Basics
Description
- Malaria is a febrile illness caused by the Plasmodium species of protozoan parasites, transmitted by the Anopheles mosquito vector.
- 5 Plasmodium strains infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. P. falciparum and P. vivax cause the majority of disease.
- Classic symptoms include stages of chills, followed by high fevers, and then sweating. However, this classic symptom pattern is less likely to be seen in children. Children may manifest initially with only fever as a complaint.
Epidemiology
- High-risk areas of endemic malaria include Africa, parts of Central and South America, Oceania, and tropical regions of Asia.
- P. falciparum is the major species in sub-Saharan Africa. Both P. falciparum and P. vivax are found in India, Southeast Asia, Oceania, and Central and South America, and P. vivax is present in some areas of Africa. P. ovale is usually found in West Africa.
- P. falciparum causes more deaths in children <5 years of age than any other organism.
- WHO reports that 86% of malaria deaths occur in children. Pregnant women are also at high risk.
Incidence
- Worldwide, an estimated 200 " 300 million cases of malaria occur annually, and 660,000 " 1.2 million deaths occur from malaria annually.
- ข ผ1,500 cases of malaria are imported into the United States each year. In 2012, almost 2,000 cases of malaria were seen in the United States, the largest number of cases in >40 years.
Risk Factors
Genetics
- Sickle cell trait is known to provide protection against malaria.
- The risk of death of severe falciparum malaria is 60 " 70% less in children with Hb AS than those with Hb AA.
- Thalassemia and G6PD deficiency also provide some protection against malaria.
- Individuals with a Duffy-negative blood type lack receptors for P. vivax merozoite invasion and are typically resistant to P. vivax, although recently, cases of P. vivax in Duffy-negative individuals have been reported.
General Prevention
- Personal protective measures against mosquito bites are extremely important.
- Remain in well-screened areas.
- Wear protective clothing, including pants and long-sleeved shirts.
- Use insect repellents containing DEET.
- Use insecticide-treated bed nets.
- Chemoprophylaxis is strongly advised for travelers to endemic areas.
- Chloroquine may be used in areas with chloroquine-sensitive parasites only (5 mg/kg once a week " max 500 mg).
- In chloroquine-resistant areas, effective options are atovaquone-proguanil (Malarone), mefloquine, or doxycycline.
- Malarone can be used in all areas but is contraindicated in severe renal impairment and pregnancy.
- Dosing: 5 " 8 kg: 1/2 pediatric tablet daily. 8 " 10 kg: 3/4 pediatric tab daily. 10 " 20 kg: 1 pediatric tab (62.5/25) daily. 20 " 30 kg: 2 pediatric tabs daily. 30 " 40 kg: 3 pediatric tabs daily. ≥40 kg: 1 adult tab (250/100) daily
- Mefloquine resistance is present in parts of Asia. Contraindications to mefloquine include seizure disorder, major psychiatric illness, or cardiac disease. It is safe in pregnancy and for young infants.
- Dosing: ≤15 kg: 5 mg/kg weekly. 15 " 19 kg: 1/4 tablet weekly. 20 " 30 kg: 1/2 tab weekly. 30 " 45 kg: 1/2 tab weekly. >45 kg: 1 tab weekly
- Doxycycline is contraindicated if <8 years of age and in pregnancy. Dosing: 2.2 mg/kg daily (max 100 mg/day)
- Chloroquine and mefloquine are begun 1 week before travel, continued during the period of exposure and for 4 weeks after leaving the endemic region. Malarone is started 2 days prior to travel and continued 1 week after return. Doxycycline is started 2 days before travel and continued for 4 weeks after return.
Etiology
- Infection is typically transmitted by the bite of the female Anopheles mosquito, but it can also be transmitted through contaminated blood transfusions or acquired congenitally.
- The majority of human disease is caused by P. falciparum and P. vivax.
- P. vivax and P. ovale can cause relapsing disease because of the persistent hepatic (hypnozoite) stage of the infection.
- Asymptomatic carriage for years may occur due to P. malariae.
- P. knowlesi is a primate parasite that can cause severe disease in humans.
Commonly Associated Conditions
- Severe malaria is most commonly caused by P. falciparum.
- Severe malaria is defined as parasitemia >5%, shock, acidosis, severe anemia or signs of CNS or other end-organ involvement such as renal failure, pulmonary edema, respiratory distress (acidotic/irregular breathing), impaired consciousness, seizures, hemoglobinuria, DIC, or hypoglycemia.
- Cerebral malaria is a serious consequence of malaria infection, defined as coma in conjunction with P. falciparum parasitemia.
