Clinical Correlates of Sleep-Disordered Breathing and Nocturnal Hypoxemia in Sickle Cell Disease
Authors: Martin Stephon T , Worsham Christopher , Cohen Robyn T , Klings Elizabeth S 
Published: October 2019

Abstract
Cardiopulmonary complications are the major cause of morbidity and mortality in sickle cell disease (SCD). In the general population, obstructive sleep apnea (OSA), has been associated with daytime sleepiness and increased risk for all-cause morbidity and mortality due to cardiovascular disease, systemic hypertension, pulmonary hypertension, and stroke-all of which are complications of SCD. Multiple small cohort studies have demonstrated that sleep-disordered breathing (SDB) is common among children and adolescents with SCD, but we do not understand the risk factors and clinical consequences of SDB in this population. Additionally, the prevalence of SDB in adults with SCD is unknown. We hypothesized that SDB and nocturnal hypoxemia are common across the lifespan in SCD and that the clinical presentation of SDB among SCD patients may be different from the general population without SCD. We performed a retrospective chart review of the overnight sleep studies performed at Boston Medical Center to gain greater understanding of the risk factors and clinical correlates of SDB in this population. We identified 29 patients with SCD who had a full polysomnogram for clinical purposes between 2012-2015. We obtained medical histories and steady state laboratory test results on these patients. Symptoms of SDB were assessed via the Epworth Sleepiness Scale (ESS). We evaluated the sleep studies for apneas, hypopneas, snoring, and the degree of hypoxemia. Data were analyzed using SAS, version 9.3. The 29 patients had a median age of 15.3 years (range 4 to 60), 66% were male, 43% were overweight or obese, and 86% had either the HbSS or HbSβ0 genotype 82% of these patients had at least one prior episode of the acute chest syndrome and 46% carried a diagnosis of asthma. Overall, the group had a median hemoglobin concentration of 9.7 (range 6.1-13.3) g/dL and median reticulocyte percentage of 7.3% (range 2.8-23.3%). 28% of the subjects had elevated scores on the ESS reflective of increased daytime sleepiness. Moderate to severe snoring, typically associated with OSA in the general population, was observed in 35% of patients. However, 48% of our patients met diagnostic criteria for OSA (defined as an apnea/hypopnea index [AHI] > 5), suggesting that a history of snoring may not be a sensitive marker to identify OSA risk in this population. Additionally, 17% of patients were considered to have nocturnal hypoxemia defined as greater than 5% of total sleep time with an oxygen saturation below 90%; this included 13% of those with OSA and 21% of those without OSA (p=0.65). In total, 38% of SCD patients referred for a sleep study had neither OSA nor nocturnal hypoxemia.
Comparing the adults (n=14) and children (n=15) showed some differences across the lifespan. AHI and ESS scores were significantly higher in adults, while the resting oxygen saturation was lower. HbSS or HbSβ0 patients typically had lower BMIs but similar findings on sleep studies compared to those with HbSC disease. Those with moderate to severe OSA were older (p=0.006), more likely to be overweight or obese and had both significantly higher hemoglobin concentrations (p=0.04) and lower reticulocyte counts (p=0.03) compared to those without moderate-severe OSA. Nocturnal hypoxemia was associated with a history of asthma (p=0.01), an increased reticulocyte percentage (p=0.005) and white blood cell count (p=0.006), and a reduced awake oxygen saturation (p=0.002) compared to those without significant nocturnal hypoxemia. Interestingly, increased age, BMI, or ESS scores were not associated with nocturnal hypoxemia.
Results from this small retrospective cohort study suggest that SDB in SCD is more complex than in the general population. SDB in SCD is common and not solely due to OSA. Additionally, traditional risk factors for OSA such as snoring and daytime sleepiness may not be present in SCD patients who have polysomnographic abnormalities. While this study needs to be confirmed with a larger prospective screening study, our findings suggest that intermittent nocturnal hypoxemia is potentially a modifiable cardiovascular risk factor in SCD.

Disclosures
Klings: Pfizer: Consultancy; Actelion Pharmaceuticals: Research Funding.