AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Malaria is an ancient scourge of humanity. Although almost eradicated from industrialized nations, malaria continues to extract a heavy toll of life and health in a substantial part of the world. Almost half the world's population lives in countries where the disease is endemic, and almost every country in the world encounters imported malaria. Children are the worst affected, especially children aged 6 months to 5 years. In parts of the world where malaria is endemic, it may cause as many as 10% of all deaths in children.

In the 1950s, the World Health Organization launched an ambitious plan to control or eradicate malaria. After initial successes, the plan foundered; today malaria is returning to areas where it was once controlled and it is entering new areas. Because of plasmodial and mosquito resistance to drugs and insecticides, the danger of malaria has worsened, and the disease is now a major global problem.

Pathophysiology

The bite of an infected mosquito introduces asexual forms of the parasite, called sporozoites, into the bloodstream. Sporozoites enter the hepatocytes and form schizonts, which are also asexual forms. Schizonts undergo a process of maturation and multiplication known as preerythrocytic or hepatic schizogony. In Plasmodium vivax and Plasmodium ovale infection, some sporozoites convert to dormant forms called hypnozoites, which can cause disease after months or years.

Preerythrocytic schizogony takes 6-16 days, and results in the host cell bursting and releasing thousands of merozoites into the blood. Merozoites enter the erythrocytes and initiate another asexual reproductive cycle, known as erythrocytic schizogony. The parasite successively passes through the stages of trophozoite and schizont, ultimately giving rise to several merozoites. Upon maturation of these merozoites, the erythrocyte ruptures, releasing the merozoites and multiple antigenic and pyrogenic substances into the bloodstream. These merozoites again infect new erythrocytes. After a few cycles of this erythrocytic schizogony, some merozoites differentiate into the sexual forms: the male and female gametocytes. A mosquito that takes a blood meal from a patient with gametocytemia acquires these sexual forms and plays host to the sexual stage of the plasmodial life cycle.

Rupture of a large number of erythrocytes at the same time releases a large amount of pyrogens, which causes the paroxysms of malarial fever. The periodicity of malarial fever depends on the time required for the erythrocytic cycle and is definite for each species. Plasmodium malariae needs 72 hours for each cycle, leading to the name quartan malaria. The other 3 species each take 48 hours for one cycle and cause fever on alternate days (tertian malaria). However, this periodicity requires all the parasites to be developing and releasing simultaneously; if this synchronization is absent, periodicity is not observed.

Frequency

United States

Approximately 1300 cases are diagnosed every year, most of them acquired outside the country. Only about 1% of patients acquire the infection in the United States. Over half the cases are acquired in Africa. Usually fewer than 10 deaths are reported in the United States annually.

International

Malaria is a major health problem in Africa, Asia, Central America, Oceania, and South America. About 40% of the world's population lives in areas where malaria is common.¹ Approximately 300-500 million cases of malaria occur every year, and 1-2 million deaths occur, most of them in young children.

Mortality/Morbidity

• Cerebral malaria: Most of the mortality of malaria is due to this complication of Plasmodium falciparum malaria, an acute illness that is mostly observed in children aged 6 months to 3 years. Early diagnosis and prompt treatment with a drug to which the parasite is susceptible is important to save the life of the child.
• Anemia: Anemia is so common in malaria that it is considered almost a part of the disease. The degree of anemia is much greater than can be explained by destruction of parasitized erythrocytes. Malarial anemia can be quite severe, sometimes causing death.
• Repeated frequent seizures: Even without cerebral malaria, a child can experience prolonged, frequent convulsions, which can lead to prostration and death.

Race

People of all races are affected, with some exceptions. People of West African origin who do not have the Duffy blood group are not susceptible to P vivax malaria.

Sex

Malaria affects females and males equally.

Age

Children of all ages living in nonmalarious areas are equally susceptible to malaria. In endemic areas, children younger than 5 years have repeated and often serious attacks of malaria. The survivors develop partial immunity. Thus, older children and adults often have asymptomatic parasitemia, ie, presence of plasmodia in the bloodstream without clinical manifestations of malaria. Most deaths resulting from malaria occur in children younger than 5 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Elicit any history of travel through, or immigration from, a malarious area. Even a few hours at an airport in an endemic area is significant. Obtain history of blood transfusion, organ transplantation, and (for newborns) malaria in the mother.