- Occurs most often in children age 3 " 6 years in Africa but often occurs in adolescents and adults in Southeast Asia
- Severe anemia is common and can be severe, especially with P. falciparum. This is due to high parasitemia, hemolysis, and sequestration.
- Respiratory distress has high mortality, particularly if combined with impaired consciousness.
- Blackwater fever is a complication associated with falciparum malaria. It occurs due to massive hemolysis with resulting hemoglobinuria and acute renal failure.
- Pulmonary edema, renal failure, distributive shock, and progression to coma or death can occur.
- Hyperreactive malarial splenomegaly is seen with chronic exposure to malaria in endemic areas. High levels of malaria IgM are present, and massive hepatosplenomegaly is seen.
- Splenic rupture may occur due to splenomegaly.
- P. malariae can cause nephrotic syndrome.
Diagnosis
History
- History of travel to malaria endemic region
- Poor compliance with malaria prophylaxis
- Signs and symptoms
- High fevers, headache, chills, and sweats are classic symptoms.
- Periodicity of fever depends on the Plasmodium species and is less commonly seen in young children and travelers.
- GI symptoms are common in children. Irritability, anorexia, vomiting, abdominal pain, cough, and arthralgias may be seen.
- 95% of malaria cases occur within 30 days of return from travel, but malaria may occur as late as months after return.
- Malaria can cause altered mental status, increased intracranial pressure, seizures, and coma.
Alert
- A high index of suspicion is necessary for the diagnosis of malaria, as failure to diagnose malaria has led to death in some instances. Fever may be the only sign in infants and young children.
Physical Exam
- Fever, malaise, ill appearance
- Pallor or jaundice
- Hepatosplenomegaly may be present.
- In severely ill patients, respiratory distress with acidotic, deep breathing may be seen.
Diagnostic Tests & Interpretation
Lab
- Hemolytic anemia is commonly seen, with severe malarial anemia most common with P. falciparum.
- Thrombocytopenia is common.
- Hypoglycemia may occur with P. falciparum.
- Peripheral blood smear
- Thick and thin peripheral smears are required for definitive diagnosis (thick smears provide better sensitivity if the parasitemia is low; thin smears provide for species identification).
- If initial smears are negative, repeated specimens should be obtained q12 " 24h over 72 hours to confirm a truly negative result with 3 smears.
- A parasitemia of >5% of red blood cells, altered mental status, or other organ involvement make the diagnosis of severe malaria and require more intensive therapy.
- Rapid diagnostic tests
- Rapid tests for antigen detection show excellent sensitivity for Plasmodium spp., require a small amount of blood for testing, and provide results in <20 minutes.
- Rapid tests should complement but not replace microscopy testing, as they do not provide an estimate of parasite density.
- PCR
- PCR is highly sensitive and can be useful for determining the Plasmodium species if it is unclear by blood smear. However, it is time-consuming and costly.
Differential Diagnosis
- Malaria should be considered in any febrile traveler from an endemic area.
- Other causes of fever in travelers should be considered based on the region of travel are as follows:
- Dengue
- Typhoid fever
- Yellow fever
- Hepatitis A
- Influenza
- Measles
- Leptospirosis
- Common causes of fever such as pneumonia and viral illnesses should also be considered.
Alert
Consider malaria when a patient with fever has a history of travel.
Treatment
Medication
Uncomplicated malaria
- Chloroquine can be used for known chloroquine-susceptible P. falciparum and P. vivax and for all P. ovale, P. malariae, and P. knowlesi infections.
- Chloroquine is dosed at 10 mg/kg base PO (max 600 mg), then 5 mg/kg PO at 6, 24, and 48 hours (max 300 mg/dose).
- Susceptible areas include Central America west of Panama Canal, Haiti, Dominican Republic, and parts of the Middle East.
- For chloroquine-resistant P. falciparum or if species is unidentified, options are as follows:
- Atovaquone-proguanil (Malarone). Malarone (mg atovaquone/mg proguanil) is given as one dose daily for 3 days. 5 " 8 kg: 2 pediatric tabs (62.5/25) per dose. 9 " 10 kg: 3 pediatric tabs per dose. 11 " 20 kg: 1 adult tab (250/100) per dose. 21 " 30 kg: 2 adult tabs per dose. 31 " 40 kg: 3 adult tabs per dose. ≥40 kg: 4 adult tabs per dose
- Artemether-lumefantrine (Coartem). Coartem is given for a 6-dose course. The 2nd dose is given 8 hours after the 1st, and then b.i.d. 5 " <15 kg: 1 tablet (20 mg artemether/120 mg lumefantrine) per dose. 15 " <25 kg: 2 tabs per dose. 25 " <35 kg: 3 tabs per dose. ≥35 kg: 4 tabs per dose
- Mefloquine. Mefloquine is dosed at 15 mg/kg (max 750 mg) PO, followed by 10 mg/kg (max 500 mg) PO 8 " 12 hours later.
