Prevalence and timing of iron deficiency among youth with sickle cell disease receiving chronic transfusions

Abstract Background Sickle cell disease (SCD) is a hereditary hemoglobinopathy affecting approximately 100,000 individuals in the United States and millions worldwide. Chronic transfusions (CT) are an established treatment for severe pediatric SCD complications, such as stroke. However, CT can lead to iron overload, necessitating routine iron monitoring with ferritin levels and magnetic resonance imaging to mitigate these risks. While the risk of iron overload with CT is well-documented, it is unclear whether children receiving CT may also be at risk for iron deficiency (ID), a common global nutritional deficiency and the leading cause of anemia in pediatric populations. Identifying and addressing ID may be particularly crucial for these youth. This is because untreated ID has the potential to cause anemia and impair myelination, neurogenesis, and neural connectivity, potentially compounding the hematologic and neurologic impacts that commonly affect youth with SCD receiving CT. Thus, the primary aim of this study was to determine the prevalence of ID (ferritin level <50 ng/mL) and possible ID (ferritin between 50-99 ng/mL) among youth with SCD on CT for ≥ 6 months who were receiving routine ferritin monitoring. We also aimed to describe the clinical characteristics of those with ID/possible ID and the timing of these diagnoses in relation to the initiation of CT. Methods This was a single-center, retrospective chart review of youth ages 6 months-21 years with SCD. The Nationwide Children's Hospital (NCH) SCD database and manual review of electronic medical records (EMR) were used to identify youth with SCD at NCH between 1/1/2015-12/31/2023 who had received CT for ≥6 months and ferritin monitoring at least every three months during the time they were receiving CT. Individuals who received a bone marrow transplant were excluded from the study. Those with ID/possible ID had their demographic (e.g., age, sex, race, insurance status), clinical (e.g., SCD genotype), laboratory (e.g., ferritin levels), and indication and duration of CT data abstracted from the EMR at the date of their first ferritin <100 ng/mL. Descriptive statistics summarized the data. Results We identified 60 eligible youth. Of these, 27 (45%) had either ID (n=6) or possible ID (n=21). Of those with ID/possible ID, 22% were 8-12 years, 48% were 13-17 years, and 30% were 18-21 years; 74% were male; and 78% had Hemoglobin (Hb) SS, 18% had Hb SC, and 7% had Hb Sβ+. They were also predominantly Black/African American/African (96%), on public insurance (74%), and receiving their CT via erthyrocytapheresis (100%). The most common indication for CT among these youth were frequent pain episodes (59%), but 19% had a prior stroke, 7% were receiving CT for an abnormal transcranial doppler, and 15% had a severe acute chest syndrome episode. In addition, all youth with ID and most with possible ID (71%) were noted to have a ferritin <100 ng/mL within two years of initiating CT. Conclusions We found that nearly half of the youth at our center on CT who were receiving ferritin monitoring had ID/possible ID suggesting that low iron stores may be common but unrecognized in youth with SCD on CT. Notably, youth who had ID/possible ID commonly were receiving CT via erythrocytapheresis, >8 years old, and male and were noted to have ID/possible ID shortly after initiating CT. While these findings need to be confirmed, they could suggest there may be additional causes of ID in youth with SCD receiving CT, such as iron losses from erythrocytapheresis, compared to youth in the general population and that some may be initiating CT with low iron stores. Our study was limited by its small size, retrospective and descriptive design, and that serum ferritin is an imperfect marker of ID in those with chronic inflammatory conditions such as SCD. Given that ID is both preventable and treatable, our findings underscore the need for larger, prospective, multi-center studies to better understand the etiology and clinical consequences of ID in this population. Futures studies should also assess if normalizing iron stores improves outcomes such as anemia, cognitive function, and patient-reported quality of life that are commonly affected in youth with SCD who are receiving CT.