Young children manifest this disease in many different ways, but the classic picture of malaria, with periodic fever, shivering, and sweating, is not observed. Malaria can mimic any febrile illness and should be suspected in any febrile child who has recently been in a malarious area. Older children may manifest the classic periodicity of fever with chills and shivering.

• Prodrome: After the mosquito bite, children are asymptomatic while the parasites complete the liver cycle and one erythrocytic cycle, which takes 8-18 days, depending on the species. Children then become restless, drowsy, apathetic, and anorexic. Older children may report aching body, headache, and nausea.
• Fever: Fever is usually continuous and may be very high (40°C) from the first day.
• Respiratory symptoms: Many children have only flulike respiratory symptoms at presentation, with mild cough and cold. These symptoms abate in 1-2 days, with or without treatment.
• Gastrointestinal symptoms: Vomiting is very common in children with malaria, and it may make oral therapy ineffective. Mild diarrhea is often observed, with dark green mucoid stools. Occasionally, profuse diarrhea with dehydration and circulatory failure is observed.
• Febrile convulsions: Seizures are common and may occur at the onset of the disease, even before high fever has set in. Differentiating postictal impairment of consciousness from cerebral malaria is often difficult.
• Congenital malaria: Parasitemia in neonates within 7 days of birth implies transplacental transmission. This congenital malaria is usually associated with placental parasitemia, which sometimes persists even after adequate treatment with antimalarial drugs. Babies have fever, are irritable, refuse feeds, and often develop anemia, jaundice, and hepatosplenomegaly.
• Malaria in immune children: Children living in an area where malaria is endemic have repeated frequent infections and develop and maintain partial immunity. These children often develop only a low-grade fever, anemia, poor appetite, and malaise. Tiredness, restlessness, cough, and diarrhea are other symptoms that may occur.
• Relapses and recrudescences: Depending on the species of Plasmodium involved, relapses and recrudescences vary in their effects. P vivax and P ovale both give rise to hypnozoites in the liver. P vivax malaria may relapse for up to 3 years and P ovale for 1-1.5 years. P falciparum and P malariae do not form hypnozoites, so they do not have true relapses. However, the disease recrudesces because of surviving erythrocytic forms. Although P falciparum can recrudesce for up to 1 year, P malariae may continue to cause clinical malarial attacks even 20 years after the original infection. Only the sporozoites (introduced by the mosquitoes themselves) can penetrate the liver cells. Thus, if malaria is acquired by blood transfusion or transplacentally, no infection of the liver occurs and relapses do not occur.

Physical

• Fever: Fever can be very high from the first day. Temperatures of 40°C and higher are often observed. Fever is usually continuous or irregular. Classic periodicity may be established after some days.
• Hepatomegaly: The liver may be slightly tender.
• Splenomegaly: Splenomegaly takes many days, especially in the first attack in nonimmune children. In children from an endemic area, huge splenomegaly sometimes occurs.
• Anemia: Prolonged malaria can cause anemia, and malarial anemia causes significant mortality.
• Jaundice: With heavy parasitemia and large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides with the treatment of malaria.
• Dehydration: High fever, poor oral intake, and vomiting all contribute to dehydration.

Causes

• Malaria is caused by Plasmodium species, which are protozoal blood parasites. The following 4 species can infect humans:
• • P vivax
  • P falciparum
  • P malariae
  • P ovale
• Most malaria acquired in Africa is due to P falciparum. P vivax dominates in Asia and the Americas.
• Transmission of malaria
• • The bite of an infected female Anopheles mosquito transmits malaria. Species of mosquito capable of transmitting malaria are found in all 48 of the contiguous states of the United States.
  • Malaria can be transmitted through blood transfusion. Among people living in malarious areas, semi-immunity to malaria allows donors to have parasitemia without any fever or other clinical manifestations. The malaria transmitted is by the merozoites, which do not enter the liver cells. Because the liver stage is not present, curing the acute attack results in complete cure.
  • Organ transplantation may transmit malaria.
  • Transplacental malaria (ie, congenital malaria) can be significant in populations who are semi-immune to malaria. The mother may have placental parasitemia, peripheral parasitemia, or both, without any fever or other clinical manifestations. Vertical transmission of this infestation may be as high as 40% and is associated with anemia in the baby.
• Risk factors
• • Residence in, or travel through, a malarious area
  • No previous exposure to malaria (hence no immunity)
  • No chemoprophylaxis or improper chemoprophylaxis

