Abstract
The Pediatric Hydroxyurea [HU] Phase III Clinical Trial [BABY HUG], an NHLBI and NICHD sponsored double-blind placebo-controlled 14 center trial (NCT00006400), was designed to critically assess the efficacy of HU in preventing chronic organ damage in infants with sickle cell anemia [SCA]. The spleen is among the first organs damaged in SCA, but loss of function is variable among patients and difficult to measure. Pretreatment splenic filtrative function as determined by uptake on 99mTc sulfur colloid liver-spleen [LS] scan was compared to surrogate markers of spleen function: pocked erythrocyte [PIT] counts and flow cytometric quantitation of Howell-Jolly Bodies [HJB]. Splenic uptake of 99mTc sulfur-colloid was qualitatively interpreted by structured consensus of 3 pediatric nuclear medicine physicians. Results were correlated with age, total hemoglobin [Hb], fetal hemoglobin[HbF], white blood cell [WBC], platelet [PLT], absolute neutrophil count [ANC], reticulocyte count [RETIC], spleen volume [SVOL] on ultrasound, maximum TCD velocity [TCD], glomerular filtration rate determined by 99mTc-DTPA [GFR], steady state oxygen saturation [O2], as well as clinical features of SCA (presence of a palpable spleen at screening, history of splenic sequestration, dactylitis, other vaso-occlusive event or transfusion). A logarithmic transformation was applied to each parameter (except age) to improve linearity with other variables and stabilize the variance of the transformed data. LS scans were available for 205 (89 male; mean age 13 mos, range 8–18 mos) of the 233 subjects who were recruited without regard to disease severity. To date 170 scans have been adjudicated into 1 of 3 categories of uptake: normal (n=21, 12.4%), reduced (n=124, 72.9%) and absent (n=25, 14.7%). Both surrogate markers of spleen function, PIT and HJB, increased with decreasing splenic function [p<.001] and correlated well with each other [R2=.57, p<.001]. Patients with absent splenic uptake had a significantly higher mean age (14.6 mos) than those with normal (12.3 mos) or reduced uptake (12.5 mos) [p=.001]. Higher PIT, HJB, WBC, RETIC, TCD and lower Hb or HbF values were significantly associated with decreased LS scan uptake [p<.001]. PLT [p=.002] and ANC [p=.02] were also differentiated by categorical spleen function, while DTPA and O2 were not. SVOL was also not associated with spleen function as assessed by LS scan, PIT, or HJB, but was associated with a palpable spleen at screening [p=.001]. Patients with diminished spleen function on LS scan were more likely to have a history of splenic sequestration [p=.027], dactylitis [p=.025], transfusion [p=.014], and vaso-occlusive events [p=.005]. Higher PIT and HJB values were associated with a history of splenic sequestration [p≤.001], palpable spleen at screening [p≤.003] and transfusion [p<.001]. No child with a normal spleen scan had a palpable spleen at screening or a history of splenic sequestration or transfusion. This is the largest structured assessment of spleen function in SCA reported to date. Baseline data from the BABY HUG trial confirms that loss of spleen function begins in the first year of life and is associated with indicators of disease severity such as lower Hb and HbF, higher WBC, and history of splenic enlargement. We conclude that a palpable spleen may not be a functional one, and that spleen volume is unrelated to function. Surrogate assessments, PIT and HJB, correlate well with LS scan results and may obviate the need for radionuclide exposure to determine splenic function. With these 3 methods to assess spleen function the BABY HUG trial is well positioned to determine whether HU impacts the loss of spleen function and the utility of surrogate markers to monitor that effect.
Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial