SEGMENT 1: Dr. Michael DeBaun shares insights into what he sees as the most compelling research questions for the sickle cell community, his research in Nigeria, and his work with the Sleep and Asthma Cohort Study.


Dr. Gary H. Gibbons, director, NHLBI:  Hi, I’m Gary Gibbons. It’s my pleasure to have as our guest today Michael DeBaun, professor of pediatrics and medicine at the Vanderbilt University School of Medicine.

Michael, thanks again for taking this time. We want you to share your thoughts about your research program and your research career and your tremendous work you have done in sickle cell disease as one of our notable investigators. I know you are currently involved in a number of NIH-funded studies in this area of sickle cell disease.

And given your interest and your engagement in patient care, I presume that some of the things you see as a clinician in providing the best possible care may influence your choice of research questions. What do you see as the most compelling research questions in sickle cell disease from your perspective? 

Dr. Michael DeBaun, Vanderbilt University:  To respond to your first question, you are absolutely right. Every RO1 or foundation grant that I’ve received has been based on listening to the family talk to me about the disease. And it’s a wonderful gift to be in an office setting, to be able to listen to the challenges that the parents have presented you with and then really go home and think about it and mull it over with your colleagues, with your family and then try to come up with a systematic strategy to address the needs that exist. But not only the families you see that day, but the other families that are so similar throughout the country and, I dare say, throughout the world. 

The biggest challenge for families going forward is this sense of hope. Families want to know that their child with this disease – when I see the 1-month-old or 2-month-old who has just been diagnosed with the disease, they want to know that their 18-year-old is going to finish high school and that they are going to have a normal life. I think the opportunity to contribute to the knowledge of care for those patients is very exciting. I look to that future for every one of those newborns that I see. I look the parents in the eye and say, “Your child, as a result of medical advances, research that has been done by others prior to your child’s birth has greatly increased the chances of your child reaching her 18th birthday, and I hope to be able to celebrate that day with you when it comes.”

Dr. Gibbons:  In that regard, as you know, the NIH and NHLBI have funded a number of studies over the last couple of decades, as you pointed out, that have made for tremendous advances and further extensions of the median survival of children with sickle cell disease, such that the likelihood is greater that they will see that 18-year-old birthday. In that regard, here in 2013, what’s at the leading edge right now in terms of the compelling research studies that need to be pursued? 

Dr. DeBaun:  Probably the biggest concern for many of the parents is not whether their child is going to make it to their 18th birthday – 95% of those children are going to do that or more. It’s going to be, can they live a normal life? One of the biggest apprehensions is the child – the student, rather, who is not doing well in school. And [it was only because of] this concept of the silent cerebral infarct, which was really a tangential benefit of the technology to screen for the MRI, screen for the silent infarcts through an MRI of the brain as a result of the cooperative study for sickle cell disease, a study that was funded by NHLBI over 30 years ago, did we begin to understand this impact of this injury to the brain on the lives of students with this disease. 

My sense is that, as we probe deeper into understanding how our students are doing in the classroom – and there are only a few programs in the country that are taking inventory on academic performance and performance copies of testing on a routine basis – we are identifying a tremendous challenge to understand how having a chronic disease has an impact on [the] development of a growing child, a student who, unlike say an adult who had a stroke where you are trying to get them back to improving the activities of daily living. For a 6-, 7-, 8-, 9-year-old who has had a stroke, you have not only the activities of daily living that you want to educate them about resuming, but you also want to keep them on a trajectory so they are learning new information. And that’s a formidable challenge, particularly in a child with a chronic disease. 

Dr. Gibbons:  With regard to perhaps some of your NIH-funded work, what are you pursuing now in terms of potential either proactive or preventative strategies that may be on the horizon to address this challenge? 

Dr. DeBaun:  There are several. The first is the issue [of] addressing the global burden of sickle cell disease. As you know, sickle cell disease occurs in about one in 1,200 births in the United States and there are about 100,000 individuals with the disease in the U.S. But if you move to sub-Saharan Africa, the burden of sickle cell disease is far greater. In Nigeria alone, there is an estimated between 100,000 and 150,000 newborns with this disease per year. 

So with funding from the Fogarty Institute and support by the NIH, obviously, we have a Primary Stroke Prevention Feasibility Trial in the northern portion of Nigeria. Our goal is to ultimately prevent strokes in this patient population, in children with sickle cell disease, with the idea that if we are able to show a reasonable strategy for preventing strokes, children who have been identified as having a high risk of strokes could benefit from hydroxyurea, again, a drug that was used in a clinical trial supported by NHLBI that showed convincingly that if used in adults with this [disease], it would decrease vaso-occlusive pain episodes, acute chest syndrome episodes, and decrease blood transfusion therapy dramatically. Also, with follow-up studies, hydroxyurea used in adults is shown to prolong their life when compared to individuals who have not taken the drug on a regular basis. So that’s one of the studies that we are engaged in. 

