Educational Immersion Experience Title: Contribution of Asthma to Morbidity in Children with Sickle
Cell Disease
Mentor(s): Robert Strunk, M.D., and Michael DeBaun, M.D., M.P.H.
Location: NWT 10th floor
Overall Educational Goals: To learn how to conduct genotype and phenotype studies among children with
sickle cell disease
Project Description:
Sleep and Asthma Cohort Study in Sickle Cell Anemia
Washington University School of Medicine, Medical College of Wisconsin,
Case Western Reserve Medical School,
University College London-Great Ormond Street.
Our overall goal is to elucidate the physiologic, genetic, and molecular aspects of two common co-morbid
conditions, asthma and nocturnal oxygen desaturation, that increase the incidence rate of pain in sickle cell
anemia (SCA). At present, we do not know the interrelationships between asthma, nocturnal desaturation and
lung disease in SCA. We propose three interrelated projects to explore these relationships. The first and
second clinical projects will delineate the physiological basis for the association of asthma and nocturnal
desaturation with SCA related morbidity.
In the first project, we are delineating the physiological basis for the association of asthma and nocturnal
oxygen desaturation to SAC related morbidity. We have successfully enrolled 120 participants that have
received longitudinal assessment of full pulmonary functions tests and sleep studies. We are on target to
enroll approximately 300 participants in this study from St. Louis, Cleveland and London. Data analyses for
this group are ongoing.
In the second project, we are delineating the potential genetic basis for why asthma increases SCA morbidity.
We are currently using biological samples and clinical information from children with SCA participating in the
Silent Cerebral Infarct (SIT) Trial (NINDS-U01NS042804). We are performing a case-control study evaluating
whether genes associated with asthma increase the risk of pain and ACS episodes. We are performing the
SNP analysis in approximately 36 asthma related genes and approximately 1,700 SNPs. All markers have
been selected and we are awaiting the genetic analysis that will occur in the winter of 2007-8. The Sleep and
Asthma Cohort Study will serve as a validation group for the findings of this genetic analysis.
Dr. James Casella at The Johns Hopkins University (collaborator for this grant) has been approved for a
genomic-wide study (GWAS) on existing SIT samples. The GWAS analysis is supported by
NINDS/NHLBI/NHGRI. The phenotype of the clinical diagnosis of asthma and the total IgE levels, as well as
specific IgE levels, will be available for analysis.
In the third project, we are focusing on the mechanism of why asthma is associated with an increase in the rate
of painful. We have established a murine model of asthma in a sickle cell disease mouse. In our first set of
experiments, we demonstrated the dramatic mortality differences between control mice and SCD mice that
were sensitized to ovalbumin (OVA)-experimental asthma model. Experimentally-induced asthma SCD mice
died 3.8 times faster than SCD mice without experimentally-induced asthma. At this time, quantitative
measures of lung histology as outlined above are ongoing. Preliminary results indicate that OVA dosage does
influence severity of inflammation as assessed by the number of infiltrating eosinophils/neutrophils and
collagen deposition in the airways of the lung.
Taken together, the results of this highly interactive collaboration of clinical and basic scientists will permit new
insights into the mechanisms of lung disease, thus providing a strong foundation for targeted therapy for this
vulnerable group.
Educational goals by week
Weeks 1-3:
Learn research governance (ethics, informed consent)
Learn how to carefully define a clinical phenotype (asthma, atopy)
Learn how to construct a clinical research protocol
Weeks 3-6:
Learn how to better define a sleep phenotype by working with the pediatric sleep experts
Learn about asthma and sickle cell disease spectrum in adults and children by attending the adult sickle cell
disease clinic
Weeks 7-9:
Learn about laboratory procedures that allows for data quality and integrity
Learn how to establish a biological repository
Weeks 10-12:
Construct a careful review of genotype and phenotype correlations in lung disease or sleep disorder breathing
in sickle cell disease and present the review during the 45 minute discussion.
Prepare a review article on genotype and phenotype correlation in sickle cell disease.
Suggested readings:
1. Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with acute chest syndrome and
pain in children with sickle cell anemia. Blood 2006;108(9):2923-7.
2. Isaak EJ, Lechien B, Lindsey T, DeBaun MR. The Charles Drew Program in Missouri: a description of a
partnership among a blood center and several hospitals to address the care of patients with sickle cell
disease. Immunohematol 2006;22(3):112-16.
3. Spivey JF, Uong EC, Strunk R, Boslaugh SE, DeBaun MR. Low Daytime Pulse Oximetry Reading is
Associated with Nocturnal Desaturation and Obstructive Sleep Apnea Syndrome in Children with Sickle
Cell Anemia. Pediatr Blood and Cancer 2006 Epub, in press.
4. DeBaun MR, Jennings JE, Boyd JH, Field JJ, Hiller C, Strunk RC. The contribution of asthma to sickle
cell disease related morbidity and mortality. In: Hematology Education: the education program for the
annual congress of the European Hematology Association, pages 140-147, ISSN 1872-5503.
5. Boyd JH, Macklin EA, Strunk RA, DeBaun MR. Asthma is associated with increased mortality in
individuals with sickle cell anemia. Haematologica 2007;92(8):1115-8.
6. Phillips KL, An P, Boyd JH, Strunk RC, Casella JF, Barton BA, DeBaun MR. Major gene effect and
additive familial pattern of inheritance of asthma exist among families of probands with sickle cell
anemia and asthma. Am J Hum Biol 2007;Dec 26. Epub ahead of print.