Clinical and laboratory findings associated with sleep disordered breathing in sickle cell disease
2017; Wiley; Volume: 92; Issue: 12 Linguagem: Inglês
10.1002/ajh.24892
ISSN1096-8652
AutoresChristopher M. Worsham, Stephon T. Martin, Mehdi Nouraie, Robyn T. Cohen, Elizabeth S. Klings,
Tópico(s)Fetal and Pediatric Neurological Disorders
ResumoAmerican Journal of HematologyVolume 92, Issue 12 p. E649-E651 E-ONLY ARTICLEFree Access Clinical and laboratory findings associated with sleep disordered breathing in sickle cell disease Christopher M. Worsham, Christopher M. Worsham orcid.org/0000-0002-1611-6871 Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorStephon T. Martin, Stephon T. Martin Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorSyed-Mehdi Nouraie, Syed-Mehdi Nouraie Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PennsylvaniaSearch for more papers by this authorRobyn T. Cohen, Robyn T. Cohen Boston University School of Medicine, Boston, Massachusetts Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts Dr. Robyn T. Cohen and Dr. Elizabeth S. Klings are co-senior authors on this manuscript.Search for more papers by this authorElizabeth S. Klings, Corresponding Author Elizabeth S. Klings klingon@bu.edu Boston University School of Medicine, Boston, Massachusetts The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts Dr. Robyn T. Cohen and Dr. Elizabeth S. Klings are co-senior authors on this manuscript.Correspondence Elizabeth Klings, Boston University School of Medicine, 72 East Concord Street, R-304, Boston, MA 02118. Email:klingon@bu.eduSearch for more papers by this author Christopher M. Worsham, Christopher M. Worsham orcid.org/0000-0002-1611-6871 Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorStephon T. Martin, Stephon T. Martin Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorSyed-Mehdi Nouraie, Syed-Mehdi Nouraie Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PennsylvaniaSearch for more papers by this authorRobyn T. Cohen, Robyn T. Cohen Boston University School of Medicine, Boston, Massachusetts Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts Dr. Robyn T. Cohen and Dr. Elizabeth S. Klings are co-senior authors on this manuscript.Search for more papers by this authorElizabeth S. Klings, Corresponding Author Elizabeth S. Klings klingon@bu.edu Boston University School of Medicine, Boston, Massachusetts The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts Dr. Robyn T. Cohen and Dr. Elizabeth S. Klings are co-senior authors on this manuscript.Correspondence Elizabeth Klings, Boston University School of Medicine, 72 East Concord Street, R-304, Boston, MA 02118. Email:klingon@bu.eduSearch for more papers by this author First published: 22 August 2017 https://doi.org/10.1002/ajh.24892Citations: 10 Funding information: Dr. Klings is funded by 1R01AT006358, H133G140186, 1U01HL128566 AboutFiguresReferencesRelatedInformationPDFSections CONFLICTS OF INTERESTREFERENCESCiting LiteraturePDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL To the Editor: Sickle cell disease is the most common life-limiting genetic disease in the United States, with median survival in the 5th or 6th decade depending on genotype. While acute and chronic pulmonary complications are among the most common causes of morbidity and mortality, our understanding of each of these conditions remains limited. Sleep-disordered breathing (SDB) is a respiratory abnormality whose true prevalence and impact on overall SCD pathogenesis are not fully understood. SDB is an umbrella term describing many types of abnormal breathing during sleep; for this manuscript, SDB refers to obstructive sleep apnea (OSA) and nocturnal hypoxemia in the absence of obstruction (NH). OSA is defined as repeated episodes of partial or complete cessation of breathing during sleep associated with a decrease in oxygen desaturation. In the general population OSA and NH are associated with pathology (poor sleep quality, pulmonary and systemic hypertension, endothelial dysfunction, and stroke) that have direct relevance to SCD; however, associations between SDB and SCD severity and progression have been inadequately studied.1 The objective of this study was to identify clinical and laboratory characteristics associated with polysomnogram-diagnosed SDB. We performed a retrospective chart review