Post-Artesunate Delayed Hemolysis in Pediatric Malaria Patients in the United States

Abstract

Post-artesunate delayed hemolysis (PADH) occurred in 6 of 24 children treated with artesunate for severe malaria in the United States; however, severe hemolysis requiring hospitalization or transfusion was rare. In children in the United States treated with artesunate, counseling, and symptom monitoring may be preferred to weekly laboratory surveillance for PADH.

We find that delayed hemolysis is common in children treated with artesunate for severe malaria in the United States. However, severe hemolysis appears rare. Counseling and symptom monitoring may be preferable to weekly laboratory surveillance for PADH in this population.

INTRODUCTION

Malaria poses a major threat to global public health, causing millions of cases and over 500 000 deaths each year [1]. Intravenous artesunate is the first-line therapy for severe malaria worldwide and has substantially reduced mortality from this disease [2]. While artesunate is generally well tolerated, multiple studies have demonstrated severe delayed hemolysis, termed post-artesunate delayed hemolysis (PADH), following therapy [3]. In response, the United States Food and Drug Administration recommends weekly posttreatment laboratory monitoring of hemoglobin and hemolytic biomarkers for 4 weeks after artesunate therapy [4].

While the exact mechanism behind PADH remains unknown, it is hypothesized to be related to the premature death of erythrocytes previously infected by malaria parasites [5]. A recent study of adult travelers with severe malaria in the United States found that 2.7% experienced PADH and 56% of those required blood transfusion [3]. However, the prevalence and characteristics of PADH in children with malaria in non-endemic countries is unknown. Understanding the frequency and severity of PADH in the pediatric population will inform posttreatment monitoring for this condition. Here, we estimate the rate of PADH in children (≦18 years of age) treated for severe malaria in the United States. As severe pediatric malaria is rare in the United States, we use 2 data sources: a multicenter retrospective case series, including follow-up and laboratory data, to identify symptomatic and asymptomatic PADH, and an analysis of the larger Pediatric Health Information Systems Database (PHIS), to estimate rates of return encounters or hospitalizations for hemolytic anemia.

METHODS

Multicenter Retrospective Chart Review

We used ICD-10 diagnosis codes (Supplementary Table 1) to identify children treated for malaria at 9 hospitals (Children’s Hospital of Philadelphia, Riley Hospital for Children, Texas Children’s Hospital, Seattle Children’s Hospital, University of Washington Medical Center, Harborview Medical Center, UCSF Benioff Children’s Hospital, Hassenfeld Children’s Hospital at NYU Langone, and Bellevue Hospital), between April 2019 and December 2023. Electronic medical records for each patient were reviewed to identify patients treated with artesunate. Demographic characteristics, treatment, and baseline laboratory values were recorded. Laboratory values for PADH monitoring and subsequent malaria-related encounters were also recorded, when available. Detailed methods are described in Supplementary Materials and Methods.

PADH Case Definition

We defined confirmed PADH as a decrease in hemoglobin of >10% from discharge levels occurring between 1 and 4 weeks after initiation of artesunate treatment, in the setting of haptoglobin <10 mg/dL, and lactate dehydrogenase (LDH) >390 U/L or increased by ≥10% from prior measurement, and suspected PADH as a decrease in hemoglobin of >10%, occurring between 1 and 4 weeks after treatment when haptoglobin or LDH trends were not available [3].

Pediatric Health Information System Database Review

The PHIS Database contains clinical data from inpatient, ambulatory surgery, emergency department, and observation unit encounters from 49 US children’s hospitals [6]. We identified cases of malaria treated with artesunate, between August 2015 and July 2023, using ICD-10 diagnosis codes and generic drug codes (Supplementary Table 1). We identified repeat encounters for possible PADH, defined as encounters with ICD-10 codes related to anemia, adverse drug reactions, or blood transfusion procedure codes, occurring within 8 weeks of discharge. We excluded visits for recurrent malaria infection (identified by ICD-10 codes and antimalarial generic drug codes). Detailed methods are described in Supplementary Materials and Methods.

Ethical Approval

Protocols were approved by each participating institution’s human subjects review board (Supplementary Materials and Methods).

RESULTS

In the retrospective case review, 38 patients were treated with artesunate and 25 had laboratory monitoring for anemia or hemolysis (Figure 1, Supplementary Table 2). Two patients with posttreatment declines in hemoglobin attributable to other causes were excluded from the analysis. We identified 6 cases of PADH (4 confirmed and 2 suspected), representing 24% (95% CI: 9–45%, binomial exact calculation) of patients who received laboratory monitoring (Figure 1). Maximum parasitemia during admission was higher in cases of PADH than in those without evidence of PADH (median 17.0% vs 4.6% P = .024) (Supplementary Table 2). Age, transfusion status, admission bilirubin, or admission hemoglobin were not significantly different between groups (Supplementary Table 2). In all cases, hemolysis was identified within 21 days of initiation of artesunate. Notably, all cases of PADH were clinically mild; all patients remained asymptomatic and none required hospitalization or blood transfusion.

Figure 1.

Laboratory trends for pediatric malaria patients identified by multicenter chart review with PADH (red) or without PADH (black). (A, B) Hemoglobin trends during hospitalization (dotted line) and after discharge (solid line) for patients with identified PADH (A) and those without (B). Patients who received blood transfusions during initial hospitalization are shown as solid circles, and those that did not are shown as open circles. One patient required readmission for recurrent malaria infection (black arrow). (C–E) Trends in haptoglobin, lactate dehydrogenase, and reticulocyte count after hospitalization in the subset of patients where this testing was available. The gray bar represents the limit of detection for most haptoglobin assays (10 mg/dL).

