Increased Reticulocytosis during Infancy Is Associated with Increased Hospitalizations in Sickle Cell Anemia Patients during the First Three Years of Life

Emily Riehm Meier,Y Terry Lee,Elizabeth C Wright,Jeffery L Miller,Colleen Byrnes,Alan N Schechter,Naomi L C Luban,Wilbur Lam

doi:10.1371/journal.pone.0070794

Abstract

ObjectiveAmong older children with sickle cell anemia, leukocyte counts, hemoglobin, and reticulocytosis have previously been suggested as disease severity markers. Here we explored whether these blood parameters may be useful to predict early childhood disease severity when tested in early infancy, defined as postnatal ages 60–180 days.Study DesignData from fifty-nine subjects who were followed at Children’s National Medical Center’s Sickle Cell Program for at least three years was retrospectively analyzed. Comparisons were made between white blood cell counts, hemoglobin and reticulocyte levels measured at ages 60–180 days and the clinical course of sickle cell anemia during infancy and childhood.ResultsA majority of subjects had demonstrable anemia with increased reticulocytosis. Only increased absolute reticulocyte levels during early infancy were associated with a significant increase in hospitalization during the first three years of life. Higher absolute reticulocyte counts were also associated with a markedly shorter time to first hospitalizations and a four-fold higher cumulative frequency of clinical manifestations over the first three years of life. No significant increase in white blood cell counts was identified among the infant subjects.ConclusionsThese data suggest that during early infancy, increased reticulocytosis among asymptomatic SCA subjects is associated with increased severity of disease in childhood.

Highlights

The genetic basis of sickle cell anemia (HbSS, SCA) is well understood, the clinical phenotype is highly variable and difficult to predict. [1] Evidence of increased hemolysis begins during the first year of life as sickle hemoglobin (HbS) replaces fetal hemoglobin (HbF; a2c2)
Increased absolute reticulocyte levels during early infancy were associated with a significant increase in hospitalization during the first three years of life
These data suggest that during early infancy, increased reticulocytosis among asymptomatic SCA subjects is associated with increased severity of disease in childhood

Summary

Introduction

The genetic basis of sickle cell anemia (HbSS, SCA) is well understood, the clinical phenotype is highly variable and difficult to predict. [1] Evidence of increased hemolysis begins during the first year of life as sickle hemoglobin (HbS) replaces fetal hemoglobin (HbF; a2c2). [6,7,8] Ongoing efforts to identify infants and children at high risk for severe disease are especially relevant for choosing treatment options. SCA subjects at risk for severe disease should be identified as complications develop to better target therapeutic choices and timing. In the United States, hemoglobinopathy screening programs permit genetic diagnosis in newborns with SCA prior to the onset of any disease manifestations. [10] With newborn screening of infants becoming more widespread in Africa, disease severity markers that are useful at an early age are a priority for translational and clinical research. In resource-poor countries, efforts to target therapy to those children who are at highest risk of disease complications are especially important. Studies of genetic markers for the clinical phenotype are advancing, [11] but clinical markers that are strongly predictive for individual infants with SCA have not yet been identified

Methods

Results

Conclusion