The Role of Heme and Heme Degradation in the Severity of Acute Chest Syndrome in Children with Sickle Cell Disease Open Access

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

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, General Health Sciences, Medicine and Surgery
Keyword	Heme Acute Chest Syndrome Sickle Cell Disease
Committee Chair / Thesis Advisor	Joiner, Clinton, Emory University
Committee Members	Shah, Amit J, Emory University Manatunga, Amita, Emory University

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