected clinically or total serum bilirubin >50 tion or parasitized erythrocytes, and cytotoxicity of
mmol/L circulating inflammatory mediators all contribute to met-
. Parasitemia of >5% in nonimmune individuals
abolic acidosis. Serum levels of lactate are occasionally
normal in the setting of metabolic acidosis, supporting
adults and children, with end-organ failure occurring that other acid metabolites play a role in the pathogenesis
more commonly in adults, and severe malarial anemia of this severe manifestation of malaria.
with cerebral involvement occurring more commonly Pulmonary edema is a feature of severe malaria that
in children. Criteria for the diagnosis of severe or compli- occurs in the absence of reduced left ventricular ejection
cated malaria are listed in Table 1. fraction, and reflects increased pulmonary vascular per-
Consistent predictors of intensive care unit mortality meability. Along with pulmonary edema, metabolic aci-
in patients with severe malaria include unrousable coma, dosis with compensatory respiratory alkalosis, and
pulmonary edema, shock, and metabolic acidosis, with malarial anemia both contribute to the development of
those patients who die having the highest day-1 parasite- ARDS, itself a harbinger of mortality. ARDS is one of the
mias, lowest Glasgow Coma Scale (GCS) scores, greatest later complications to occur in the setting of severe,
need for mechanical ventilation, lowest arterial pH, and acute malaria, usually arising on day 4 or 5 after admis-
highest serum lactate levels. Metabolic acidosis is the sion. Anticipation of this complication is prudent.
single best independent predictor of adverse outcome Cerebral malaria is typified by unrousable coma (GCS
in children and adults with severe malaria. <11 with no localizing pain response) in a patient with
asexual P. falciparum parasitemia. The cerebral malaria that
occurs in adults differs from that occurring in children.
Nonimmune adults Typical clinical manifestations of cerebral malaria
Adults traveling to P. falciparum-endemic areas, particularly in adults include: coma (which occurs several days follow-
sub-Saharan Africa, and those residing in regions where ing the onset of benign symptomatology), seizures
transmission is sporadic (Southeast Asia) are at risk of (2050%), upper motor neuron lesions (characterized
severe malaria. In addition to fever, common presenting by increased tone and hyperreflexia), decorticate or
signs include jaundice (2/3 patients), hyperparasitemia decerebrate posturing, dysconjugate gaze, and retinal
(1/2 patients), prostration (1/2 patients), ARF (1/3 patients), hemorrhages (15%). Pupillary, oculocephalic, and oculo-
and bleeding diatheses (1/6 patients). Less than 10% of adult vestibular reflexes are generally intact. Coma likely results
patients with severe malaria will present with severe acido- from a combination of vasoocclusion due to sequestion,
sis, coma, seizures, ARDS, or shock, however, those in whom metabolic acidosis, toxic cytokine milieu, and compromise
diagnosis and appropriate management are delayed are at of the bloodbrain barrier leading to increased cerebral
increased risk of developing these complications. vascular permeability. Long-term neurological sequelae
Jaundice in severe malaria arises due to dysfunction at occur in only ~5% of adults who survive cerebral malaria.
prehepatic, hepatic, and posthepatic levels. Hemolysis, hepa-
tocyte dysfunction (as evidenced by reduced clotting factor Semi-immune and nonimmune children
synthesis and gluconeogenesis), and an acalculous chole- Ninety percent of deaths due to falciparum malaria
static phenomenon all contribute to hyperbilirubinemia, occur in African children under the age of 5 years. Unlike
374 Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

