Airway hyperreactivity detected by methacholine challenge in children with sickle cell disease

Özbek, Özlem; Malbora, Barış; Şen, Nazan; Yazıcı, Ayşe Canan; Ozyurek, Emel; Özbek, Namık

doi:10.1002/ppul.20716

Cited by 72 publications

(58 citation statements)

References 23 publications

(31 reference statements)

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“…The latter is a feature of airway reactivity, another known association with SCD. [65][66][67] As anticipated, PHT and other associated pulmonary pathologies were absent in HbA chimeras.…”

Section: Reduction In Fii Results In Improved Scd-associated Cardiopusupporting

confidence: 75%

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Arumugam

Mullins²,

Shanmukhappa

et al. 2015

Blood

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• Reduced prothrombin improves survival and ameliorates inflammation and end-organ damage without spontaneous bleeding in sickle cell mice.• An individual procoagulant, prothrombin, represents a novel therapeutic target that can improve sickle cell disease outcome.Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to ∼10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII lox/2 mice (constitutively carrying ∼10% normal FII) and FII WT mice were tracked in parallel for a year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies. (Blood. 2015;126(15):1844-1855

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“…The latter is a feature of airway reactivity, another known association with SCD. [65][66][67] As anticipated, PHT and other associated pulmonary pathologies were absent in HbA chimeras.…”

Section: Reduction In Fii Results In Improved Scd-associated Cardiopusupporting

confidence: 75%

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Arumugam

Mullins²,

Shanmukhappa

et al. 2015

Blood

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“…A high prevalence of asthma in children with SCD has been reported in one study (Knight-Madden et al, 2005), but not in others (Bernaudin et al, 2008;Boyd et al, 2004). In addition, the response to bronchial challenges in SCD patients, such as cold air, exercise, or methacholine has been variable ranging from no response (Chaudry et al, 2014) to 78% of those tested having a positive response (Ozbek et al, 2007).…”

Section: Introductionmentioning

confidence: 96%

Lung function, transfusion, pulmonary capillary blood volume and sickle cell disease

Lunt¹,

McGhee

Robinson

et al. 2016

Respiratory Physiology & Neurobiology

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Lung function abnormalities occur in children with sickle cell disease (SCD) and may be associated with elevated pulmonary blood volume. To investigate that association, we determined whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and increased respiratory system resistance (Rrs5). Measurements of Rrs5 and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6-18.5) years. Diffusing capacity for carbon monoxide and nitric oxide were assessed to calculate the PCBV. Post transfusion, the median Rrs5 had increased from 127.4 to 141.3% predicted (p<0.0001) and pulmonary capillary blood volume from 39.7 to 64.1 ml/m2 (p<0.0001); forced expiratory volume in one second (p=0.0056) and vital capacity (p=0.0008) decreased. The increase in Rrs5 correlated with the increase in PCBV (r=0.50, p=0.0493). Increased pulmonary capillary blood volume may at least partially explain the lung function abnormalities in SCD children.

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“…57 The degree of airway hyper-responsiveness to a stimulus, most commonly the parasympathetic agonist methacholine, reflects airway inflammation and provides evidence for a diagnosis of asthma. The prevalence of airway hyper-responsiveness in children and adults with SCD has been reported as high as 78% 56 ; in contrast, the prevalence of airway hyper-responsiveness is 18% in children in the general population. 60 Further, the presence or absence of airway hyper-responsiveness has not been clearly associated with a diagnosis of asthma in children or There are three possibilities to describe the relationship between asthma and SCD, ranging from asthma and SCD as distinct, non-overlapping diseases to asthma symptoms largely being related to SCD pathogenesis (Figure 3).…”

Section: Evidence To Suggest That Asthma Symptoms Are a Manifestationmentioning

confidence: 99%

“…Airway hyper-responsiveness and pulmonary function abnormalities are more common in children and adults with SCD than in the general population, suggesting that these clinical features of asthma may be related to the pathogenesis of SCD [52][53][54][55][56][57][58] (Table 1). Measures of airway hyperresponsiveness are thought to be relatively specific for the diagnosis of asthma in children and adults in the general population.…”

Section: Evidence To Suggest That Asthma Symptoms Are a Manifestationmentioning

confidence: 99%

Asthma and sickle cell disease: two distinct diseases or part of the same process?

Field¹,

DeBaun²

2009

Hematology

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A physician diagnosis of asthma in children and adults with sickle cell disease (SCD) has been associated with increased rates of pain and acute chest syndrome (ACS) episodes and premature death. Despite the clinical significance of a doctor’s diagnosis of asthma in individuals with SCD, the criteria for a physician diagnosis of asthma are not well defined. Many features of asthma are common in individuals with SCD, including symptoms of wheezing, obstructive lung disease and airway hyper-responsiveness. However, it is not clear if these signs and symptoms of asthma reflect a physician diagnosis of asthma, or if these asthma features are related to SCD. Further complicating the diagnosis of asthma in children with SCD is the significant overlap in clinical manifestations between an asthma exacerbation and an ACS episode. Evidence supporting the concept that asthma and SCD are separate co-morbid conditions includes a similar prevalence of asthma between children with SCD and those in the general population and the observation that asthma is inherited in a familial pattern in the families of children with SCD. In contrast, there is significant evidence that asthma-like features may be associated with SCD without a diagnosis of asthma, including a higher than expected prevalence of airway hyper-responsiveness and obstructive lung disease. Regardless of whether SCD and asthma are distinct or overlapping co-morbid conditions, we recommend a systematic and complete evaluation of asthma when the diagnosis is suspected or when patients have multiple episodes of pain or ACS.

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Airway hyperreactivity detected by methacholine challenge in children with sickle cell disease

Cited by 72 publications

References 23 publications

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Lung function, transfusion, pulmonary capillary blood volume and sickle cell disease

Asthma and sickle cell disease: two distinct diseases or part of the same process?

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