Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial

Abstract

We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by 99m Tc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of < 1.2% or HJB < 55/10 6 red blood cells and absent function by PIT > 4.5% or HJB > 665/10 6 . HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400. (Blood. 2011;117(9): 2614-2617) IntroductionThe spleen is one of the first organs damaged in sickle cell anemia (SCA). Consequences of this damage, increased risk of invasive pneumococcal infection and splenic sequestration, are difficult to predict for a given child. The "gold standard" for assessment of splenic filtrative function is a 99m Tc sulfur-colloid liver-spleen (LS) scan. However, LS scans yield qualitative results and require low-dose radiation exposure.BABY HUG, the Pediatric Hydroxyurea phase 3 Clinical Trial, is an National Heart, Lung, and Blood Institute and National Institute of Child Health and Human Development-sponsored 14-center, randomized double-blind placebo-controlled trial of the efficacy of hydroxyurea in preventing chronic organ damage in infants with SCA. The trial was approved by the institutional review boards of all participating centers. Prevention of loss of splenic function is a primary endpoint. 1 After written informed consent in accordance with the Declaration of Helsinki, splenic filtrative function of children in BABY HUG was assessed by LS scan and compared with 2 surrogate biomarkers: pitted erythrocyte (PIT) counts by Nomarski optics and Howell-Jolly Bodies (HJBs) quantitated by flow cytometry. These pretreatment baseline data form the largest reported assessment of spleen function in young children with SCA by LS scan, define parameters of loss of function, and validate both biomarkers as accurate noninvasive measures of splenic function. Methods LS scanA standardized dose of 0.05 mCi/kg (minimum 0.5 mCi, 1 mCi if local practice) of 99m Tc sulfur-colloid was injected into a peripheral vein. Liver and spleen were imaged 30 minutes later in the posterior, anterior, left anterior oblique, and right posterior oblique planes. Splenic uptake was qualitatively interpreted on de-identified films by structured consensus of 3 pediatric nuclear medicine physicians as normal (spleen uptake equal to li...

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“…The evaluation of splenic function still rests chiefly on indirect markers, such as the pitted erythrocyte count, Howell Jolly body count, and Tc99m uptake. These tools have produced robust data regarding spleen function in vast longitudinal cohort studies of SCD infants (Rogers et al, 2011). However, the correlation between the results and the vulnerability to infection remains indirect.…”

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Potential Reduction of Mortality from Invasive Pneumococcal Infection among Children with Sickle Cell Disease in Haiti

“…The BABY HUG Multicenter Clinical Trial (NCT00006400), a placebocontrolled study, assessed the benefit of hydroxyurea over placebo in infants with SCA at a mean age of 13 months. Only 12% of these infants at baseline had normal spleen uptake by 99m technetium sulfur-colloid liver-spleen scans, with the majority having decreased uptake, and some no uptake, indicating that hyposplenia occurs frequently in children with SCA younger than 1 year of age [5]. This early hyposplenia requires prompt identification of infants at risk and the institution of preventive measures, including prophylactic penicillin by 2 months of age and immunization with available vaccines against encapsulated bacteria.…”