in adults, severe malaria in children is more likely to where malaria transmission is low or unstable, HIV-positive
be characterized by severe anemia, hypoglycemia, and adults with malaria are two- to fivefold more likely to have
cerebral manifestations including repeated generalized a complicated or severe course. HIV has also been shown
seizures, and less likely to be accompanied by pulmonary to impair the response to antimalarial therapy, with higher
edema, jaundice, and coagulopathy. rates of treatment failure among those who are co-infected.
Severe malarial anemia refers to a hemoglobin level Malaria has been shown to upregulate HIV transcription,
<50 g/L (<5 g/dl) coupled with a parasitemia >10 000 with those who are co-infected demonstrating a two- to
parasites per cubic ml, and arises due to parasite-dependent sevenfold increase in HIV viral load during acute malaria
lysis of red blood cells, autoimmune hemolysis, and bone infection. Whether this acute rise in viremia is clinically
marrow toxicity. Up to 20% of African children under significant is debatable. However, at least one study in
5 years of age with malaria will fulfill criteria for severe Uganda has shown a significant decline in CD4 counts in
malarial anemia, and an additional 10% will fulfill criteria HIV-positive patients following episodes of malaria.
for cerebral malaria, the latter of which carries a mortality
rate of 1030%. Compared to adults with cerebral malaria,
coma is rapid in onset and resolution in children. Gen- Management
eralized seizures are both more common and frequent in
children with cerebral malaria versus adults. Children There are three cardinal questions that must be addressed
are also more likely than adults to exhibit focal cranial for optimal management of malaria:
nerve and brainstem reflex abnormalities in the context of
1. Is the infection caused by P. falciparum?
cerebral malaria. Furthermore, in children with cerebral
2. Is the malaria complicated or severe?
malaria, tone tends to be more flaccid than rigid, which is
3. Is the parasite likely to be drug-resistant?
more reminiscent of lower motor neuron disease. Retinal
hemorrhages are found in up to one-third of children with The answers to these questions will greatly influence
cerebral malaria. Children who have survived cerebral the decisions made in managing these patients.
malaria carry double the risk of long-term neurologic
sequelae of adults. Persistent neurologic abnormalities Is the infection caused by P. falciparum?
include seizure disorder, developmental delay, behavioral Species identification of the infecting organism is critical
disturbance, hemiparesis, ataxia, aphasia, blindness, and to appropriate management. P. falciparum can cause life-
tone deficits, most likely spasticity. threatening disease in nonimmune adults and children,
and should be considered a medical emergency. The
clinical descent down the slope of severe manifestations
Malaria in Pregnancy
can be rapid; therefore, prompt initiation of therapy is
Malaria in pregnancy can have catastrophic consequences essential. While the management objectives for P. vivax,
for both the mother and fetus, and is more likely to take P. malariae, and P. ovale are to cure disease and, in the
a severe or complicated course, including pulmonary case of P. vivax and P. ovale, to prevent relapse, because
edema and severe hypoglycemia, than in nonpregnant P. falciparum can cause fatal disease, its treatment objec-
women. Severe and cerebral malaria in pregnancy also tives are to cure disease and to prevent death. Thick and
carry higher mortality rates, with up to 50% of pregnant thin Giemsa-stained blood smears allow for species iden-
women with cerebral malaria dying of the disease. Reduced tification and quantification of parasitemia. Point-of-care
systemic and placental cell-mediated immunity can lead to speciation is also available through use of sensitive rapid
hyperparasitemia with concomitant severe anemia. Placen- dipstick assays, which detect P. falciparum antigens such as
tal sequestration and cytokine activation can further lead to HRP-2. While molecular assays also permit speciation,
placental insufficiency, which translates into fetal intrauter- as yet, their turnaround times are prohibitive for point-of-
ine growth restriction, and ultimate low birth weight. care diagnostics.
In holo- and hyperendemic areas of malaria transmission,
this risk of low birth weight is confined to the first preg- Is the malaria complicated or severe?
nancy, whereas in areas of low or unstable transmission, this Severe or cerebral malaria necessitates immediate admin-
risk applies to multigravid women as well. istration of combination parenteral antimalarials (Table 2)
and ongoing supportive care. Artemisinin derivatives
are the most potent antimalarials known to man, and
Malaria and HIV Co-Infection
are derived from the leaves of the Artemisia annua plant.
Current evidence supports that HIVand malaria each nega- Artemisinin combination therapy (ACT), which pairs an
tively affect the outcome and course of the other. It has been artemisinin derivative with another antimalarial drug,
suggested that HIV-related immune suppression compro- is recommended by the WHO for management of all
mises innate host malaria clearance mechanisms. In regions P. falciparum malaria, whether severe or not, in areas
Table 2 Drugs used in the management of severe malariaa

Chloroquine-sensitive Chloroquine (base) 10 mg/kg IV over 8 h, followed by 15 mg/kg IV over 24 h

Chloroquine-resistant: Quinine (base) 5.8 mg/kg loading doseb [quinine dihydrochloride (salt) 7 mg/kg] diluted in Plus one of Doxycycline 3.5 mg/kg (max 100 mg) IV or PO q

Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

With infusion pump 10 mL/kg isotonic fluid by IV infusion over 30 min, followed immediately by a maintenance the 12 h  7 days
dose of quinine (base) 8.3 mg/kg [quinine dihydrochloride (salt) 10 mg/kg] diluted in followingd
10 mL/kg of isotonic fluid by IV infusion over 4 h, repeated q 8 h for up to 72 h, or until oral
therapy is tolerated (600 mg salt tid). Complete 37 days of treatmentc
Quinidine (base) 6.2 mg/kg loading doseb [quinidine gluconate (salt) 10 mg/kg] by IV infusion Clindamycine 10 mg base/kg IV  1, followed by
over 12 h, followed immediately by a maintenance dose of quinidine (base) 0.0125 mg/kg 5 mg base/kg IV q 8 h (or 300 mg PO q
per min [quinidine gluconate (salt) 0.02 mg/kg per min] by infusion pump for up to 72 h, or 6 h)  5 days
until oral therapy is tolerated. Then, quinine tablets (600 mg salt tid) to complete 37 days
of treatmentc
Chloroquine-resistant: Quinine (base) 16.7 mg/kg loading doseb [quinine dihydrochloride (salt) 20 mg/kg] diluted in Plus one of Doxycycline 3.5 mg/kg (max 100 mg) IV or PO q
Without infusion 10 mL/kg isotonic fluid by IV infusion over 4 h, followed immediately by a maintenance the 12 h  7 days
pump dose of quinine (base) 8.3 mg/kg [quinine dihydrochloride (salt) 10 mg/kg] diluted in followingd
10 mL/kg of isotonic fluid by IV infusion over 4 h, repeated q 8 h for up to 72 h, or until oral
therapy is tolerated (600 mg salt tid). Complete 37 days of treatmentc
Quinidine (base) 15 mg/kg loading doseb [quinidine gluconate (salt) 24 mg/kg] in a volume of Clindamycine 10 mg base/kg IV  1, followed by
250 mL normal saline infused over 4 h, followed by a maintenance dose, beginning 8 h 5 mg base/kg IV q 8 h (or 300 mg PO q
after the start of the loading dose, of quinidine (base) 7.5 mg/kg [quinidine gluconate (salt) 6 h)  5 days
12 mg/kg] infused over 4 h, q 8 h for up to 72 h, or until oral therapy is tolerated. Then,
quinine tablets (600 mg salt tid) to complete 37 days of treatmentc
Recommendations for regions where ACT is unavailable. For complete ACT dosing schedules, see WHO (2006) Guidelines for the Treatment of Malaria.
TreatmentGuidelines2006.pdf (accessed November 2007).
Loading dose should not be used if patient received quinine, quinidine, or mefloquine within the preceding 1224 h. In patients requiring more than 48 h of parenteral therapy, reduce the
quinine maintenance dose by one-third to one-half.
Seven-day therapy is recommended for P. falciparum infections acquired in Southeast Asia. Three-day therapy is recommended for all other regions of acquisition (Africa, Latin America,
Doxycycline or clindamycin should be administered concurrently with or immediately after quinine, quinidine, or artemisinin derivative.
Use clindamycin over doxycycline in pregnant women and in children <8 years of age.
Reprinted with permission from Suh KN, Kain KC, and Keystone JS (2004) Malaria. Canadian Medical Association Journal 170: 16931702. 2004 Canadian Medical Association.