Another study that we are engaged in and [that is] supported by the NHLBI is the Sleep and Asthma Cohort Study. We are in our ninth year of this study. Our focus here is to understand the interface between asthma, a very common disease in African American children, particularly urban African American children, and sleep-disordered breathing on sickle cell disease morbidity and mortality. That’s again a strategy that is born by listening to the families of our children with the disease describe symptoms of asthma and having originally those symptoms being attributed to their sickle cell disease, but later, with more thorough probing, understanding the fact that many of those children had actually a separate diagnosis of asthma that often times made their disease worse. 

Dr. Gibbons:  Just to be clear about that, as you pointed out, African American children often have a higher prevalence of asthma. And obviously, in the context of sickle cell, is this something that is disproportionate amongst patients with sickle cell or is it again just the coincidence of these two conditions in this particular patient population? 

Dr. DeBaun:  Well, it’s probably a combination of both. Symptoms of asthma include wheezing, recurrent wheezing, and many children with asthma present with recurrent wheezing who have sickle cell disease. But if you – which we have done with the NHLBI study -- look carefully at the history of those children, perform pulmonary function tests, what we find is that even if the child has no evidence of atopy, specifically no evidence of a family history of asthma, no eczema, relatively normal IgE level, you will find a subgroup of children who have recurrent wheezing. Our sense is that the recurrent wheezing is related to the sickle cell disease in and of itself and not related specifically to the phenotype of asthma. 

Dr. Gibbons:  Interesting. And is this suggestive of other aspects of sickle cell disease where increasingly people are thinking there is an inflammatory component and in this way sort of manifesting itself in the lung? 

Dr. DeBaun:  Yes. Again, with support from NHLBI, we were able to use the transgenic sickle cell disease mouse and invoke an experimental model of asthma. And what we were able to show is that the mouse model of sickle cell disease, once given the standard antigen to invoke experimental asthma as per protocol, actually had a precipitous death.  This is exactly what we would have anticipated – that there would have been an exaggerated inflammatory response in the setting of a sickle cell mouse when compared to a wild-type mouse. And, as a result, the exaggerated inflammatory response would result in death. That is exactly what the histology of the lung demonstrated was a much exaggerated inflammatory response of the lung, mimicking, essentially, what you see in experimental asthma. 

In another set of studies that were also funded by NHLBI, we looked specifically at the sickle cell mouse lung and compared it to the wild-type mouse to determine whether there was any evidence of abnormal pulmonary physiology. And again, what we found was that in the setting of just sickle cell disease, without any provocation for inflammation, the sickle cell mouse had a much higher baseline assessment of histologic findings associated with inflammatory lung disease. And the physiology was also suggestive of obstructive lung disease. 

Dr. Gibbons:  That’s fascinating, Michael. I also understand that you have been exploring a very emerging topic that actually is part of the NHLBI portfolio that relates to sleep and the effect that is clearly emerging in a number of different fields, where sleep abnormalities or disturbances are associated with obesity and diabetes and cardiovascular complications. Could you say a word about your research on sleep in the context of sickle cell disease? 

Dr. DeBaun:  Yes. As part of our Sleep and Asthma Cohort Study, we have performed rigorous sleep studies in over 250 children, and then have repeated those sleep studies approximately five years later. The ultimate goal was to understand the intersection between sleep-disordered breathing and sickle cell disease-related morbidity. This is a complex area of scientific inquiry in part because so much of the parameters that we depend on in assessing sleep relate to the oxygen saturation level at night. Children with sickle cell disease have an abnormal oxygen disassociation curve when compared to individuals who have predominantly hemoglobin A. The oxygen disassociation curve has shifted to the right and their slope of that curve is actually shifted as well, so that you could imagine a patient with an oxygen saturation of 94-95% may slip off of that shoulder on that oxygen disassociation curve much faster if they have sickle cell disease, than if they don’t. And yet all of the parameters that we use to determine whether a patient has sleep-disordered breathing is dependent upon the 3% drop in oxygen saturation during the night. 

Our preliminary findings are really quite intriguing. It does show that there is a decrease in nocturnal desaturation in children with sickle cell disease, when compared to what you would expect in normal controls. Also, as you know, there is an increase in obstructive sleep apnea syndrome in children of African descent. Given the fact that 95% of our children in this cohort are of African descent, we’ve actually eliminated race in looking at the subgroup for children with this disease. We are seeing pathology, particularly as it relates to sleep-disordered breathing, according to the formal criteria. 

Dr. Gibbons:  That is fascinating.