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ABSTRACT: ABSTRACT BACKGROUND: The contribution of environmental tobacco smoke exposure (ETS) to pulmonary morbidity in children with sickle cell anemia (SCA) is poorly understood. We tested the hypothesis that children with SCA and ETS would have an increased prevalence of obstructive lung disease and respiratory symptoms compared to children with SCA but without ETS. METHODS: Parent-report of ETS and respiratory symptom frequency were obtained for 245 children with SCA as part of a multi-center prospective cohort study. 196 children completed pulmonary function testing. Multivariable regression models evaluated the associations between ETS exposures at different time points [prenatal, infant (birth-2 years), preschool (2 years -first grade) and current], and lung function and respiratory symptoms. RESULTS: Among 245 participants, a high prevalence of prior (44%) and current (29%) ETS was reported. Of the 196 children who completed pulmonary function testing, those with parent-reported infant and current ETS were more likely to have airway obstruction (defined as Forced Expiratory Volume in 1 second /Forced Vital Capacity ratio (FEV1/FVC) below the lower limit normal) compared to unexposed children (22.0% vs. 3.1%, p<0.001). Those with ETS also had a lower FEF25-75/FVC ratio (0.82 vs. 0.97, p=0.001) and were more likely to have evidence of bronchodilator responsiveness(23% vs. 11%, p=0.03). Current and prior ETS and in utero exposure were associated with increased frequency of respiratory symptoms. CONCLUSIONS: ETS exposure is associated with evidence of lower airway obstruction and increased respiratory symptoms in SCA.
Chest 05/2013; · 5.25 Impact Factor
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ABSTRACT: Autopsy and biopsy studies have shown that there is significantly more fibrosis in hearts of patients with hypertensive heart disease compared to normal hearts. Fibrocytes, a population of circulating bone marrow-derived cells, have been shown to home to tissues and promote scar formation in several diseases, but their role in human hypertensive heart disease has not been investigated to date. Our objective was to determine whether fibrocyte levels are elevated in individuals with hypertensive heart disease.
We measured peripheral blood fibrocyte levels and their activated phenotypes in 12 individuals with hypertensive heart disease as determined by increased left ventricular mass on noninvasive imaging and compared them to fibrocyte levels from 19 healthy normal controls and correlated them to cardiac MRI findings.
Compared to normal controls, individuals with hypertensive heart disease had significantly higher circulating levels of total fibrocytes [median (interquartile range); 149000 (62200-220000) vs. 564500 (321000-1.2900e(+006)), P < 0.0001, respectively] as well as activated fibrocytes [15700 (6380-19800) vs. 478500 (116500-1.2360e(+006)) P < 0.0001]. Moreover, the fibrocyte subsets expressing the chemokine markers CXCR4 (P < 0.0001), CCR2 (P < 0.0001), CCR7 (P < 0.0001) and coexpression of both CXCR4 and CCR2 (P < 0.0001) were significantly elevated in patients with hypertensive heart disease compared to controls. Lastly, in patients with hypertensive heart disease there was a strong correlation between left ventricular mass index and total fibrocytes (r = 0.65, P = 0.037) and activated fibrocytes (r = 0.70, P = 0.016).
Our data suggest that bone marrow-derived circulating fibrocytes are associated with the presence and extent of left ventricular hypertrophy in patients with hypertensive heart disease.
Journal of hypertension 07/2012; 30(9):1856-61. · 4.02 Impact Factor
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ABSTRACT: Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.
Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.
These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.
PLoS ONE 01/2012; 7(3):e33702. · 4.09 Impact Factor
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ABSTRACT: Prior studies of asthma in children with sickle cell disease (SCD) were based on reports of a doctor-diagnosis of asthma with limited description of asthma features. Doctor-diagnoses of asthma may represent asthma or wheezing unrelated to asthma. Objectives of this study were to determine if asthma characteristics are present in adults with a doctor-diagnosis of asthma and/or wheezing, and to examine the relationship between doctor-diagnosis of asthma, wheezing and SCD morbidity. This was an observational cohort study of 114 adults with SCD who completed respiratory symptom questionnaires and had serum IgE measurements. A subset of 79 participants completed pulmonary function testing. Survival analysis was based on a mean prospective follow-up of 28 months and data were censored at the time of death or loss to follow-up. Adults reporting a doctor-diagnosis of asthma (N = 34) were more likely to have features of asthma including wheeze, eczema, family history of asthma, and an elevated IgE level (all P < 0.05). However, there was no difference in pain or ACS rate, lung function, or risk of death between adults with and without a doctor-diagnosis of asthma. In contrast, adults who reported recurrent, severe episodes of wheezing (N = 34), regardless of asthma, had twice the rates of pain and ACS, decreased lung function and increased risk of death compared with adults without recurrent, severe wheezing. Asthma features were not associated with recurrent, severe wheezing. Our data suggest that wheezing in SCD may occur independently of asthma and is a marker of disease severity.
American Journal of Hematology 09/2011; 86(9):756-61. · 4.67 Impact Factor
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ABSTRACT: In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/sec) is associated with increased mortality. The relationships among TRJ velocity and left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD.
A prospective study was conducted in 53 ambulatory adults with SCD (mean age, 34 years; range, 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity using echocardiography.
Subjects with SCD had larger left and right atrial volumes and increased LV mass compared with controls. When patients with SCD were compared with controls, LV and RV relaxation (i.e., E') were similar. Among subjects with SCD, pulmonary hypertension (TRJ ≥ 2.5 m/sec) was present in 40%. Higher TRJ velocity was correlated with larger left atrial volumes in patients with SCD. Additionally, some measures of LV (peak A, lateral and septal annular E/E' ratio) and RV (tricuspid valve E/E' ratio) compliance were correlated with TRJ velocity. No other measures of LV and RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity.
Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared with the control group. In subjects with SCD, few abnormalities of LV and RV structure and function were associated with TRJ velocity.
Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 08/2011; 24(11):1285-90. · 2.98 Impact Factor
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Joshua J Field,
Janet Stocks,
Fenella J Kirkham,
Carol L Rosen,
Dennis J Dietzen,
Trisha Semon,
Jane Kirkby,
Pamela Bates,
Sinziana Seicean,
Michael R DeBaun,
Susan Redline,
Robert C Strunk
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ABSTRACT: The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained.
To determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS.
Methacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV1<4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age (P<.001), IgE (P=.009), and lactate dehydrogenase (LDH) levels (P=.005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma (P=.986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airflow obstruction.
In children with SCA, AHR to methacholine is prevalent. Younger age, serum IgE concentration, and LDH level, a marker of hemolysis, are associated with AHR. With the exception of serum IgE, no signs or symptoms of an allergic diathesis are associated with AHR. Although the relationship between methacholine responsiveness and LDH suggests that factors related to SCA may contribute to AHR, these results will need to be validated in future studies.
Chest 03/2011; 139(3):563-8. · 5.25 Impact Factor
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ABSTRACT: Sickle cell disease (SCD) causes widely disseminated vaso-occlusive episodes. Building on evidence implicating invariant NKT (iNKT) cells in the pathogenesis of ischemia/reperfusion injury, recent studies demonstrate that blockade of iNKT cell activation in mice with SCD reduces pulmonary inflammation and injury. In patients with SCD, iNKT cells in blood are increased in absolute number and activated in comparison to healthy controls. iNKT cell activation is reduced by agonists of adenosine 2A receptors (A(2A)Rs) such as the clinically approved coronary vasodilator, regadenoson. An ongoing multi-center, dose-finding and safety trial of infused regadenoson, has been initiated and is providing preliminary data about its safety and efficacy to treat SCD. Very high accumulation of adenosine may have deleterious effects in SCD through activation of adenosine 2B receptors that are insensitive to regadenoson. Future possible therapeutic approaches for treating SCD include selective A(2B)R antagonists and antibodies that deplete iNKT cells.
Clinical Immunology 03/2011; 140(2):177-83. · 4.05 Impact Factor
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ABSTRACT: In one prospective cohort study, a diagnosis of asthma was associated with an increased risk of mortality in individuals with sickle cell anemia or HbSS. However, a direct relationship between death and asthma exacerbation could not be documented. This report examines two adolescents with sickle cell disease (SCD) who died during worsening symptoms consistent with asthma. Autopsies in both individuals demonstrated pulmonary airway smooth muscle hyperplasia, basement membrane thickening, and eosinophilia, consistent with bronchial asthma. Individuals with SCD and asthma warrant ongoing education, treatment, and surveillance for life-threatening complications of asthma. Pediatr Blood Cancer 2011;56:454–457. © 2010 Wiley-Liss, Inc.