376 Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

where these drugs are available. However, the lack of q 24 h), neurologic status, arterial blood gas, urine out-
availability of ACT in many Western countries limits put, and parasitemia.
its use predominantly to endemic areas in Africa and Fluid therapy in the context of severe malaria remains
Southeast Asia. The choice of therapy will also therefore controversial, and must be assessed on an individual basis.
depend on location and local formularies. Table 2 sum- A balance must be struck between the risk of fluid over-
marizes the current recommendations for therapy of severe load, to which adults with severe disease are particularly
P. falciparum malaria in areas where ACT is unavailable. vulnerable, and dehydration, which will necessarily
Table 3 lists the currently recommended ACT regimens worsen concomitant renal failure. Children with severe
for P. falciparum malaria. A comprehensive discussion of malaria are more likely than adults to be volume-
ACT dosing schedules and practicalities of administra- depleted, and may respond favourably to a fluid bolus.
tion can be found in the 2006 WHO Guidelines for the The hyperventilation and respiratory distress seen in
Treatment of Malaria. Oral therapy alone, while indicated children with severe malaria is attributable to metabolic
for uncomplicated malaria (Table 4), is inadequate in acidosis and severe anemia. Blood transfusion is therefore
the setting of severe disease, or in patients who are indicated in children with hemoglobin <50 g/L (<5 g/dl)
vomiting. Adverse effects and contraindications to cur- who are from high-transmission zones. A more conserva-
rently used antimalarials are listed in Table 5. Vigilant tive threshold for transfusion of hemoglobin, <70 g/L
patient monitoring in an ICU setting is ideal, with par- (<7 g/dl), can be applied to those with severe anemia
ticular attention paid to vital signs, glycemia (accuchecks who reside in low-transmission zones or are residents of

Table 3 Artemisinin combination therapy (ACT) regimens used in the management of P. falciparum malaria

Clinical syndrome Recommended ACT regimens

Uncomplicated P. falciparum malaria First line: Artemether-lumefantrinea

Artesunatebplus amodiaquinec
Artesunatebplus mefloquined
Artesunatebplus sulfadoxine-pyrimethaminee
Alternate: Artesunateb plus one of doxycylinef or clindamycing,h
Severe P. falciparum malaria, low Artesunate 2.4 mg/kg IV on admission, at 12 h, and at 24 h, then OD to complete 7 days
transmission zone or non-endemic area of therapy
plus one of
Doxycyline 3.5 mg/kg (maximum 100 mg) IV or PO q 12 h  7 days
Clindamycinh 10 mg base/kg IV  1, followed by 5 mg base/kg IV q 8 h (or 300 mg PO q
6 h)  7 days
Severe P. falciparum malaria, high Artesunate 2.4 mg/kg IV on admission, at 12 h, and at 24 h, then OD to complete 7 days
transmission zone of therapy
Artemether 3.2 mg/kg IM on admission, then 1.6 mg/kg OD to complete 7 days of
plus one of
Doxycyline 3.5 mg/kg (maximum 100 mg) IV or PO q 12 h  7 days
Clindamycinh 10 mg base/kg IV  1, followed by 5 mg base/kg IV q 8 h (or 300 mg PO q
6 h)  7 days
Fixed-dose combination of 20 mg artemether 120 mg lumefantrine. Standard adult dose is 6 tabs bid  3 days. Weight-based
pediatric guidelines available in WHO (2006) Guidelines for the Treatment of Malaria.
Guidelines2006.pdf (accessed November 2007).
Artesunate available in 50 or 200 mg tablets; standard adult and pediatric dosage 4 mg/kg OD  3 days (maximum standard daily dose
200 mg). When used in combination with doxycycline or clindamycin, recommended duration is 7 days.
Amodiaquine available in 153 mg base tablets; standard adult and pediatric dosage 10 mg base/kg OD  3 days (maximum standard
daily dose 612 mg).
Mefloquine available in 250 mg base tablets; standard adult and pediatric dosage 25 mg base/kg divided over 23 days (maximum
standard dose 1000 mg day 2, 500 mg day 3).
Fixed-dose combination of 500 mg sulfadoxine 25 mg pyrimethamine. Standard adult and pediatric dosage 25/1.25 mg/kg  1 on
day 1 (maximum standard dose 1500/75 mg (3 tabs)  1).
Doxycycline available in 100 mg tablets; standard adult and pediatric (age >8 years) dosage 23.5 mg/kg OD or divided bid  7 days
(maximum standard daily dose 200 mg divided OD or bid).
Protozoan Diseases: Malaria Clinical Features, Management, and Prevention 377