DIFFERENTIALS

Section 4 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Ascending cholangitis
Enteric fever
Encephalitis
Heatstroke
Hepatitis
Lobar pneumonia
Pharyngitis
Viral pneumonia
Tonsillitis
Pelvic inflammatory disease

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• Examination of blood smear
• • Demonstration of the parasite in a smear of the blood definitely establishes the presence of malaria.
  • A negative finding on examination does not rule out malaria. Only 50% of children with malaria have positive smear findings, even on repeated examination.
  • Asymptomatic parasitemia is common in children from an endemic area who have partial immunity to the disease. A positive smear for malaria parasite does not always confirm a diagnosis of malaria in these children. More importantly, a positive smear should not stop the diagnostic effort in a febrile illness.
  • Both thick and thin films are essential. If the parasitemia is light, a thin film examination may miss the diagnosis. Thick films save time in diagnosis of scanty infections but make species identification of the parasite difficult.
  • At least 100-200 fields of a thick film should be scrutinized before a slide is reported as negative for malaria. In doubtful cases, the examination can be repeated after 4 hours.
  • Various techniques to enhance the diagnostic utility of the peripheral blood smear examination are in use. Fluorescent staining and microscopy, centrifugation, selective magnetic separation techniques, and other techniques have been used but have only a moderate effect.
• Serological tests
• • Serological tests provide confirmation of past malaria in patients and are valuable for epidemiological studies. These tests are also useful for screening donated blood and diagnosing hyperactive malarial splenomegaly. Among the tests used are the indirect fluorescent antibody test (IFAT), indirect hemagglutination antibody (IHA) test, enzyme-linked immunosorbent assay (ELISA), and the immuno-chromatographic test (ICT) for filariasis.
  • All these tests produce positive results several days after malaria parasites appear in the blood and so do not help in the diagnosis of the acute infection for treatment purposes.
• Dipstick tests
• • Dipstick tests based on the detection of P falciparum histidine-rich protein-2 (PfHRP-2) antigen are specific for P falciparum infections and do not detect the other 3 species. Dipstick tests based on the detection of parasite lactate dehydrogenase are now available; these tests can detect both P falciparum and P vivax.
  • These tests have high sensitivity and specificity, require no special equipment or training, and produce results rapidly. However, they remain positive for a week or more after the treatment and cure, and, in this situation, can yield false-positive results.
• Molecular biological detection tests: DNA and RNA probes and polymerase chain reaction (PCR) have good sensitivity and specificity but require sophisticated expensive equipment.

Imaging Studies

• Imaging studies are not needed in malaria.

Other Tests

• Lumbar puncture is indicated to rule out meningitis in cerebral malaria and febrile seizures with malaria.
• Severe P falciparum malaria is often associated with hypoglycemia. Lower blood glucose levels are associated with higher mortality rates.

Procedures

• Obtaining thick and thin blood films at the bedside is important.
• • These films may have to be taken repeatedly for diagnosis.
  • Earlobe or finger prick is used for older children; the great toe is used in infants.
  • Take a large drop of blood on one end of a clean slide, spread uniformly, and air-dry. A smaller drop should be spread thinly so that the end of the smear does not reach the end of the slide.
  • Giemsa staining is suitable for identifying malaria parasites in these films.

Histologic Findings

The appearance of the parasite varies in the thick and thin films. The thick unfixed film shows only leucocytes and parasites; erythrocytes are destroyed in the staining process. The parasites themselves are also altered. Young trophozoites appear as incomplete rings or spots of blue cytoplasm with discrete red nuclei. In mature trophozoites, the cytoplasm may be fragmented, and the various characteristics of the different species are often indistinct. Gametocytes and schizonts usually retain their characteristic appearances. Thin film examination is essential for the accurate identification of plasmodial species, which has an important bearing on treatment.