Pediatric Blood & Cancer 02/2011; 56(3):454 - 457. · 1.89 Impact Factor
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ABSTRACT: To determine the role of platelets in stimulating mouse and human neutrophil activation and pulmonary injury in sickle cell disease (SCD).
Both platelet and neutrophil activation occur in SCD, but the interdependence of these events is unknown. Platelet activation and binding to leukocytes were measured in mice and patients with SCD and in controls. Relative to controls, blood obtained from mice or patients with SCD contained significantly elevated platelet-neutrophil aggregates (PNAs). Both platelets and neutrophils found in sickle PNAs were activated. Multispectral imaging (ImageStream) and conventional flow cytometry revealed a subpopulation of activated neutrophils with multiple adhered platelets that expressed significantly more CD11b and exhibited greater oxidative activity than single neutrophils. On average, wild-type and sickle PNAs contained 1.1 and 2.6 platelets per neutrophil, respectively. Hypoxia/reoxygenation induced a further increase in PNAs in mice with SCD and additional activation of both platelets and neutrophils. The pretreatment of mice with SCD with clopidogrel or P-selectin antibody reduced the formation of PNAs and neutrophil activation and decreased lung vascular permeability.
Our findings suggest that platelet binding activates neutrophils and contributes to a chronic inflammatory state and pulmonary dysfunction in SCD. The inhibition of platelet activation may be useful to decrease tissue injury in SCD, particularly during the early stages of vaso-occlusive crises.
Arteriosclerosis Thrombosis and Vascular Biology 11/2010; 30(12):2392-9. · 6.37 Impact Factor
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Blood 05/2010; 115(18):3852-4. · 9.90 Impact Factor
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American Journal of Hematology 12/2009; · 4.67 Impact Factor
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American Journal of Hematology 08/2009; 84(10):686-8. · 4.67 Impact Factor
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ABSTRACT: Asthma is associated with increases in sickle cell disease (SCD)-related morbidity and mortality. A thorough evaluation for asthma in children with SCD is important and may involve methacholine challenge (MCh). In this report, we present a 14-year-old male with SCD who was admitted for an acute painful episode following MCh. Pain events after MCh have not been previously reported in children with SCD. The risk-benefit ratio should be strongly considered prior to performance of MCh in this patient population, and all possible complications, including an acute painful episode, should be openly discussed with the parents and pediatric patient.
Pediatric Pulmonology 07/2009; 44(7):728-30. · 2.53 Impact Factor
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ABSTRACT: Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69(+), interferon-gamma(+) [IFN-gamma(+)]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-gamma, IFN-gamma-inducible chemokines (CXCL9, CXCL10), and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation reverses baseline pulmonary dysfunction manifested as elevated vascular permeability, decreased arterial oxygen saturation, and increased numbers of activated leukocytes. Anti-CD1d antibodies decrease pulmonary levels of IFN-gamma and CXCR3 chemokines. Neutralization of CXCR3 receptors ameliorates pulmonary dysfunction. Crossing NY1DD to lymphocyte-deficient Rag1(-/-) mice decreases pulmonary dysfunction. This is counteracted by the adoptive transfer of 1 million NKT cells. Like mice, people with SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in SCD mice by a pathway involving IFN-gamma and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease.
Blood 06/2009; 114(3):667-76. · 9.90 Impact Factor
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ABSTRACT: The National Association of Children's Hospitals (NACHRI) and the Centers for Medicare and Medicaid Services (CMS) recently introduced 30-day hospital readmission rate as a quality care indicator in children with sickle cell disease (SCD). Based on previous research identifying risk factors for 30-day readmission in our patient population, we designed and implemented a multi-modal intervention to reduce 30-day readmission rate in children with SCD and pain.
A before-and-after study design was performed to evaluate an intervention containing three components: (1) standardized SCD-pain admission orders; (2) monthly SCD-pain in-service for house physicians for the first 6-months; and (3) continuous patient/caregiver education. Following order implementation, we prospectively collected data on all children admitted for SCD-pain over a 6-month period. We compared the 30-day readmission rate after the intervention to the rate during the same 6-month interval in the previous calendar year prior to the availability of pre-specified SCD-pain orders.
A total of 89 admissions, in 68 individuals, were eligible for the standardized orders during the prospective time period and were compared to 85 admissions in 56 individuals during the control period. Pre-specified SCD-pain orders were used in 93% of eligible admissions during the intervention. Readmission rate within 30 days was lower for the intervention cohort than the control cohort, 11% (10/89) versus 28% (24/85), P = 0.007, 95% CI 0.1-0.7.