of patients with SCD who had overnight polysomnography (PSG) as part of their outpatient care at Boston Medical Center (BMC) between 2012 and 2016. Obstructive sleep apnea (OSA) was defined in this analysis as an apnea-hypopnea index (AHI) ≥ 5.0 events per hour. Nocturnal hypoxemia was defined as having ≥5% of total sleep time (TST) with an oxygen saturation below 90%. Clinical and laboratory data were obtained from review of the electronic medical record. All PSGs were performed while patient was clinically stable as defined as at least 4 weeks after a vaso-occlusive event (pain or ACS) or a blood transfusion. Analyses were conducted using Stata 14.0 (StataCorp., College Station, TX). This study was approved by the Boston University Institutional Review Board. Our cohort included 45 African-American individuals (22 adults and 23 children) with SCD who underwent PSG. Seventy eight percent had the HbSS or HbSβ0 genotype (96% of children and 61% of adults); remaining subjects had the HbSC genotype. While 51% of patients were referred for sleep studies because of a history of snoring, additional indications included: nocturnal enuresis (43% of children), daytime somnolence, oxygen desaturation at rest or during exertion, or as follow-up after tonsillectomy/adenoidectomy. Individuals with OSA were older compared to those without OSA. The association of OSA with age was driven by gender differences as there was a steady increase in the frequency of OSA after age 15 in males while the frequency of OSA in females did not change significantly change as age increased (Figure 1). There was no association between BMI and frequency of OSA (p = 0.30), though obesity was rare in our cohort. In a multivariable logistic regression model adjusted for age and gender, a higher rate of ACS events prior to the PSG was not associated with increased odds of having OSA (OR 2.09, 95% CI 0.39–11.14, P = .39), nor was OSA associated with increased likelihood of a future vaso-occlusive (pain or ACS) episodes. Figure 1Open in figure viewerPowerPoint Lowess plot of the association between age and frequency of OSA in a referred population of patients with sickle cell disease, stratified by gender As shown in Table 1, individuals with nocturnal hypoxemia had a lower daytime oxygen saturation, higher reticulocyte percentage, higher white blood cell counts, and higher serum aspartate aminotransferase (AST) concentrations compared to those without nocturnal hypoxemia. Individuals with asthma were more likely to have NH than those without asthma. There was a significant inverse correlation between the percent of total sleep time with oxygen saturation below 90% and an individual's daytime resting oxygen saturation (Spearman ρ = −0.40, P = .008). Those with NH were not more likely to have OSA (P = .70); several patients with NH did not have OSA (n = 5, 63%). There was no significant difference in age, genotype, BMI, systolic or diastolic blood pressures, or hydroxyurea use between those with and without nocturnal hypoxemia. In a multivariable model adjusted for reticulocyte count, the rate of prior ACS episodes was not associated with the odds of having NH (OR 1.42, 95% CI 0.40–5.04, P = .60). We did not detect an association between NH and future rates of vaso-occlusive (pain or ACS) episodes (OR 2.99, 95% CI 0.53–16.80, P = .20). Table 1. Clinical and laboratory characteristics of individuals with sickle cell disease referred for sleep study, stratified by presence or absence of obstructive sleep apnea and nocturnal hypoxemia OSA- OSA+ P value NH- NH+ N Results N Results N Results N Results P value Age (years), median (IQR) 31 13.5 (9.9–12.6) 14 31.0 (20.6–41.6) .007 37 17.7 (10.2–29.8) 8 17.5 (13.2–29.9) .5 Male sex, N (%) 31 13 (42%) 14 10 (71%) .07 37 16 (43%) 8 7 (88%) .047 Genotype, N (%) 31 14 .24 37 8 .66 SS 26 (84%) 9 (64%) 28 (76%) 7 (88%) SC/Sβ+ 5 (16%) 5 (36%) 9 (24%) 1 (12%) Systolic blood pressure (mm Hg), median (IQR) 31 108 (104–118) 14 127 (111–143) .002 37 110 (104–119) 8 119 (112–127) .11 Diastolic blood pressure (mm Hg), median (IQR) 31 68 (63–71) 14 75 (64–85) .12 37 69 (64–73) 8 66 (63–70) .6 Resting oxygen saturation in clinic, median (IQR) 31 98 (97–100) 14 98 (97–99) .4 37 98 (97–100) 8 97 (95–98) .023 Taking hydroxyurea at time of sleep study, N (%) 31 20 (65%) 14 7 (50%) .4 37 22 (59%) 8 