Treatment of Severe Malaria

Criteria for severe malaria

Patients with any manifestations of severe malaria, e.g., impaired consciousness/coma, hemoglobin <7 g/dL, acute kidney injury, acute respiratory distress syndrome, circulatory collapse/shock, acidosis, jaundice (with other signs of severe malaria), disseminated intravascular coagulation, and/or parasite density of ≥5% should be treated promptly and aggressively with parenteral antimalarial therapy regardless of the species of malaria seen on the blood smear. If severe malaria is strongly suspected but a laboratory diagnosis cannot be made at that time, blood should be collected for diagnostic testing to be done as soon as it becomes available and parenteral antimalarial drugs should be started.

Patients on treatment for severe malaria should have one set of blood smears (thick and thin smear) performed on admission and every 12 – 24 hours until a negative result (no Plasmodium parasites are detected) is reported.

IV artesunate

Severe malaria can progress to a fatal outcome rapidly, so its treatment should be initiated as soon as possible. Patients with severe malaria, regardless of infecting species, should be treated with intravenous (IV) artesunate.

Interim oral treatment

Clinicians at hospitals where IV artesunate is not in stock should provide interim treatment with an effective oral antimalarial while obtaining IV artesunate emergently from a commercial source. If the patient is unable to tolerate oral medications, clinicians will need to consider alternative ways to administer oral medications while awaiting IV artesunate. For example, for patients with nausea and vomiting, an anti-emetic preceding the antimalarial may help, and, for comatose patients, a nasogastric tube can be considered.

The preferred antimalarial for interim oral treatment is artemether-lumefantrine (Coartem^®) because of its fast onset of action. Other oral options include atovaquone-proguanil (Malarone™), quinine, and mefloquine. Because of a risk of severe neuropsychiatric adverse events at treatment doses, mefloquine should only be used if other options are not available. IV or oral clindamycin and tetracyclines, such as doxycycline, are not adequate for interim treatment. These drugs are slow-acting antimalarials that would not take effect until well after 24 hours, and they are not effective antimalarials for treatment of severe malaria when used alone. As for any malaria treatment, the interim regimen should not include the medication used for chemoprophylaxis if possible.

When IV artesunate arrives, immediately discontinue the oral medication and start parenteral treatment.

Dosing

Each dose of IV artesunate is 2.4 mg/kg. A dose of IV artesunate should be given at 0, 12, and 24 hours. Note that the weight-based dosing applies to both adults and children. Previously, weight-based dosing was differentiated between children <20kg and those ≥20kg. Current dosing in small children <20kg is based on an unpublished FDA analysis modeling pharmacokinetics in this population using available data.

When to transition to oral treatment

After the initial course of IV artesunate is completed, if parasite density is ≤1% (assessed on a thin blood smear collected 4 hours after the last dose of IV artesunate) and patient can tolerate oral treatment, a full treatment course with a follow-on regimen must be administered and can be started 4 – 24 hours after the last dose of IV artesunate. Artemether-lumefantrine (Coartem^®) is the preferred follow-on treatment but adequate alternatives are atovaquone-proguanil (Malarone™), quinine plus doxycycline or clindamycin, or mefloquine. If the patient received oral treatment prior to receiving IV artesunate, the same medication can be used as follow-on treatment, but a full regimen is required. As for any malaria treatment, the regimen selection should not include the medication used for chemoprophylaxis.

If, after the third IV artesunate dose, the patient's parasite density is >1%, IV artesunate treatment should be continued with the recommended dose once a day for a maximum of seven days until parasite density is ≤1%. Doses given at 0, 12, and 24 hours count as one day, which means up to six additional days. Clinicians should proceed with full course of oral follow-on treatment as above as soon as parasite density ≤1% and the patient is able to tolerate oral medications. Clinicians can consider placement of nasogastric tube or use of antiemetics to facilitate administration of oral treatment.

For those patients with parasite density ≤1% but who still cannot tolerate oral medications after completing IV artesunate treatment, clinicians can continue IV artesunate, one dose daily not to exceed a total course of seven days.

Infants, children, and pregnant women

IV artesunate can be used in infants, children, and pregnant women. Given that severe malaria is especially life threatening for pregnant women and their fetuses, and the lack of other treatment options for severe malaria in the United States, the benefits of treatment with IV artesunate outweigh the risks and IV artesunate should not be withheld.

Complications

IV artesunate is well tolerated. The only formal contraindication to IV artesunate treatment is known allergy to IV artemisinins.

While rare, delayed post-artemisinin hemolytic anemia has been noted in published case reports following treatment of severe malaria with IV artesunate. Persons with higher parasite density seem to have a higher likelihood of delayed hemolytic anemia after treatment. All persons treated for severe malaria with IV artesunate should be monitored weekly for up to four weeks after treatment initiation for evidence of hemolytic anemia. Weekly laboratory evaluation should include hemoglobin concentration, reticulocyte count, haptoglobin, lactate dehydrogenase (LDH), and total bilirubin. Depending on the intensity of hemolysis and presence of anemia signs and symptoms, blood transfusion may be needed. Cases of delayed post-artemisinin hemolytic anemia in patients who received Artesunate for Injection^TM should be reported to MedWatch, FDA's Safety Information and Adverse Event Reporting Program.

CDC no longer recommends the use of exchange transfusion as an adjunct procedure for the treatment of severe malaria because it has not been shown to be effective.