The association of nocturnal hypoxia and an echocardiographic measure of pulmonary hypertension in children with sickle cell disease

Mondal, Pritish; Stefek, Bryan; Sinharoy, Ankita; Sankoorikal, Binu John; Abu-Hasan, Mutasim; Aluquin, Vincent

doi:10.1038/s41390-018-0125-6

Cited by 16 publications

(19 citation statements)

References 30 publications

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“…The intricate pathophysiology of chronic inflammation, increased pulmonary capillary blood volume (PCBV), pulmonary hypertension, and reactive airway disease contribute to the complex progression of SCLD . Worsening of airway resistance in older C‐SCD could be related to SCLD specific etiologies of OAD, like PCBV in addition to asthma.…”

Section: Discussionmentioning

confidence: 99%

“…The study was conducted at Penn State Comprehensive Pediatric SCD program, where C-SCD were followed biannually and PFTs were obtained annually. 19 We completed a retrospective chart review of 137 C-SCD and identified 56 children who had been referred to the comprehensive SCD clinic and had completed PFTs on or around the day of their initial comprehensive clinic visit. We identified 36 control subjects from our clinic, who were age and race-matched asthmatic children without SCD.…”

Section: Methodsmentioning

confidence: 99%

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Diagnostic value of spirometry vs impulse oscillometry: A comparative study in children with sickle cell disease

Mondal

Yirinec

Midya

et al. 2019

Pediatric Pulmonology

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Background Spirometry is conventionally used to diagnose airway diseases in children with sickle cell disease (C‐SCD). However, spirometry is difficult for younger children to perform, is effort dependent, and it provides limited information on respiratory mechanics. Impulse oscillometry (IOS) is an effort‐independent pulmonary function test (PFT), which measures total airway resistance (R5Hz) and reactance (AX). IOS could be advantageous without certain limitations of spirometry. Aim To compare the accuracy of IOS vs spirometry in making the diagnosis of asthma and assessing age‐related pulmonary changes in C‐SCD. Study design Retrospective chart review. Subject selection Fifty‐six C‐SCD and thirty‐six controls (asthmatics without SCD) followed at Penn State with PFTs obtained during the initial pulmonary evaluation. Methodology We grouped C‐SCD into asthmatics and non‐asthmatics based on pre‐referral diagnosis and compared PFTs between two groups. Receiver operating characteristic (ROC) curve analyses and machine learning tools (XGBoost and artificial neural network) were used to rank the spirometry and IOS measures based on their ability to predict a diagnosis of asthma. Robust linear regression was used to analyze association among height/age with various PFT measures. Results Both ROC and XGBoost indicated that FEF25‐75%, forced expiratory volume in 1 second (FEV1)/forced vital capacity, and R5Hz(%) were the top three predictors for asthma diagnosis. R5Hz(%) and AX had superior bronchodilator response (BDR) than FEV1. IOS parameters had significant association with height/age in C‐SCD (possibly due to the stiff lungs) but not in controls. Conclusion IOS had advantages over spirometry in C‐SCD because it is feasible in early childhood, provides insights into the pulmonary mechanics, and is more sensitive to detect BDR.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Diagnostic value of spirometry vs impulse oscillometry: A comparative study in children with sickle cell disease

Mondal

Yirinec

Midya

et al. 2019

Pediatric Pulmonology

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“…Moreover, nocturnal hypoxia may also be present in several major cardiovascular complications of SCD, including pulmonary hypertension and higher end-diastoclic left ventricular diameters [37]. As per the recommendations [38], children with SCD usually undergo routine echocardiography screening every 1-3 years in the absence of further indication, and in our cohort none of the enrolled patients developed any cardiac complications within the studied period.…”

Section: Discussionmentioning

confidence: 77%

Beneficial effects of adenotonsillectomy in children with sickle cell disease

et al. 2020

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Tonsillectomy and adenoidectomy (T&A) is frequently performed in children with sickle cell disease (SCD). Our aim was to evaluate the impact of this surgery on overnight oxygenation and rates of complications in these patients.Children with SCD who underwent T&A between 2008 and 2014 in two tertiary hospitals were retrospectively evaluated. Overnight oximetry and admission rates due to vaso-occlusive pain episodes (VOEs) and acute chest syndrome (ACS) in the year preceding and following the surgery were compared.19 patients (10 males, 53%) with a median age of 6 years (range 3.5–8) were included. A significant increase of mean overnight arterial oxygen saturation measured by pulse oximetry (SpO2) (from 93±3.6% to 95.3±2.8%, p=0.001), nadir SpO2 (from 83.0±7.1% to 88±4.1%, p=0.004) and a reduction of 3% oxygen desaturation index (from a median value of 5.7 to 1.8, p=0.003) were shown. The mean annual rate of ACS decreased from 0.6±1.22 to 0.1±0.2 events per patient-year (p=0.003), while the mean cumulative rate of hospitalisations for all causes and the incidence of VOEs were not affected.T&A improved nocturnal oxygenation and was also associated with a reduction in the incidence of ACS at 1-year follow-up after surgery.

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“…Freshly isolated sickle cells were simultaneously incubated in basal medium for 4 h and perfused through the microchannels at a physiological shear stress level of 1 dyne/cm 2 in precisely controlled physiological hypoxia (SpO 2 of 83%) 16 . The SpO 2 level was chosen to be pathologically relevant to SCD, based on clinical studies 46 . Non‐adherent RBCs were washed away and adherent erythrocytes were counted (see details in Supplemental Information).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease

et al. 2020

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Summary Many hypotheses have been proposed to explain how a glutamate to valine substitution in sickle haemoglobin (HbS) can cause sickle cell disease (SCD). We propose and document a new mechanism in which elevated tyrosine phosphorylation of Band 3 initiates sequelae that cause vaso‐occlusion and the symptoms of SCD. In this mechanism, denaturation of HbS and release of heme generate intracellular oxidants which cause inhibition of erythrocyte tyrosine phosphatases, thus permitting constitutive tyrosine phosphorylation of Band 3. This phosphorylation in turn induces dissociation of the spectrin‐actin cytoskeleton from the membrane, leading to membrane weakening, discharge of membrane‐derived microparticles (which initiate the coagulation cascade) and release of cell‐free HbS (which consumes nitric oxide) and activates the endothelium to express adhesion receptors). These processes promote vaso‐occlusive events which cause SCD. We further show that inhibitors of Syk tyrosine kinase block Band 3 tyrosine phosphorylation, prevent release of cell‐free Hb, inhibit discharge of membrane‐derived microparticles, increase sickle cell deformability, reduce sickle cell adhesion to human endothelial cells, and enhance sickle cell flow through microcapillaries. In view of reports that imatinib (a Syk inhibitor) successfully treats symptoms of sickle cell disease, we suggest that Syk tyrosine kinase inhibitors warrant repurposing as potential treatments for SCD.

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The association of nocturnal hypoxia and an echocardiographic measure of pulmonary hypertension in children with sickle cell disease

Abstract: Our study indicates that NH is associated with PH in C-SCD, and that screening for NH may help to identify C-SCD with higher morbidity risk.

Cited by 16 publications

References 30 publications

Diagnostic value of spirometry vs impulse oscillometry: A comparative study in children with sickle cell disease

Diagnostic value of spirometry vs impulse oscillometry: A comparative study in children with sickle cell disease

Beneficial effects of adenotonsillectomy in children with sickle cell disease

Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease

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