TREATMENT

Section 6 of 11  

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Medical Care

• Children who are fully conscious, who have low-to-moderate fever, and who are maintaining their nutrition and hydration orally can be treated on an outpatient basis.
• Oral paracetamol (acetaminophen) is safe and effective for fever and should be used in doses of 10 mg/kg. This dose can be repeated 3-6 times a day, as required. If the child has hyperpyrexia, tepid sponging can rapidly bring the temperature down.
• Many children with malaria develop anemia. Because onset is gradual, the child withstands a low level of hemoglobin quite well, and blood transfusions are rarely needed. Standard hematinic therapy is effective.
• If repeated vomiting has led to dehydration, the child needs appropriate parenteral fluids to correct it. Glucose-containing fluids help counter the hypoglycemia that sometimes accompanies severe malaria. Vomiting is common in malaria. An antiemetic such as domperidone can be used, and antimalarials should be continued. Vomiting stops when the malaria is cured.
• Indications for immediate hospitalization include the following:
• • Intractable vomiting
  • Dehydration
  • Seizures
  • Altered consciousness or coma
  • Repeated convulsions
  • Difficulty in breathing or acidotic breathing
  • Severe pallor (indicating severe anemia)
  • Hypoglycemia (blood glucose <2.5 mmol/L or 3 mmol/L in malnourished children)
  • Oliguria or anuria, signifying renal affliction
  • Shock
  • Hyperparasitemia
  • Bleeding diathesis
• In a child with malaria, impaired consciousness, respiratory distress, hypoglycemia, and jaundice are risk factors for death. Such a child should be treated as an emergency.

Consultations

Consult an infectious diseases specialist.

Diet

• No restrictions are needed in the diet for patients well enough for outpatient management. Indeed, the appetite and activity level are remarkably well preserved for the degree of fever.
• Advise increased fluid intake.

Activity

Children should be allowed to decide their own activity levels. If the fever is intermittent, many children feel quite well between paroxysms of fever and come to no harm through activity.

MEDICATION

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Blood schizonticides are the first-line drugs for the treatment of malaria and must be started as soon as the diagnosis is made or even suspected. They act on the asexual forms in the erythrocytes and interrupt clinical attacks. Delay in treatment of P falciparum malaria can lead to development of severe malaria, which has a poorer prognosis than uncomplicated malaria. Chloroquine, quinine, quinidine, mefloquine, halofantrine, and artemisinin compounds are the rapidly acting drugs that can terminate an acute malaria attack. While chloroquine acts rapidly, resistance is widespread and an accurate travel history should be obtained before choosing the antimalarial drug.

Malaria imported from Asia or the Americas is mostly P vivax and is chloroquine responsive. Malaria acquired in Africa is mostly P falciparum and is chloroquine resistant; quinine is an effective drug. P falciparum malaria incurred in South East Asia may be quinine and mefloquine resistant as well; a combination of artesunate and mefloquine is recommended. Time wasted in trials of a drug to which the parasite is resistant can result in a poor outcome, including death.

P vivax and P ovale have dormant stages (hypnozoites) in the liver, and the treatment of an episode of malaria requires eradication of these forms also. The classic treatment is a 3-day course of chloroquine, followed by a 14-day course of primaquine. A shorter course of 5 days of primaquine, started with chloroquine, has been described but is associated with higher relapse rates.

