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King's Research Portal View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by King's Research Portal King’s Research Portal DOI: 10.1016/j.ebiom.2017.08.006 Document Version Peer reviewed version Link to publication record in King's Research Portal Citation for published version (APA): Nkya, S., Mgaya, J., Urio, F., Makubi, A., Thein, S. L., Menzel, S., ... Makani, J. (2017). Fetal Hemoglobin is Associated with Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania. EBioMedicine. DOI: 10.1016/j.ebiom.2017.08.006 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. 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Download date: 06. Nov. 2017 Accepted Manuscript Fetal Hemoglobin is Associated with Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania Siana Nkya, Josephine Mgaya, Florence Urio, Abel Makubi, Swee Lay Thein, Stephan Menzel, Sharon E. Cox, Charles R. Newton, Fenella J. Kirkham, Bruno P. Mmbando, Julie Makani PII: S2352-3964(17)30323-7 DOI: doi: 10.1016/j.ebiom.2017.08.006 Reference: EBIOM 1153 To appear in: EBioMedicine Received date: 23 June 2017 Revised date: 31 July 2017 Accepted date: 5 August 2017 Please cite this article as: Siana Nkya, Josephine Mgaya, Florence Urio, Abel Makubi, Swee Lay Thein, Stephan Menzel, Sharon E. Cox, Charles R. Newton, Fenella J. Kirkham, Bruno P. Mmbando, Julie Makani , Fetal Hemoglobin is Associated with Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ebiom(2017), doi: 10.1016/j.ebiom.2017.08.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Fetal hemoglobin is associated with peripheral oxygen saturation in sickle cell disease in Tanzania Siana Nkya1,2, Josephine Mgaya1, Florence Urio1, Abel Makubi1, Swee Lay Thein3,4, Stephan Menzel3, Sharon E Cox1,5, Charles R Newton1,6, Fenella J Kirkham7,8,9, Bruno P Mmbando1,10, Julie Makani1,6 1Sickle cell Programme, Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania 2Dar-es-Salaam University College of Education, Dar-es-Salaam, Tanzania 3King’s College London, Molecular Haematology, Division of Cancer Studies, UK 4Sickle cell branch, National heart, Lung and Blood Institute, The National Institutes of Health, USA 5 Graduate School of Tropical Medicine & Global Health, Nagasaki University, Nagasaki, Japan, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK 6 Nuffield Department of Medicine, University of Oxford, UK 7 UCL Great Oromnd Street Institute of Child Health, London, UK 8 Clinical and Experimental Sciences, University of Southampton, UK 9Southampton Children’s Hospital, UK 10National Institute for Medical Research, Tanga Centre, Tanga, Tanzania, Corresponding author: Siana Nkya Department of Haematology and Blood Transfusion, P. O. Box 65001, Dar-es-Salaam, Tanzania. Phone: +255784193349 Email: [email protected] ABSTRACT Fetal hemoglobin (HbF) and peripheral hemoglobin oxygen saturation (SpO 2) both predict clinical severity in sickle cellACCEPTED disease (SCD), while reticulocytosis MANUSCRIPT is associated with vasculopathy, but there are few data on mechanisms. HbF, SpO2 and routine clinical and laboratory measures were available in a Tanzanian cohort of 1175 SCD individuals aged ≥5 years and the association with SpO2 (as response variable transformed to a Poisson distribution) was assessed by negative binomial model with age and sex as covariates.. Increase in HbF was associated with increased SpO2 (rate ratio, RR=1.19; 95% confidence intervals [CI] 1.04, 1.37 per natural log unit of HbF; P=0.0004). In 1 ACCEPTED MANUSCRIPT univariable analysis, SpO2 was inversely associated with age, reticulocyte count, and log (total bilirubin) and directly with pulse, SBP, hemoglobin, and log (HbF). In multivariable regression log(HbF) (RR 1.191; 95%CI 1.04, 1.37; p=0.013), pulse (RR 1.01; 95%CI 1.00, 1.01; p=0.026), SBP (RR 1.008; 95%CI 1.00, 1.02; p=0.014), and hemoglobin (1.120; 95%CI 1.05, 1.19; p=0.001) were positively and independently associated with SpO2 while reticulocyte count (RR 0.985; 95%CI 0.97, 0.99; p=0.019) was independently inversely associated with SpO2. In SCD, improving SpO2, in part through cardiovascular compensation and associated with reduced reticulocytosis, may be a mechanism by which HbF reduces disease severity. KEY WORDS: Fetal hemoglobin (HbF), sickle cell disease, hypoxia, oxygen saturation, reticulocytes HIGHLIGHTS Fetal hemoglobin may moderate sickle cell disease through increased oxygen saturation Low oxygen saturation is associated with reticulocytosis which might moderate cerebral vasculopathy and stroke risk Higher pulse rate and systolic blood pressure in those with higher SpO2 suggests cardiovascular compensation for low SpO2 RESEARCH IN CONTEXT Fetal hemoglobin (HbF) is normally synthesized during intrauterine life and it starts to decline before birth being replaced by adult hemoglobin (HbA). However some individuals continue to synthesize HbF to adulthood and are relatively protected from severe sickle cell disease. The mechanism of HbF protection in SCD has not been entirely established. This study reports a positive association between HbF and oxygen saturationACCEPTED (SpO2). Higher SpO MANUSCRIPT2 is associated with decreased reticulocytes but increased pulse rate and systolic blood pressure, suggesting SpO2 is maintained in part through cardiovascular compensation. Increasing HbF may reduce disease severity partly through increasing SpO2. INTRODUCTION 2 ACCEPTED MANUSCRIPT Sickle Cell disease (SCD) remains the most common hemoglobinopathy worldwide. Clinically, there is great variability amongst individuals with SCD; predictors of severity include hemoglobin F levels, reticulocytosis and alpha globin gene number. A major factor is the wide variation in the innate ability to synthesize fetal hemoglobin (HbF) beyond early childhood. Individuals with high levels of HbF experience milder forms of the disease with lower morbidity and improved survival. HbF level of 10% and above is believed to reduce the risk of major organ failure such as stroke, while much higher levels (20% and above) may be required to prevent recurrent clinical events such as painful crises and pulmonary disorder(Meier et al., 2017). The mechanisms underlying the reduction in the severity of SCD in people with high HbF are not clear. Therefore, studying the associations of HbF and clinical phenotypes of SCD may provide insights into the underlying mechanisms. Peripheral hemoglobin oxygen saturation (SpO2), measured non-invasively by pulse oximetry, is related to several disease complications. Lower SpO2 has been associated with anemia (Quinn and Ahmad, 2005), increase in reticulocytes (Quinn and Ahmad, 2005), hemolysis (Campbell et al., 2009) and increased episodes of acute chest syndrome (Rackoff et al., 1993) and appears to predict central nervous system complications (including stroke (Quinn and Sargent, 2008), higher transcranial doppler velocity (Quinn et al., 2009), number of days per year admitted for pain (Hargrave et al., 2003), tricuspid regurgitant jet velocity (TRV) (Minniti et al., 2009) and diastolic dysfunction (Johnson et al., 2010) in SCD. Studies in fetuses, children with cyanotic heart disease and adults ascending to high altitude suggest that HbF synthesis increases in hypoxia (Bard et al., 1994). Furthermore, hemolysis may induce HbF synthesis further (DeSimone et al., 1978). There is limited information on the magnitude and direction of any association between HbF and SpO2 in patients with SCD not on hydroxyurea, but the available data suggest that, as for neonates (Shiao, 2005), SpO2 is higher in SCD patients with higher HbF (Homi et al., 1997),(Halphen et al., 2014, Cox et al., 2013). In this report, we describe the
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