- Quinine sulfate (10 mg salt/kg PO t.i.d.) plus doxycycline or clindamycin for 3 days (malaria acquired outside Southeast Asia) or 7 days (malaria acquired in Southeast Asia)
- For chloroquine-resistant P. vivax, options are Malarone, mefloquine, or quinine +doxycycline, all in addition to primaquine.
- Primaquine is used for the prevention of P. vivax and P. ovale relapses, in addition to primary treatment. It should not be used in patients with G6PD deficiency or in pregnancy.
Severe malaria
- Quinidine gluconate, 10 mg salt/kg IV initial dose (max 600 mg) over 2 hours followed by 0.02 mg salt/kg/min infusion + doxycycline or clindamycin
- In 2011, WHO guidelines made artesunate the drug of choice for children with severe malaria worldwide. Artesunate IV is available from the CDC under an investigational protocol for severe malaria in the United States.
- Change to an oral agent once parasite density <1% and the patient can take oral medication. The use of exchange transfusion for patients with hyperparasitemia is controversial, as no controlled trial has shown a clear benefit to this treatment.
Inpatient Considerations
Admission Criteria
Travelers diagnosed with malaria infection should be managed as inpatients.
Ongoing Care
Patient Education
- Consultation with a travel clinic is advised prior to travel to a malaria-endemic region.
- Chemoprophylaxis and mosquito bite prevention methods are both essential.
Prognosis
- The prognosis depends on the severity of illness, Plasmodium species, underlying health conditions, and age of the patient.
- Infants with P. falciparum infection account for most of the mortality due to malaria.
- In African children, highest risk of death occurs in children with impaired consciousness and respiratory distress.
- If treated promptly, even P. falciparum malaria will likely respond well to treatment.
Complications
- Cerebral malaria has significant morbidity and mortality and can cause long-term neurocognitive impairment.
- Severe malarial anemia is frequent due to P. falciparum. However, death rates with adequate treatment are low.
- Chronic relapses can occur from P. vivax and P. ovale infections.
- Pregnant women are at higher risk for complications from malaria infection.
Additional Reading
- Agarwal D, Teach SJ. Evaluation and management of a child with suspected malaria. Pediatr Emerg Care. 2006;22(2):127 " 133. [View Abstract]
- Dondorp A, Fanello C, Hendriksen I, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376(9753):1647 " 1657. [View Abstract]
- Freedman DO. Clinical practice. Malaria prevention in short-term travelers. N Engl J Med. 2008;359(6):603 " 612. [View Abstract]
- John CC, Bangirana P, Byarugaba J, et al. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics. 2008;122(1):e92 " e99. [View Abstract]
- Kiang KM, Bryant PA, Shingadia D, et al. The treatment of imported malaria in children: an update. Arch Dis Child Educ Pract Ed. 2013;98(1):7 " 15. [View Abstract]
Codes
ICD09
- 084.6 Malaria, unspecified
- 084.0 Falciparum malaria [malignant tertian]
- 084.1 Vivax malaria [benign tertian]
- 084.3 Ovale malaria
ICD10
- B54 Unspecified malaria
- B50.9 Plasmodium falciparum malaria, unspecified
- B51.9 Plasmodium vivax malaria without complication
- B53.0 Plasmodium ovale malaria
SNOMED
- 61462000 Malaria (disorder)
- 62676009 Falciparum malaria (disorder)
- 27052006 Vivax malaria (disorder)
- 19341001 Ovale malaria (disorder)
FAQ
- Q: What drugs are acceptable choices for treatment of malaria in pregnancy?
- A: Options for uncomplicated malaria treatment in pregnant women in the United States include chloroquine (if sensitive), mefloquine, or quinidine + clindamycin.
- Q: Is there a vaccine available to prevent malaria?
- A: No vaccination is commercially available; however, antimalarial vaccines are currently in clinical trials and are showing some efficacy. The RTS,S subunit vaccine is in large-scale trials at this time.
- Q: How can I determine if the area my patient is traveling to has chloroquine-resistant malaria?
- A: The CDC Web site at www.cdc.gov/malaria has extensive information for travelers, including parasite sensitivity patterns and treatment recommendations. A malaria hotline is also available for clinician questions at 770-488-7788.