Post Artesunate Delayed Hemolysis in Pediatric Patients in the United States
Authors: Sundararaman Sesh A , Hanze Villavicencio Karen L , Roper Brianne , Wang Ziyi , Davis Amy K F , Mayhew Jonathan A , Wang Michelle L , Tang Nina L , Soma Vijaya L , Shust Gail F , Feeney Margaret E , Trehan Indi , Weatherhead Jill E , John Chandy C , Gerber Jeffrey S , John Audrey O 
Published: October 2024

Abstract

Background
Malaria continues to pose a major threat to global public health, causing millions of infections and hundreds of thousands of deaths each year. Intravenous artesunate is the current first line therapy for severe malaria and has substantially reduced its mortality. Some patients develop severe delayed hemolysis after artesunate therapy, a phenomenon termed post artesunate delayed hemolysis (PADH). A recent study of U.S. adults treated with artesunate found that 2.7% of patients experienced PADH and 56% of those patients required blood transfusion. Thus, the U.S. Food and Drug Administration recommends that patients treated with artesunate receive weekly post-treatment monitoring of hemoglobin and hemolytic markers for four weeks after therapy.
While PADH in adults frequently requires blood transfusion, the frequency and severity of PADH in pediatric patients in non-endemic countries is not known. Understanding the risk of PADH in pediatric patients is essential to determine appropriate monitoring for this condition.

Methods
Multicenter Retrospective Chart Review
To estimate rates of PADH in pediatric patients (0-18 years of age), we used ICD-10 diagnosis codes to identify patients treated for malaria at seven hospitals (The Children’s Hospital of Philadelphia, Riley Hospital for Children, Texas Children’s Hospital, Seattle Children’s Hospital, UCSF Benioff Children’s Hospital, NYU Langone Medical Center, and Bellevue Hospital), between April 2017 and July 2022. We reviewed post-discharge laboratory values and clinic visits to identify patients with laboratory findings of PADH and determine clinical outcomes.
Pediatric Health Information System (PHIS) Database Review
To estimate rates of severe PADH requiring repeat emergency room visit or hospitalization, we used ICD-10 diagnosis codes to identify patients who were treated for malaria with artesunate between January 2019 and July 2023 in a database of 49 children’s hospitals (PHIS). We reviewed patient visits within eight weeks of treatment to identify patients with repeat presentations related to anemia or hemolysis.

Results
In our retrospective chart review, four of seventeen patients (25%) treated with artesunate had laboratory evidence of PADH. None of these patients were symptomatic and none required readmission or medical intervention. Haptoglobin levels remained low in most patients up to four weeks after treatment, regardless of the presence of PADH, and lactate dehydrogenase (LDH) levels slowly declined over this period.
We identified 92 patients in the PHIS database who were treated with artesunate. Of these, three patients (3.3%) had a repeat presentation within four weeks with one or more diagnosis suggestive of new onset anemia. Repeat presentations occurred 5-13 days after initial admission for malaria.

Conclusion
PADH is common in US pediatric patients treated with artesunate for severe malaria. However, severe hemolysis requiring repeat emergency room visit or readmission is rare. We find that haptoglobin and LDH levels were not useful as initial screening labs for PADH in pediatric patients. Together, our findings call into question the utility of weekly laboratory monitoring, as opposed to symptom-based monitoring, to identify pediatric patients at risk of readmission for PADH. Additional studies are necessary to determine which patients would benefit from weekly laboratory monitoring and which can be monitored clinically.