5 (63%) .6 History of asthma, N (%) 31 12 (39%) 14 2 (14%) .10 37 9 (24%) 8 5 (63%) .034 History of ACS prior to the sleep study, N (%) 30 22 (73%) 14 9 (64%) .5 36 25 (69%) 8 5 (83%) .8 Hemoglobin (g/dL), median (IQR) 31 9.3 (8.1–10.2) 14 10.1 (8.9–11.5) .07 37 9.7 (8.4–10.4) 8 8.4 (6.9–10.0) .16 Reticulocyte percent, median (IQR) 30 7.2 (4.6–20.7) 11 7.3 (4.0–11.0) .5 33 5.5 (4.0–9.9) 8 19.7 (11.7–23.0) <.001 WBC (cells x103/µL), median (IQR) 31 9.5 (5.9–11.8) 14 8.2 (7.0–10.3) .4 37 8.6 (5.9–10.4) 8 12.3 (9.6–13.1) .031 Creatinine (mg/dL), median (IQR) 31 0.6 (0.5–0.7) 14 0.8 (0.7–0.9) .019 37 0.7 (0.5–0.8) 8 0.5 (0.5–0.7) .2 AST (IU), median (IQR) 30 42 (27–58) 14 42 (23–44) .7 36 39 (23–44) 8 57 (51–61) .004 ALT (IU), median (IQR) 30 20 (16–30) 14 26 (18–33) .3 36 24 (16–33) 8 21 (18–33) .8 Results presented for continuous variables are medians (interquartile range). N is the number of available data points. Abbreviations: ACS: acute chest syndrome; ALT: alanine aminotransferase; AST: aspartate aminotransferase; IU: international units. IQR: interquartile range; NH: nocturnal hypoxemia; OSA: obstructive sleep apnea; WBC: white blood count. Clinical, laboratory, and sleep-related characteristics were compared between groups using a Fisher's exact test for categorical variables and a Wilcoxon Rank Sum test for continuous variables. Sleep study abnormalities were common in our referral population of adults and children with SCD; 31% had OSA, 18% had nocturnal hypoxemia, and 7% had both. Historically, oxygen desaturations during sleep in the SCD population have been attributed to OSA from adenotonsillar hypertrophy.2 Our findings of nocturnal hypoxemia in children and adults irrespective of the presence of OSA are consistent with other studies3 which report nocturnal hypoxemia in the absence of obstructive events. This study and others implicate a link between nocturnal and daytime hypoxia which could have a persistent deleterious impact on vascular remodeling. The association between NH, higher reticulocyte counts, and elevations in AST concentration suggest that NH may be linked to increased hemolysis which also modulates endothelial dysfunction in SCD. The association of a leukocytosis with NH is of interest not only because it suggests dysregulated inflammation, which may modulate SCD-related vasculopathy, but also because of the association between leukocytosis and increased mortality risk.4 The finding of increased frequency of OSA in males over the age of 15 suggests that OSA may be related to the accelerated mortality5 and increased endothelial dysfunction during flow-mediated dilation testing6 among males compared to females. Taken together, these data begin to link OSA to increased vascular risk in patients with SCD. In conclusion, sleep disordered breathing was a common finding among children and adults referred for a sleep study (including among those without snoring or obesity) and may have important links to disease severity. The presence of OSA and NH in the absence of sleep-related symptoms suggests current SCD guideline recommendations for symptom screening alone may be inadequate for this population. Prospective, longitudinal research is needed to determine if the identification and treatment of SDB can reduce morbidity and mortality for individuals with SCD. CONFLICTS OF INTEREST Dr. Klings receives research grant support from Actelion, Bayer, Eiger, Reata, and Arena Pharmaceuticals; no conflict with this work. REFERENCES 1 Gileles-Hillel A, Kheirandish-Gozal L, Gozal D. Hemoglobinopathies and sleep–The road less traveled. Sleep Med Rev. 2015; 24: 57– 70. 2 Strauss T, Sin S, Marcus CL, et al. Upper airway lymphoid tissue size in children with sickle cell disease. Chest. 2012; 142: 94– 100. 3 Needleman JP, Franco ME, Varlotta L, et al. Mechanisms of nocturnal oxyhemoglobin desaturation in children and adolescents with sickle cell disease. Pediatr Pulmonol. 1999; 28: 418– 422. 4 Asadollahi K, Beeching NJ, Gill GV. Leukocytosis as a predictor for non-infective mortality and morbidity. QJM. 2010; 103: 285– 292. 5 Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994; 330: 1639– 1644. 6 Gladwin MT, Schechter AN, Ognibene FP, et al. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation. 2003; 107: 271– 278. 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