Table 4 Drugs used in the management of uncomplicated malaria

organism Drug Adult dose Pediatric dose

P. falciparuma
Chloroquine- Chloroquine (base) 600 mg initially, then 10 mg/kg initially, followed by 10 mg/kg at 24 h, then
sensitive 600 mg at 24 h, then 5 mg/kg at 48 h (total dose 25 mg/kg to max of 1.5 g
300 mg at 48 h over 3 days)
Chloroquine- or Atovaquone- 4 tabs OD  3 days 58 kg: 2 pedc tabs OD  3 days
mefloquine- proguanilb 910 kg: 3 ped tabs OD  3 days
resistant 1120 kg: 1 tab OD  3 days
2130 kg: 2 tabs OD  3 days
3140 kg: 3 tabs OD  3 days
OR >40 kg: 4 tabs OD  3 days
Quinine sulfate (base) 500 mg tid  37 daysd 7.5 mg/kg (max 500 mg) tid  37 daysd
PLUS one of
or 100 mg bid  7 days 8 years: 1.52 mg/kg (max 100 mg) bid  7 days
clindamycin (base) 300 mg qid  5 days 5 mg/kg (max 300 mg) tid  5 days
P. vivax
Chloroquine- and Chloroquine (base) As above As above
primaquine- plus
sensitive primaquine (base) 30 mg OD  14 days 0.5 mg/kg (max 30 mg) OD  14 days
Chloroquine- Atovaquone-proguanil As above As above
resistant plus
primaquine As above As above
Primaquine- Chloroquine (base) As above As above
resistant plus
primaquine As above As above
P. malariae Chloroquine (base) As above As above
P. ovale Chloroquine (base) As above As above
primaquine 15 mg OD  14 days 0.3 mg/kg (max 15 mg) OD  14 days
Recommendations for regions where ACT is unavailable. For complete ACT dosing schedules, see WHO (2006) Guidelines for the
Treatment of Malaria. (accessed November 2007).
Fixed-dose combination contains 250 mg atovaquone 100 mg proguanil.
Pediatric tablets contain 62.5 mg atovaquone 25 mg proguanil.

the developed world who have returned from travel to an Hyperparasitemia is a major risk factor for death
endemic area. from severe malaria. Parasitemia should therefore be fol-
Acute pulmonary edema should be managed as per lowed every 612 h over the first 2448 h of therapy. In
standard of care with supplemental oxygen, positive pres- addition to parenteral antimalarials, exchange transfusion
sure ventilation if available and the patient is hypoxic, and or aphoresis has been touted as an effective way to reduce
therapeutic maneuvers that reduce preload on the heart, parasite burden, though evidence to support this maneu-
including diuresis, venodilation, hemofiltration, and dial- ver is scant and it thus remains controversial. Its use
ysis. In patients with significant coagulopathy, vitamin should probably be limited to situations in which progno-
K and fresh frozen plasma can be given. Correction of sis is grave, parasitemia is >30%, or parasitemia is >10%
hypovolemia and anemia are key to ameliorating meta- with accompanying evidence of end-organ dysfunction
bolic acidosis. To date, no other intervention has proven including cerebral, pulmonary, or renal manifestations.
valuable. The continued high rate of mortality in severe and
Seizures are a common complication of cerebral cerebral malaria has led to the investigation of a number
malaria, especially in children. Administration of intrave- of adjuvant therapies for P. falciparum malaria including
nous benzodiazepines is the mainstay of treatment of corticosteroids, monoclonal antibodies to TNFa, TNFa
seizures due to cerebral malaria. The WHO currently inhibitors, heparin, prostacyclin, and desferroxamine.
recommends against use of phenobarbital in children None of these adjuvant therapies has proven efficacious
with malarial seizures, due to its association with in clinical trials, and therefore none is recommended.
increased mortality (WHO, 2006). Preemptive adminis- In cases of severe malaria, where presentation is that of
tration of antiseizure medication is not recommended. a systemic febrile illness with evidence of multisystem
378 Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

Table 5 Mechanism of action, adverse effects, and contraindications to antimalarial drugs

Parasite life-cycle
Drug Mechanism of action target Adverse effectsa Contraindications

