Artemisinin-based therapies form the backbone of treatment for severe malaria. Yet, as with any drug, rare life-threatening adverse reactions may occur. We reviewed the potential severe reactions to artemisinin derivatives (such as artemether, artesunate, and artemether–lumefantrine), discussed management principles, and considered alternative antimalarial strategies in such scenarios.
Case Sketch
A patient with severe malaria who initially had a “3+” parasite density developed reactions shortly after receiving an artemisinin-based antimalarial. Their reactions ranged from mild (itching, rash, nausea, headache, dizziness) to serious events such as a generalized seizure and loss of consciousness. Treatment included antihistamines, corticosteroids, and epinephrine for suspected anaphylaxis; seizures were aborted. The antimalarial regimen was switched: Malarone for 3 days was used, and repeat malaria testing on day 4 showed parasite density falling to “1+” with resolution of symptoms.
While many of the mild symptoms are expected nuisance effects, the seizure and altered consciousness raise concern that a severe hypersensitivity or neurotoxic event occurred in this patient. We will examine what is known in the literature about such occurrences, and how to respond in practice.
Artemisinin Derivatives: Safety and Rare Adverse Events
Common and moderate side effects
Artemisinin derivatives are generally well tolerated. Common side effects include nausea, vomiting, anorexia, dizziness, and headache. They may also cause mild skin reactions such as rash or pruritus (itching).
Laboratory abnormalities sometimes appear: transient increases in liver enzymes (ALT, AST) have been reported, though it is uncertain whether malaria itself or the drug is the principal cause. Hematologic effects—such as mild cytopenias or hemolysis (particularly delayed hemolysis after intravenous therapy)—are also documented.
Allergic and hypersensitivity reactions
Hypersensitivity reactions to artemisinins are relatively rare, but they range from mild (rash, urticaria) to severe (anaphylaxis, Stevens–Johnson syndrome). The NCBI LiverTox monograph notes that artesunate can cause rash, urticaria, anaphylaxis, and in extreme cases Stevens–Johnson syndrome. Cell-based reviews emphasize that clinical presentations of hypersensitivity span this spectrum.
Given the clinical features in our case (rash, itching, sudden neurologic event), a severe allergic (anaphylactic) or immune-mediated reaction must be considered.
Neurotoxicity and seizures
Concerns over neurotoxicity of artemisinin derivatives stem largely from animal studies: at high doses, some artemisinins (especially lipophilic ones such as arteether or artemether) induced brainstem lesions in laboratory animals. However, in human clinical practice at therapeutic doses, clear evidence of permanent neurotoxicity is lacking. Some surveillance and clinical reports note neurologic adverse events (e.g. headache, dizziness, insomnia) but seizures are exceptionally rare.
Given the low incidence in humans, the occurrence of a seizure and loss of consciousness in this patient likely reflects a severe systemic reaction (e.g., anaphylaxis with hypoxia or hypotension) rather than pure neurotoxicity. The timing and accompanying “allergic” signs (rash, itching) support that interpretation.
Cardiac, hepatic, renal risks
Other serious but uncommon events with artemisinin therapies include cardiac arrhythmias (QT prolongation), acute renal failure, acute respiratory distress syndrome (ARDS), pulmonary edema, and hematologic derangements. Also, artesunate has been associated with post-artesunate delayed hemolysis (PADH), which may occur about one to three weeks after therapy.
Because malaria itself often stresses multiple organs, the distinction between disease-induced injury and drug-induced toxicity can be challenging.
Clinical Management of Severe Reaction
When facing a suspected life-threatening reaction to an artemisinin derivative, clinicians should act promptly:
- Immediate stabilization: As with any severe allergic reaction, ensure airway, breathing, and circulation. Administer intramuscular epinephrine (adrenaline) if anaphylaxis is suspected, with supportive measures (oxygen, IV fluids).
- Withdraw the offending drug: Discontinue the artemisinin derivative immediately.