Treatment guidelines for malaria in the United States were recently updated by the Centers for Disease Control and Prevention (CDC).²

Drug Category: Antimalarials

Blood schizonticides are the first-line drugs for the treatment of malaria.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Malaria can be life threatening, and intensive care may be required. Indications for admission to ICU include the following:
• • Suspicion of cerebral malaria (ie, seizures, prolonged postictal coma, repeated seizures)
  • Complications of malaria (eg, bleeding, renal failure, pulmonary edema)
  • Heavy parasitemia: Admit patients from nonmalarious areas to the ICU if more than 2% of erythrocytes have malaria parasites. Patients from an endemic area can tolerate higher levels, but patients should be admitted to the ICU if more than 5% of erythrocytes are parasitized.
• Proof of cure blood smear examination
• • Blood smears should be repeated after 24-48 hours to ensure that the drug is effective. This is especially important with P falciparum.
  • If parasites are not cleared in 48 hours, a change in drug is required.
• Exchange transfusion
• • An exchange transfusion is valuable in a very sick child. It reduces parasite load rapidly, corrects any bleeding diatheses, and corrects anemia.
  • Erythrocytapheresis, the use of cell separation techniques to remove only the erythrocytes, has been used successfully in adults. It removes the parasites and has the added advantage of hemodynamic stability.
• Radical cure
• • This implies the destruction of the dormant forms in the liver.
  • Primaquine is the only drug active against the hypnozoites in the hepatocytes.

Transfer

• If appropriate drugs and experience in treating malaria are not available, the patient may need urgent transfer to a referral hospital.

Deterrence/Prevention

• Measures to prevent mosquito bites are very important for people living in or traveling through a malarious area.
• Chemoprophylaxis is never fully effective and is undermined by poor adherence and parasite resistance to almost all drugs. Therapy should be started a week before entering a malarious area and continued for 4 weeks after leaving it.
• • Chloroquine is the most commonly used drug, at a dose of 5 mg/kg once a week; however, significant resistance to it is now present.
  • Mefloquine (5 mg/kg once a week) is recommended in areas where chloroquine resistance is common.
  • The CDC provides country-specific advice on malaria chemoprophylaxis.
  • Infants younger than 6 weeks should not be administered chemoprophylaxis.
• Prevention of mosquito bites is the most effective means of individual malaria protection.
• • Cover the body while outdoors. Wear full-length sleeves and trousers. Clothes can also be treated with an insecticide, such as permethrin, which is safe for this purpose. Diethyl-m-toluamide (DEET) is an effective mosquito repellent when applied on the skin.
  • Increased precautions are needed during the night because Anopheles species are nocturnal in habit. Sleeping under insecticide treated (permethrin 0.2 g/m² of material every 6 mo) mosquito nets is perhaps the most beneficial antimalarial measure available. Bedrooms should be sprayed with an aerosol insecticide at dusk.
  • A vaccine for malaria would be a major medical advance, but it is proving elusive. Vaccines against various malarial antigens have been tried for many years, all around the world. Unfortunately, the immunity provided is inadequate and short lived. A vaccine with a good rate and duration of protection will not be available for some years yet.

Complications

• Cerebral malaria: P falciparum causes sequestration of erythrocytes in the microvasculature of the brain (and other organs). Seizures and coma are common in a child with malaria, and prolonged postictal state should raise suspicion of this dangerous entity. Cerebral malaria can be rapidly fatal, and trying drugs to which resistance is common is dangerous. Prompt diagnosis and immediate treatment with a drug known to be effective in the area where the malaria was acquired can be lifesaving. The presentation is varied and may suggest other conditions, such as meningitis, encephalitis, or epilepsy. Thus, cerebral malaria should be considered in the differential diagnosis of a febrile neurological illness if a history of residence or travel through a malarious area exists.
• Bleeding tendency: A nonimmune child with heavy parasitemia sometimes develops generalized bleeding. Such bleeding is usually due to disseminated intravascular coagulation and is sometimes associated with a bacterial infection.
• Hemolysis: Some degree of hemolysis is part of malaria, but some children have excessive hemolysis, putting them at risk for renal failure. This hemolysis may be related to glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency or an antibody-mediated destruction of erythrocytes.
• Anemia: Anemia is a faithful companion of malaria. Some children have anemia far exceeding that attributable to erythrocyte destruction by the malaria parasite. Other mechanisms of anemia are dyserythropoiesis, hypersplenism, shortened erythrocyte survival, and bone marrow suppression.
• Hypoglycemia: The malarial parasites consume glucose voraciously. Heavy parasitemia can result in hypoglycemia, which may be compounded by quinine and quinidine therapy. Hypoglycemia can be difficult to differentiate from cerebral malaria.
• Acute renal failure: Blackwater fever is a condition of hemolysis and acute renal failure. It is rarely observed now, being more common when quinine was used for prophylaxis.
• Pulmonary edema
• Hyperpyrexia
• Circulatory collapse (algid malaria)
• Jaundice