Amodiaquine 4-aminoquinoline, which Blood Agranulocytosis; hepatitis Caution in liver disease

interferes with heme Schizonticide or heavy alcohol use
Artemisinin Sesquiterpene lactones, which Blood Type I hypersensitivity in First trimester
derivatives inhibit calcium adenosine Schizonticide 1/3000; ECG abnormalities pregnancy
triphosphatase (PfATPase 6) Gametocytocidal
Atovaquone- Hydroxynaphtho-quinone, which Blood and tissue Well-tolerated; cough Pregnancy
proguanil inhibits parasite cytochrome Schizonticide
oxidase (atovaquone); Gametocytocidal
Biguanide, which is
metabolized to active
cycloguanide by CYP 450
2C19 and inhibits plasmodial
DHFR (proguanil)
Chloroquine 4-aminoquinoline, which Blood Unpleasant taste; pruritus; Seizure disorder;
interferes with parasite heme Schizonticide keratopathy/retinopathy psoriasis
detoxification with prolonged use
Clindamycin Lincosamide antibiotic, which Blood Diarrhea (20%); Caution in those with
inhibits protein synthesis via Schizonticide pseudomembranous colitis; history of C. difficile
the 50S ribosome hypersensitivity reaction in disease and
10% (rash, urticaria) pseudomembranous
Doxycyline Tetracycline derivative, which Blood Photosensitivity; erosive Pregnancy and
binds to 30S ribosomal subunit Schizonticide esophagitis lactation; children
and inhibits protein synthesis under the age of 8
Mefloquine 4-methanolquinoline, which is Blood Neuropsychiatric effects such Psychiatric disorder;
related to quinine Schizonticide as seizure and psychosis in seizure disorder;
1/1001/2000 at treatment electrical conduction
doses delays
Primaquine 8-aminoquinoline, which Tissue Abdominal pain G6PD deficiency;
possibly induces Schizonticide pregnancy
mitochondrial dysfunction Gametocytocidal
Quinidine Cinchona alkaloid, which inhibits Blood QT-interval prolongation; Prolonged QT interval;
parasite heme detoxification Schizonticide cardiac arrhythmias; AV conduction delay;
cinchonism (tinnitus, myasthenia gravis
high-tone deafness,
headache, nausea,
Quinine Cinchona alkaloid, which inhibits Blood Hyperinsulinemic G6PD deficiency;
parasite heme detoxification Schizonticide hypoglycemia; reversible tinnitus or optic
Gametocytocidal cinchonism neuritis; myasthenia
for P. vivax, gravis;
P. ovale, and thromobocytopenic
P. malariae purpura
All antimalarial agents are associated with gastrointestinal side effects such as nausea, vomiting, and diarrhea.

involvement, the concurrent use of parenteral broad- hypoglycemia, administration of antimalarial therapy
spectrum antibiotics should be liberal. Intercurrent bacte- must not be delayed. Prompt initiation of parenteral ther-
rial infection is common, particularly in children, and apy is indicated in pregnant women with severe malaria.
may be overshadowed by the diagnosis of malaria. Thus, In later stages of pregnancy, artesunate may be preferred
this entity must be anticipated, especially in the setting of over quinine due to the latters association with recurrent
unexplained deterioration despite effective antimalarial hypoglycemia.
and supportive therapy. Pharmacotherapy of uncomplicated malaria is sum-
Because P. falciparum infection in pregnancy is marized in Table 4. Unless a patient cannot tolerate oral
associated with low birth weight, adverse fetal out- medication due to vomiting or is believed to have poor
come, severe maternal anemia, and increased risk of gastrointestinal absorption, therapy of uncomplicated
severe sequelae, particularly pulmonary edema and malaria should be via the oral route. Outside of Africa,
Protozoan Diseases: Malaria Clinical Features, Management, and Prevention 379