Haptoglobin, LDH, and reticulocyte counts were monitored for a subset of patients with or without PADH (Figure 1). Haptoglobin levels remained undetectable (<10 mg/dL) in almost all subjects up to 4 weeks after admission, regardless of PADH status. LDH levels gradually declined over time but remained elevated in many patients without PADH at 4 weeks. Reticulocyte counts generally increased after discharge, but did not differ between children with vs without PADH.

We conducted a complementary analysis of the PHIS database to determine if patients treated with artesunate returned with symptomatic hemolysis. Of 92 patients treated with artesunate between May 2019 and July 2023 (Supplementary Table 3), 3 patients (3.3%, 95% CI: 0.7%–9.2%, binomial exact calculation) were readmitted within 4 weeks (5, 12, and 13 days) of treatment with a diagnosis of nonhereditary anemia. One patient required blood transfusion, although our validation of transfusion procedure codes in the PHIS database suggests that transfusions may be underreported (see Supplementary Materials and Methods). The durations of readmission were between 1 and 2 days, and none of the 3 patients had further encounters within the monitoring period.

DISCUSSION

We utilized a chart review of 9 hospitals coupled with administrative data from 49 children’s centers to describe PADH in children treated in the United States. Although one-quarter of children treated with artesunate developed PADH, the majority were asymptomatic, and <4% required readmission for acquired anemia. It therefore appears that cases of PADH in children are typically mild and infrequently require intervention.

Studies have found a correlation between the risk of PADH and increasing parasitemia or total bilirubin levels during admission, although these associations have been inconsistent [3, 5, 7]. We found that elevated parasitemia, but not elevated total bilirubin, was associated with PADH. This finding is biologically plausible, as PADH is thought to be caused by premature lysis of previously infected erythrocytes. Future studies should examine the predictive value of biomarkers of parasite burden, such as peripheral parasitemia and levels of parasite histidine-rich protein [8].

Current recommendations for monitoring for PADH include weekly monitoring of CBC, LDH, haptoglobin, and reticulocyte counts. In this study, haptoglobin levels remained low and LDH levels remained elevated for a prolonged period after initial infection in children without PADH, and reticulocyte counts also did not differentiate children with vs without PADH. These findings suggest that haptoglobin, LDH, and reticulocyte counts would not distinguish PADH from other causes of anemia following severe malaria infection, and that monitoring hemoglobin alone may be sufficient to assess for PADH.

The true incidence of PADH is unknown. The rate of PADH in our study is similar to that reported in a case series of pediatric patients in Germany (33%), and a study of predominantly adult patients in France (27%), but higher than what was reported in a recent study of predominantly adult patients in the United States (2.7%) [3, 9, 10]. These differences may be due to study design; the US study relied on passive case reporting, which may miss patients with asymptomatic PADH, underestimating the true incidence. In the current study, we were able to confirm follow-up for all patients and limited our analyses to those with sufficient laboratory follow-up. Alternatively, the risk of PADH may differ between children and adults in the United States.

Our study has limitations. First, cases of severe malaria in children in the United States are rare, limiting sample sizes. Thus, we leveraged 2 data sources to identify cases of severe hemolysis after artesunate. Of note, as most of the hospitals from the retrospective chart review are included in the PHIS database, we analyzed these 2 datasets separately to avoid counting individual cases twice. Second, we assumed most patients with malaria treated at a regional pediatric hospital would re-present to the same hospital in the setting of posttreatment hemolysis. Third, cases of acquired anemia following hospital discharge may not have been identified if incorrect diagnostic codes were used at subsequent encounters. Finally, due to incomplete transfusion reporting in the PHIS database, we may have underestimated rates of blood transfusion in the larger dataset. Additional studies, and a database of US pediatric malaria cases, would further elucidate rates of symptomatic PADH, hospitalization, and need for transfusion.

Weekly laboratory monitoring has been recommended to aid in the early recognition of PADH. Given the high rate of mild PADH but the low rate of symptomatic anemia observed in our study, approaches to PADH monitoring should balance the need to identify severe PADH with the burden of frequent laboratory testing. British guidelines for PADH monitoring include patient counseling and a follow-up hemoglobin screen at 2 weeks [11]. Adopting this approach would decrease unnecessary laboratory monitoring in asymptomatic patients. More frequent laboratory monitoring may be warranted for patients at increased risk for symptomatic anemia (eg, patients with preexisting hyperproliferative anemias) or in whom symptoms of hemolytic anemia might be missed, such as young children.

Supplementary Data

Supplementary materials are available at the Journal of The Pediatric Infectious Diseases Society online (http://jpids.oxfordjournals.org).

Notes

Financial support. This work was supported by the PIDS-St. Jude Children’s Research Hospital Fellowship Award in Basic and Translational Science, the National Institutes of Health (grant numbers T32AI118684, R01AI103280), the Doris Duke Foundation Paragon of Research Excellence Award, and the Children’s Hospital of Philadelphia.

Potential conflicts of interest. The authors: No reported conflicts of interest.

Authors’ Contributions

S. A. S., J. S. G., and A. R. O. J. contributed to the conception and design of this work. S. A. S., K. L. H. V., B. R., Z. W., A. K. F. D., J. A. M., M. L. W., N. L. T., V. L. S., and G. F. S., reviewed records and collected epidemiologic data. All authors contributed to manuscript revisions. All authors have agreed to final approval for submission.

Data Availability

The data in the study include pseudonymized (coded) personal data, which cannot be shared in full. De-identified data can be made available upon request to the extent allowed by regulatory agencies who oversaw the ethical conduct of this study. Data requests can be made to sundarars@chop.edu.