Prognosis

• Uncomplicated malaria due to P vivax, P malariae, and P ovale has an excellent prognosis. Most patients have a full recovery with no sequelae.
• Malaria due to P falciparum is dangerous. If not treated quickly and completely, complicated and severe malaria can result, which carries a grave prognosis.
• Malaria in children younger than 5 years carries the worst prognosis in endemic areas. In a nonimmune population, malaria is equally deadly at all ages.
• Cerebral malaria has a mortality rate of 25%, even with the best treatment. Survivors may have sequelae (eg, hemiparesis, cerebellar ataxia, aphasia, spasticity).
• Repeated attacks of malaria can lead to chronic anemia, malnutrition, and stunted growth.

Patient Education

• Advise persons visiting a malarious area regarding chemoprophylaxis and the need to continue the regimen for some weeks after leaving the area.
• • Motivate travelers regarding chemoprophylaxis.
  • Fewer than 20% of people diagnosed with imported malaria in the United States have taken recommended prophylaxis; more than 50% have taken no chemoprophylaxis at all.
• Recommend mosquito bite avoidance measures (ie, mosquito nets with insecticides, mosquito coils, and appropriate clothing).
• Advise persons visiting a malarious area regarding treatment of malaria and provide them doses of appropriate medicines to be started if attendance at a hospital is not immediately possible.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Malaria.

MISCELLANEOUS

Section 9 of 11  

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• Miscellaneous
• Multimedia
• References

Special Concerns

Malaria can be severe in pregnancy. This is a major problem because many antimalarial drugs are considered unsafe during pregnancy.

MULTIMEDIA

Section 10 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  The various stages of Plasmodium life cycle are shown. Knowledge of the life cycle of the malarial parasite is essential to understanding the chemotherapy of malaria.
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Media type:  Chart

Media file 2:  The various stages of Plasmodium vivax as observed on Giemsa staining of a peripheral blood smear.
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Media type:  Illustration

Media file 3:  The various stages of Plasmodium falciparum as observed on Giemsa staining of a peripheral blood smear are shown. The presence of more than one parasite in an erythrocyte is unique to this species.
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Media type:  Illustration

REFERENCES

Section 11 of 11

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. World Health Organization. WHO Fact Sheet on Malaria. Fact Sheet No 94. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/fs094/en/print.html. Accessed June 29, 2007.
2. Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: a systematic review. JAMA. May 23 2007;297(20):2264-77. [Medline]. [Full Text].
3. Eliades MJ, Shah S, Nguyen-Dinh P, et al. Malaria surveillance--United States, 2003. MMWR Surveill Summ. Jun 3 2005;54(2):25-40. [Medline]. [Full Text].
4. Emanuel B, Aronson N, Shulman S. Malaria in children in Chicago. Pediatr. 1993;92:83-85. [Medline].
5. Okie S. Betting on a malaria vaccine. N Engl J Med. Nov 3 2005;353(18):1877-81. [Medline]. [Full Text].
6. Thapa BR, Marwaha RK, Walia BN, et al. Falciparum malaria. Indian Pediatr. Mar 1987;24(3):221-5. [Medline].
7. Tracy JW, Webster LT. Malaria. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9^th ed. New York, NY: McGraw Hill; 1996:965-985.
8. Warrell DA. Treatment and prevention of malaria. In: Bruce-Chwatt's Essential Malariology. 3^rd ed. London, England: Edward Arnold; 1993:164-95.
9. Warrell DA. Clinical features of malaria. In: Bruce-Chwatt's essential malariology. 3^rd ed. London, England: Edward Arnold; 1993:35-49.
10. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J. Feb 2005;81(952):71-8. [Medline]. [Full Text].

Article Last Updated: Oct 17, 2007