P. vivax is the predominant species causing disease. P. vivax Table 6 Global distribution of drug-resistant malaria
and P. ovale have a persistent liver phase that is responsible
Chloroquine- Multi-drug
for clinical relapses. In order to reduce the risk of relapse resistant resistant Chloroquine-
following the treatment of symptomatic P. vivax or P. ovale P. falciparum P. falciparum resistant P. vivax
infection, primaquine may be indicated to provide
Chloroquine- Multi-drug- Chloroquine-
radical cure. Primaquine use is contraindicated in preg- resistant P. resistant resistant P. vivax
nancy; therefore, P. vivax and P. ovale infections occurring falciparum is (chloroquine, is found in
during pregnancy should be treated with standard doses found in ALL sulfadoxine- Papua New
of chloroquine. Relapses can then be prevented by malarious areas pyrimethamine, Guinea, Irian
weekly chemosuppression with chloroquine until after EXCEPT in the mefloquine) Jaya, Indonesia,
Americas north P. falciparum Myanmar, the
delivery. Because of primaquines oxidant hemolytic of the Panama is found in Solomon
potential, patients should undergo testing for glucose-6- Canal (Mexico, Southeast Asia Islands, and in
phosphate dehydrogenase deficiency prior to initiation of Hispaniola, along the Thai countries of
primaquine therapy. other Central borders of South America
American Myanmar including
countries) and (Burma) and Colombia,
Is the parasite likely to be drug-resistant? parts of the Cambodia, in Brazil, Guyana,
In most areas of the world where malaria is transmitted, it Middle East Burma, Vietnam, and Peru
is caused by drug-resistant parasites (Table 6). Antima- and in parts of
larial resistance has been described in all species of Plas- the Amazon
modium infecting humans, except P. ovale. P. falciparum basin
resistance to most antimalarials, with the exception of
artemisinin derivatives, has been documented. However,
in only a few of these drugs can genetic markers of Table 7 Genetic markers of resistance in selected
resistance be identified (Table 7). Chloroquine resistance
in P. falciparum is widespread, with efficacy confined to Antimalarial
P. falciparum-endemic areas north of the Panama Canal in drug Genetic marker of resistance
Central America and the Caribbean. Mefloquine and
Atovaquone Point mutation at position 268 of cyt b gene
multidrug resistance in P. falciparum is, for the most part, Chloroquine Mutations in transporters (PfCRT, PfMDR1),
confined to the ThaiBurmese and ThaiCambodian which decrease the concentration of
borders, along with parts of Vietnam and eastern Burma. chloroquine at its site of action
P. falciparum resistance to quinine monotherapy has been Mefloquine Amplification of Pfmdr gene
Proguanil Triple codon mutation of dhfr gene
reported in Southeast Asia, but is of little consequence when
Pyrimethamine Mutation in dhfr gene
quinine is used as a component of combination therapy. Sulfadoxine Mutation in Pfdhps gene
Chloroquine resistance in P. vivax is mainly found in
Papua New Guinea and Papua (Irian Jaya), along with
other countries of Oceania such as Indonesia, East Timor,
and the Solomon Islands. There have also been isolated
reports of chloroquine-resistant P. vivax from the Amazo- Prevention in Travelers
nian regions of Peru, Brazil, and Guyana. Chloroquine
Malaria is a preventable disease in travelers. A general
remains an effective antimalarial for most P. vivax
approach to the prevention of malaria in travelers involves
acquired in Southeast Asia (other than in Thailand, Korea,
an assessment of individual risk, a discussion of mosquito
and Myanmar), subcontinental India, the Middle East, and
bite avoidance measures, and the prescription of chemo-
Latin America. Only recently has chloroquine resistance in
prophylactic agents where appropriate.
P. malariae from Indonesia been described (Maguire et al.,
2002). To date, P. ovale remains fully sensitive to the existing
Assessment of individual risk
antimalarial pharmacologic armamentarium.
Many factors contribute to an individuals risk of acquir-
Treatment is considered to have failed if fever and
ing malaria when traveling and include, but are not
parasitemia fail to resolve or recur within 1428 days
limited to:
of treatment initiation. These failures may arise due to
drug-resistant organisms, malabsorption of the drug . Geographic destination;
(vomiting or diarrhea), or poor adherence. A full course . Type of travel (urban vs. rural);
of retreatment with an alternate regimen is indicated in . Type of accommodations (tents vs. screened rooms);
these cases. If fever and parasitemia recur >2 weeks post- . Itinerary during travel (trekking, altitude, river or jun-
treatment, this likely reflects recrudescence, or reinfec- gle exposure);
tion in an endemic zone. . Season of travel (wet vs. dry);
380 Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

. Duration of travel (short-term vs. long-term); Table 8 Recommended antimalarial agents for
. Likelihood of compliance with preventive measures. chemoprohylaxis

All travelers to malarious areas should receive specific Recommended chemoprophylactic

Region of travel agent
pretravel counseling from a qualified professional who
can provide an educated assessment of the individual Chloroquine-sensitive First line: Chloroquine
travelers risk of acquiring malaria abroad, and who can Second line: Mefloquine, doxycycline,
address the following two pillars of malaria prevention.
Chloroquine-resistant First line: Atovaquone-proguanil,
mefloquine, doxycycline
Mosquito bite avoidance Chloroquine- and First line: Atovaquone-proguanil
Use of personal protective measures and behaviors to mefloquine-resistant
Second line: Doxycycline
reduce the likelihood of being bitten by a female anophe-
line mosquito is key to the prevention of malaria. These
measures and behaviors include, but are not limited to: Tables 8 and 9 summarize the antimalarials that are
. Avoidance of outdoor activity after dusk (Anopheles currently recommended for chemoprophylaxis in trave-
mosquitos bite from dusk from dawn); lers to malarious regions. It is important to emphasize to
. Use of long-sleeved shirts and long pants when expo- the traveler that all chemoprophylactic regimens must be
sure is likely; started prior to arrival in the risk area, taken throughout
. Use of N,N-diethyl-3-methylbenzamide (DEET)- travel in the risk area, and continued for one to four
based mosquite repellants; weeks post-travel, depending on the regimen. Drugs
. Use of permethrin- or other insecticide-impregnated such as atovaquone-proguanil that work by preventing
bed net. the preerythrocytic development of the parasite (causal
prophylaxis) need only be taken one week post-travel.
Aerosol, pump, and gel-based formulations containing Conversely, drugs such as mefloquine, chloroquine, and
2050% DEET can be used safely and efficaciously in doxycycline that work by suppressing blood stage infec-
adults and children over 2 months of age. Picardin is tion need to be taken for a full four weeks post-travel.
another commonly used repellant that is safe and effective In travelers who will not have timely access to medical
in both adults and children, and tends to cause less skin care, standby therapy (self-treatment) can be life-saving.
irritation than DEET. Insecticide-impregnated bed nets Self-treatment may also be an appropriate option for
can be used safely by both pregnant women and children. those in whom the chemoprophylactic regimen is subop-
Permethrin is also available in liquid or spray formula- timal due to underlying medical condition. Options for
tions for impregnation of clothing. standby therapy include atovaquone-proguanil, chloro-
quine (in a chloroquine-sensitive region), or quinine
Chemoprophylactic agents plus doxycycline. Dosing is as outlined in Table 4. It
Following a detailed assessment of individual risk of should be emphasized to travelers that self-treatment in
malaria and counseling around personal protective mea- no way obviates the need for timely medical attention, nor
sures for bite avoidance, the pretravel encounter can be should it be perceived as an alternative to prophylaxis. In
directed toward a needs assessment for chemoprophy- addition, travelers should be discouraged from purchasing
laxis. In order to prescribe an appropriate agent, the travel self-treatment regimens overseas or from switching their
medicine practitioner will want to determine: prophylactic regimen while abroad.
Prevention of malaria in the pregnant traveler presents
. If the traveler will be exposed to malaria;
a challenge due to widespread chloroquine resistance in
. Which species of Plasmodium predominates in his or her
P. falciparum, and the lack of chemoprophylactic agents
region of travel;
that can be used safely in all trimesters. Chloroquine can
. If there is likely to be drug-resistant P. falciparum at his
be safely used during all trimesters of pregnancy, and is
or her destination;
appropriate for prophylaxis against chloroquine-sensitive
. Whether or not the traveler is likely to adhere to the
P. falciparum. The decision to travel to an area with high
prescribed regimen;
transmission of chloroquine-resistant P. falciparum while
. If there are any contraindications to the prescribed
pregnant should not be taken lightly. P. falciparum malaria
regimen such as pregnancy or likelihood of pregnancy;
can have grave consequences for mother, fetus, and neo-
. Whether or not the traveler will have ready access to
nate. If transmission is thought to be high and likelihood
medical attention during travel.
of exposure will be great, and travel cannot be deferred,
A detailed past medical history is important to gather then mefloquine prophylaxis is a reasonable option.
in order to determine if there are contraindications to a While there is mounting evidence that atovaquone-
particular class of antimalarials. proguanil is likely to be safe in pregnancy, insufficient
Protozoan Diseases: Malaria Clinical Features, Management, and Prevention 381