- Adjunctive therapies: Administer antihistamines (e.g. H1 blockers), corticosteroids, and IV fluids, as in standard anaphylaxis protocols.
- Seizure management: If seizures occur, terminate with benzodiazepines (e.g. lorazepam or diazepam) then consider further anticonvulsants depending on clinical context.
- Organ support and monitoring: Monitor renal, hepatic, cardiac parameters; manage complications (e.g. dialysis for renal failure, ventilatory support if ARDS).
- Alternative antimalarial therapy: Because the patient still has active severe malaria, prompt initiation of an alternative effective antimalarial is vital (discussed below).
Note: because the patient likely has high parasite load and systemic illness, a switch to a less reactive but still effective antimalarial is essential; stopping therapy entirely risks uncontrolled malaria.
Alternative Antimalarial Options in Hypersensitive Patients
When artemisinins cannot be used due to allergy or contraindication, alternative regimens must be carefully selected. The choices depend on severity (severe vs. uncomplicated malaria) and local resistance patterns.
WHO / CDC guidance
For severe malaria, first-line therapy is intravenous artesunate, followed by a full course of an oral artemisinin-based combination therapy (ACT) once the patient can tolerate oral intake. If follow-on therapy cannot use the same artemisinin class, acceptable alternatives include:
- Atovaquone-proguanil (Malarone)
- Quinine (plus doxycycline or clindamycin)
- Mefloquine (in certain settings)
CDC guidance states: “artemether–lumefantrine is the preferred follow-on treatment but adequate alternatives are atovaquone-proguanil, quinine plus doxycycline or clindamycin, or mefloquine.” (CDC)
Nonetheless, none of these are ideal in severe malaria because IV therapy is preferred, and delayed switching may worsen outcomes.
A more standard alternative would have been atovaquone-proguanil (if oral route is acceptable and parasite density has dropped) or quinine plus doxycycline/clindamycin for at least 7 days.
In regions where drug resistance is low, mefloquine might be used. Close monitoring is essential.
However, the clinical result in this scenario—parasite reduction from 3+ to 1+ over a few days and resolution of symptoms—suggests some efficacy that might reflect residual effect from prior therapy or host immunity. The outcome is favorable, but whether proguanil alone was sufficient per se is unclear.
Monitoring and follow-up
- Repeat malaria microscopy (or rapid diagnostic test) at day 3–4 or earlier, depending on parasite clearance goals.
- Monitor for recrudescence or resistance.
- If parasitemia does not decline adequately (e.g. >1 % after 48 h), consider escalation to intravenous therapy or switching drug classes.
- Watch for delayed hemolysis (especially if any artemisinin exposure occurred) and for organ function changes.
In our case, the repeat test on day 4 showing residual parasitemia (1+) and symptomatic improvement is reassuring, though further follow-up is necessary.
Prognosis and Lessons for Practice
This case underscores several principles:
- Although artemisinin derivatives are safe in the vast majority of patients, life-threatening hypersensitivity reactions, though rare, can occur.
- In any acute neurologic event (seizure, loss of consciousness) during malaria therapy, clinicians should assess for allergic reaction, hypoxia, electrolyte disturbance, or cerebral malaria itself.
- Management requires prompt withdrawal of the offending agent, emergency stabilization, and initiation of an alternative antimalarial regimen.
- Close monitoring—parasitologic, hematologic, and organ function—is vital to ensure treatment success and detect late complications like delayed hemolysis.
Importantly, the favorable outcome in the example (resolution of symptoms, decline in parasitemia) is a positive sign—but in actual practice, repeated assessments and readiness to escalate therapy are essential.
Final assessment: Artemisinin derivatives are cornerstone antimalarials with generally excellent safety profiles. But clinicians must remain vigilant for hypersensitivity and neurologic events. In such cases, rapid recognition, withdrawal of the drug, acute supportive care, and a switch to evidence-based alternative antimalarials are required and further follow-up and monitoring are critical to ensure cure and avoid relapse.
