Abstract

Introduction Transcranial doppler ultrasound (TCD) screening for primary stroke prevention in children with sickle cell anemia (SCA) was established in higher-resource regions, targeting interventions for highest velocity (“abnormal”). We sought to identify additional stroke risk factors in Uganda.

Methods We conducted a 30-month open-label single-arm Ugandan hydroxyurea trial, dose-escalated to maximum tolerated dose, aimed to test brain protection for children aged 3-9 years with SCA. Study procedures included history, clinical stroke examination and prospective TCD and laboratory assessments.

Results Overall, 264 children received study HU, mean age 5.6±1.7, hemoglobin 7.8±1.2g/dL, fetal hemoglobin (HbF) 11.9±8.1%, enrolment TCD maximum velocity 148.4±29.3cm/second; 15 (5.7%) had abnormal TCD. Mean TAMV at trial completion was131.9±SD25.7 cm/sec. Four participants without abnormal enrolment TCD developed acute stroke within the initial 16 months (incidence 0.62 per 100 person years); Two had enrolment HbF ≤3.1%, 2 had low oxygen saturation (90%), 1 had recurring severe anemia necessitating multiple transfusions. Apparent stroke precipitants were severe malaria, acute chest syndrome, recent pain crisis or uncertain cause. At trial completion, 8 additional participants had a higher risk TCD category than at enrolment.

Conclusion Effectiveness of TCD screening for stroke prevention may vary by region, as no participant with incident stroke was at highest risk. Antecedent and/or ongoing SCA-related risks of anemia, low HbF, hypoxemia, infections and/or disease complications likely contributed to stroke despite trial HU. Results suggest that TCD alone may not fully identify highest stroke risk in the region, and need for primary stroke prevention from early and continuous hydroxyurea therapy.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT04750707

Clinical Protocols

https://www.sciencedirect.com/science/article/pii/S2451865424001510?via%3Dihub

Funding Statement

The work was supported by grants the National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD096559 (Idro, Green) and the Fogarty International Center D43TW010928 (John, Idro).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All study procedures were approved by the Makerere University School of Medicine Ethics Committee, the institutional review boards (IRB) of Columbia University and Mulago Hospital.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Yes

Data Availability

All aggregated, de-identified data produced in the present study are available upon reasonable request to the authors

Abbreviation Complete TermTCDTranscranial doppler ultrasoundSCASickle cell anemiaMTDMaximum tolerated doseHbFFetal hemoglobinSSASub-Saharan AfricaMHSCCMulago Hospital Sickle Cell ClinicHbHemoglobinTAMVTime-averaged maximum mean velocityHUHydroxyureaIRBInstitutional review boardsPedNIHSSPediatric NIH stroke scaleO2saturation Percutaneous oxygen saturationANCAbsolute neutrophil countMCVRed cell mean corpuscular volumeAE or SAEAdverse events or severe AEsACSAcute chest syndromeMRIMagnetic resonance imaging