Table 9 Dosing schedule for antimalarial chemoprophylactic agents

Drug Adult dose Pediatric dose Duration

Atovaquone- 1 adult tab PO OD 58 kg: 1=2 ped tab OD

Start 1 day before exposure, continue during exposure, and
proguanil 910 kg: 3=4 ped tab OD complete 7 days following exposure
1120 kg: 1 ped tab OD
2130 kg: 2 ped tab OD
3140 kg: 3 ped tab OD
>40 kg: 1 adult tab OD
Chloroquine 300 mg PO q 5 mg/kg (max 300 mg) Start 1 week before exposure, continue during exposure, and
(base) weekly PO q weekly complete 4 weeks following exposure
Doxycycline 100 mg PO OD <8 yr: not recommended
8 yr: 1.5 mg/kg (max Start 1 day before exposure, continue during exposure, and
100 mg) PO OD complete 4 weeks following exposure
Mefloquine 250 mg PO q <5 kg: 5 mg/kg q week Start 13 weeks before exposure, continue during exposure,
(base) weekly 59 kg: 1=8 tab q week and complete 4 weeks following exposure
1019 kg: 1=4 tab q week
2029 kg: 1=2 tab q week
3045 kg: 3=4 tab q week
>45 kg: 1 tab q week

data are available to recommend its use as a prophylactic hampered the development of successful candidate vac-
agent in pregnancy. Doxycycline and primaquine are cines, as immunity to one life cycle stage (e.g., liver stage)
contraindicated in pregnancy. confers no protection to other stages (e.g., blood stages).
Natural immunity to P. falciparum is highly strain-specific
and ephemeral, and requires multiple episodes of infection
Prevention in Residents of Endemic Areas (boosting) to maintain both humoral and cell-mediated
immunity. That P. falciparum expresses approximately
Due to the prohibitive costs and infrastructural require-
5300 antigens further hinders vaccine development, as it
ments of mass prophylaxis campaigns, insecticide-treated
is currently unknown which of these antigens are key
bed nets and targeted chemoprophylaxis remain the
players in the genesis of immunity.
mainstays of malaria prevention in endemic areas. Chil-
One preerythrocytic stage vaccine, RTS,S/AS02, has
dren less than 5 years of age and pregnant women are
shown promise in early clinical trials. This vaccine was
candidates for intermittent preventive therapy (IPT)
designed to target the malarial circumsporozoite protein,
or continuous chemoprophylaxis. IPT consists of twice
and the vaccine antigen is comprised of a fusion pro-
or thrice pre-emptive therapy during the course of
tein (RTS) expressed in yeast, which binds to hepatitis
pregnancy (or infancy) with an agent such as chloroquine
B surface antigen (S) to form RTS,S. When mixed with an
or chloroquine-proguanil. This strategy in pregnancy
adjuvant, AS02, and given intramuscularly to volunteer
reduces the risk of severe malarial anemia, low birth weight,
vaccinees, RTS,S induces a high-titer antibody response
and severe disease in pregnant women, though these
to both circumsporozoite protein and hepatitis B surface
benefits are largely seen in primigravidae. Insecticide-
antigen. In a randomized controlled trial in the Gambia,
treated bed nets have been shown to significantly reduce
adults given three doses of RTS,S/AS02 were protected
the burden of childhood mortality secondary to malaria,
from developing natural P. falciparum malaria (Bojang
and to reduce the incidence of anemia and malaria in
et al., 2001). Vaccine efficacy was 71% in the first nine
weeks of the surveillance period, and 34% during the
entire 15-week surveillance period (Bojang et al., 2001).
Malaria vaccine No protection was afforded by the vaccine in the final six
Malaria vaccine initiatives have been ongoing for over weeks of surveillance, reiterating that immunity is very
30 years now; however, only recently have candidate short-lived. In a follow-up study, it was shown that the
malaria vaccines been tested in humans in clinical trials. protection conferred by RTS,S/AS02 was not strain-
To date, investigational vaccines have been designed to specific (Alloueche et al., 2003). Additional studies are
target specific stages of the parasite (notably P. falciparum) ongoing in Mozambique. While there are many other
life cycle, including the preerythrocytic/liver stages, candidate vaccines entering the early stages of clinical
asexual erythrocytic stages, sexual blood stages, and mos- evaluation in humans, RTS,S/AS02 is the first to demon-
quito stages. The complexity of the parasite life cycle has strate efficacy in natural P. falciparum infection. These
382 Protozoan Diseases: Malaria Clinical Features, Management, and Prevention

results are very promising, and a commercially available Hewitt K, Stekete R, Mwapas V, et al. (2006) Interactions between HIV
and malaria in non-pregnant adults: Evidence and implications. AIDS
vaccine is on the horizon. 20: 19932004.
Leder K, Black J, OBrien D, et al. (2004) Malaria in travelers: A review of
See also: Anemia; Antimicrobial Resistance; The History of the GeoSentinel surveillance network. Clinical Infectious Diseases
39: 11041112.
Malaria and its Control; Maternal Mortality and Morbidity. Mackintosh CL, Beeson JG, and Marsh K (2004) Clinical features and
pathogenesis of severe malaria. Trends in Parasitology 20: 597603.
Moorthy VS, Good MF, and Hill AVS (2004) Malaria vaccine
developments. Lancet 363: 150156.
Citations Schlagenhauf P and Kain KC (2007) Malaria chemoprophylaxis. In:
Keystone J, Kozarsky P, Nothdurft H, Freedman D, and Conner B
(eds.) Travel Medicine, 2nd edn. ch.12. Philadelphia, PA: Elsevier
Alloueche A, Milligan P, Conway DJ, et al. (2003) Protective efficacy Science.
of the RTS,S/AS02 Plasmodium falciparum malaria vaccine is not Suh KN, Kain KC, and Keystone JS (2004) Malaria. Canadian Medical
strain specific. American Journal of Tropical Medicine and Hygiene Association Journal 170: 16931702.
68: 97101. Targett GA (2005) Malaria vaccines 19852005: A full circle? Trends in
Bojang KA, Milligan P, Pinder M, et al. (2001) Efficacy of RTS,S/AS02 Parasitology 21: 499503.
malaria vaccine against Plasmodium falciparum infection in Warrell DA (1997) Cerebral malaria: Clinical features, pathophysiology,
semi-immune adult men in The Gambia: A randomized trial. Lancet and treatment. Annals of Tropical Medicine and Parasitology 91:
358: 19271934. 875884.
Maguire JD, Sumawinata IW, Masbar S, et al. (2002) Chloroquine- White NJ (2004) Malaria. In: Cook GC and Zumla AI (eds.) Mansons
resistant Plasmodium malariae in south Sumatra, Indonesia. Lancet Tropical Diseases, 21st edn, pp. 12051295. London: WB
360: 5860. Saunders.
World Health Organization (2000) Severe falciparum malaria.
Transactions of the Royal Society of Tropical Medicine and Hygiene
94(supplement 1): 190.
World Health Organization (2006) Guidelines for the Treatment of Relevant Websites
Malaria. Geneva, Switzerland: World Health Organization. World Health Organization, International Travel

and Health, 2007.
Further Reading Centers for Disease Control and
Prevention, Malaria.
Baird JK (2005) Effectiveness of antimalarial drugs. New England Centers for Disease Control and Prevention, Treatment of Malaria
Journal of Medicine 352: 15651577. (Guidelines for Clinicians).
Franco-Paredes C and Santos-Preciado JI (2006) Problem pathogens: Centers for
Prevention of malaria in travelers. Lancet Infectious Diseases 6: Disease Control and Prevention, Travelers Health.
139149. Centers for
Greenwood BM, Bojang K, Whitty CJM, and Targett GA (2005) Malaria. Disease Control and Prevention, CDC Health Information for
Lancet 365: 14871498. International Travel, 2008.

Protozoan Diseases: Toxoplasmosis

E Petersen, Aarhus University Hospital, Skejby, Denmark
R Salmi, G Chene, and R Thiebaut, University of Bordeaux, Bordeaux, France
R Gilbert, Institute of Child Health, London, UK
2008 Elsevier Inc. All rights reserved.

Introduction Infection in pregnant women with T. gondii may be

transmitted to the fetus where it may cause permanent
Toxoplasma gondii is a zoonotic protozoan infection with damage of the fetus including retinochorioditis and hydro-
a reservoir in mammals and birds. Transmission to cephalus. Congenital infection of the fetus in women
humans is through ingestion of tissue cysts in poorly infected just before conception is extremely rare and even
cooked meat of infested animals or ingestion of oocysts during the first few weeks of pregnancy the maternalfetal
that are shed in the feces of the definitive host (felines) transmission rate is only a few percent (Dunn et al., 1999).
and contaminate the environment. Infection in healthy Infection before pregnancy causes immunity against trans-
persons is usually subclinical or causes mild symptoms mission to the fetus. The infection can reactivate after
such as self-limited enlargement of lymph nodes and birth with attacks of retinochorioditis, and if lesions
fever. affect the macula, reduced eyesight. However, acquired