A multi-modal intervention was successful in decreasing 30-day hospital readmission rate for children with SCD and pain. Provider education was the most important component of the multi-modal intervention.
Pediatric Blood & Cancer 06/2009; 53(3):401-5. · 1.89 Impact Factor
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ABSTRACT: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease mediated by autoantibodies directed against ADAMTS-13. A number of small series and case reports have shown promising results with rituximab in refractory or relapsed TTP. In this report, we present 13 patients with TTP treated with rituximab. Twelve of the 13 patients (92%) achieved complete response; no subsequent relapses occurred with median follow-up of 24 months (range, 13-84 months). The addition of rituximab to standard therapy appears to be effective in sustaining long-term remission in TTP. However, the optimal dosing and timing of rituximab warrant further investigation. Am. J. Hematol., 2009. (c) 2009 Wiley-Liss, Inc.
American Journal of Hematology 05/2009; 84(7):418-21. · 4.67 Impact Factor
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ABSTRACT: Baseline level of the cysteinyl leukotriene (CysLT), leukotriene E4 (LTE4), is associated with an increased pain rate in children and adults with sickle cell disease (SCD). To provide additional evidence for a role of CysLTs in the pathogenesis of vaso-occlusion, we tested the hypothesis that LTE4 levels will increase within an individual during painful episodes compared to baseline. In a cohort of 19 children and adults with SCD, median LTE4 levels increased from 82.36 pg/mg creatinine at baseline to 162.81 pg/mg creatinine during a painful episode (P < 0.001). These data further support a contribution of CysLTs to the process of vaso-occlusion.
American Journal of Hematology 04/2009; 84(4):231-3. · 4.67 Impact Factor
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ABSTRACT: Sickle cell disease (SCD) is characterized by recurrent episodes of vaso-occlusion, resulting in tissue ischemia and end-organ damage. Inflammation is critical to the pathogenesis of vaso-occlusion and has been associated with SCD-related morbidity and mortality. Despite the impact of inflammation, no directed anti-inflammatory therapies for the treatment or prevention of vaso-occlusive events currently exist. Among individuals with SCD, asthma is a comorbid inflammatory condition that increases the risk of pain episodes, acute chest syndrome and death. Inflammation associated with asthma could augment the proinflammatory state of SCD, increasing episodes of vaso-occlusion. Leukotrienes are inflammatory mediators that play a prominent role in the pathogenesis of asthma and have been associated with SCD-related morbidity. Targeting inflammatory mediators, such as leukotrienes, is a promising approach for the development of novel therapies for the treatment of SCD. This review will examine the relationship between inflammation and vaso-occlusion, with particular focus on the leukotriene pathway.
Expert Review of Hematology 02/2009; 2(1):57-68. · 1.16 Impact Factor
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ABSTRACT: 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.
Hematology 01/2009; · 1.49 Impact Factor
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ABSTRACT: The National Association of Children's Hospitals and Related Institutions (NACHRI) established hospital readmission within 30 days as a benchmark for quality care in children with Sickle Cell Disease (SCD). Among children with SCD, limited data exists to identify risk factors for readmission and whether they are modifiable.
We performed a retrospective cohort study to identify risk factors for readmission. All admissions for children with SCD in a 1-year period were reviewed; cases were defined as children with SCD readmitted within 30 days after their first admission during the study period and controls, children with SCD who were not readmitted.
We identified 30 cases and 70 controls. No difference in demographic data was found between groups. The most common admission and readmission diagnosis was pain, 78 and 70%, respectively. The greatest risk factor for readmission was no outpatient hematology follow-up within 30 days of discharge (OR 7.7, 95% CI 2.4-24.4). A diagnosis of asthma was also a risk factor for readmission (OR 2.9, 95% CI 1.2-7.3). Patients who required supplemental oxygen to maintain saturations in the normal range and were on room air for < or =24 hr at discharge were also more likely to be readmitted (OR 3.3, 95% CI 1.1-9.7). Multivariate analysis identified lack of outpatient follow-up and disease severity, defined as > or =3 admissions in the previous 12 months as predictors for readmission (R(2) = 0.41).
Potentially modifiable risk factors exist to decrease the rate of readmission of children with SCD admitted to the hospital for pain.
Pediatric Blood & Cancer 01/2009; 52(4):481-5. · 1.89 Impact Factor
