Abstract
Acute chest syndrome (ACS), a leading cause of morbidity in
sickle cell disease (SCD) occurs most commonly in children aged 2
to 4 years, but only a minority having recurrent and severe
episodes. A severe rapidly-progressive ACS phenotype is described
in adults, but rare in children. Infection, fat emboli, infarction,
heme and microthrombosis have been implicated in ACS pathogenesis,
however in the largest ACS study; an etiologic factor was not
identified in a majority (46%). Heterogeneity in the incidence and
severity of ACS, coupled with the lack of established biomarkers
that predict its occurrence or severity prompted our study of
children with SCD, aged 2-20 years, admitted to Children's
Healthcare of Atlanta with ACS (n=52), to identify modifiable
biochemical predictors of ACS severity.
We defined ACS as a new pulmonary infiltrate on chest
radiograph, associated with fever, cough or other respiratory
symptoms, and classified ACS events into severe and non-severe.
Severe ACS was defined as ACS with respiratory failure (≥3L
of oxygen to maintain saturations ≥92%), within 48hours of
diagnosis. Our severe ACS group (n=7) had lower oxygen saturations,
more red cell transfusions, intensive care admissions, and longer
hospitalizations. ACS diagnosis associated with a drop in
hemoglobin (Hb), suggesting hemolysis and release of heme into the
circulation. Total plasma heme (TPH), plasma free heme (PFH),
bilirubin and the major heme degradation enzymes; Hemopexin (Hpx)
and Heme Oxygenase-1 (HO-1) were measured in both acute (within 48
hours of ACS diagnosis) and follow-up (≥4 weeks from ACS
diagnosis) phases. Using the Wilcoxon signed-rank test, we found
that HO-1 (p=0.0652) and Hpx (p=0.0009) were higher at ACS
diagnosis, while Hb (p<0.0001), TPH (p=0.0488), PFH and
bilirubin were higher at follow-up. At ACS diagnosis, PFH related
positively with Hpx (r=0.3383, p=0.0163) but negatively with HO-1
(r=-0.4426, p=0.0026). Using multivariable regression analysis, Hpx
and the difference in Hb at ACS diagnosis were associated with
increased odds of severe ACS (P=0.0042, OR; 0.307, CI=0.056,
0.918). Our findings coupled with preclinical studies in sickle
mice, where respiratory failure was averted after the onset of
ACS-like symptoms following treatment with recombinant Hpx, suggest
that Hpx is a predictor of ACS severity.
Table of Contents
TABLE OF CONTENTS
A.
INTRODUCTION-------------------------------------------------------------------
1
B.
BACKGROUND---------------------------------------------------------------------
5
C.
METHODS----------------------------------------------------------------------------
12
D.
RESULTS-----------------------------------------------------------------------------
19
E.
DISCUSSION/CONCLUSIONS---------------------------------------------------
23
F.
REFERENCES-----------------------------------------------------------------------
26
G. TABLES AND
FIGURES-----------------------------------------------------------
Table I. Demographic and baseline clinical characteristics of the
study population comparing differences between severe and
non-severe ACS events------------------- 29
Table II. Associations of severe ACS with demographic and baseline
clinical characteristics of the study
population-----------------------------------------------------
30
Table III. Associations of severe ACS with laboratory
characteristics of the study population at ACS
diagnosis-----------------------------------------------------------------
31
Table IV. Associations of severe ACS with laboratory
characteristics of the study population at follow
up-----------------------------------------------------------------------
32
Table V. Associations of severe ACS with heme and biomarkers of
heme degradation during
ACS-------------------------------------------------------------------------------------
33
Table VI. Associations of severe ACS with heme and biomarkers of
heme degradation at follow
up----------------------------------------------------------------------------------------
34
Table VII. Association between plasma concentration of TPH, PFH,
HO-1, and Hpx during ACS compared with follow
up------------------------------------------------------ 35
Figure 1. Heme and biomarkers of heme degradation during ACS and at
follow up
----------------------------------------------------------------------------------------------------
36
Table VII. Correlation between heme degradation biomarkers (TPH,
PFH, HO-1and Hpx), during ACS and at
follow-up----------------------------------------------------------
37
Table VIII. Association between individual biomarkers of heme
degradation (TPH, PFH, HO-1and Hpx) and severe ACS in children with
SCD----------------------------------- 38
Figure 2. Model Diagnostics using the Hosmer-Lemeshow goodness of
fit test and the area under the ROC (Receiver Operator
Characteristic) curve--------------------------- 39
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