Jennifer Knight-Madden

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

Background The up‐regulation of P‐selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso‐occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P‐selectin, were evaluated in patients with sickle cell disease. Methods In this double‐blind, randomized, placebo‐controlled, phase 2 trial, we assigned patients to receive low‐dose crizanlizumab (2.5 mg per kilogram of body weight), high‐dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell–related pain crises with high‐dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient‐reported outcomes were also assessed. Results A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high‐dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high‐dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high‐dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high‐dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high‐dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active‐treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. Conclusions In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361.)

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

Background Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. Design and Methods Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. Results Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. Conclusions Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.

Prevalence of the metabolic syndrome and its components in relation to socioeconomic status among Jamaican young adults: a cross-sectional study.

BackgroundThe metabolic syndrome has a high prevalence in many countries and has been associated with socioeconomic status (SES). This study aimed to estimate the prevalence of the metabolic syndrome and its components among Jamaican young adults and evaluate its association with parental SES.MethodsA subset of the participants from the 1986 Jamaica Birth Cohort was evaluated at ages 18-20 years between 2005 and 2007. Trained research nurses obtained blood pressure and anthropometric measurements and collected a venous blood sample for measurement of lipids and glucose. Prevalence of the metabolic syndrome and its components were estimated using the 2009 Consensus Criteria from the International Diabetes Federation, National Heart Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity. SES was assessed by questionnaire using occupation of household head, highest education of parent/guardian, and housing tenure of parent/guardian. Analysis yielded means and proportions for metabolic syndrome variables and covariates. Associations with levels of SES variables were obtained using analysis of variance. Multivariable analysis was conducted using logistic regression models.ResultsData from 839 participants (378 males; 461 females) were analyzed. Prevalence of the metabolic syndrome was 1.2% (95% confidence interval [95%CI] 0.5%-1.9%). Prevalence was higher in females (1.7% vs. 0.5%). Prevalence of the components [male: female] were: central obesity, 16.0% [5.3:24.7]; elevated blood pressure, 6.7% [10.8:3.3]; elevated glucose, 1.2% [2.1:0.4]; low HDL, 46.8% [28.8:61.6]; high triglycerides, 0.6% [0.5:0.6]. There were no significant differences in the prevalence of the metabolic syndrome for any of the SES measures used possibly due to lack of statistical power. Prevalence of central obesity was inversely associated with occupation (highly skilled 12.4%, skilled 13.5%, semi-skilled/unskilled 21.8%, p = 0.013) and education (tertiary 12.5%, secondary 14.1%, primary/all-age 28.4%, p = 0.002). In sex-specific multivariate logistic regression adjusted for hip circumference, central obesity remained associated with occupation and education for women only.ConclusionPrevalence of the metabolic syndrome is low, but central obesity and low HDL are present in 16% and 47% of Jamaican youth, respectively. Central obesity is inversely associated with occupation and education in females.

African Ancestry is a Risk Factor for Asthma and High Total IgE Levels in African Admixed Populations

Characterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean ± SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (β = 1.3, P = 0.04), Barbadians (β = 3.8, P = 0.03), and Brazilians (β = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels.

Stroke recurrence in children with sickle cell disease treated with hydroxyurea following first clinical stroke

Chronic transfusion therapy is the treatment of choice for preventing stroke recurrence in children with sickle cell disease (SCD). The majority of children affected by this devastating complication live in the developing world where access to regular blood transfusions may be impractical. Since 2000, in the absence of regular blood supplies, all children at the Sickle Cell Unit who had experienced a first clinical stroke were offered hydroxyurea (HU) as the only intervention to prevent stroke recurrence. Forty‐four children were identified as having experienced a first clinical stroke between January 1, 2000 and September 30, 2009; one died at that presentation. Forty‐three children were therefore followed for 111 person‐years, of whom 10 (23.3%) agreed to start HU. Only one child in the HU group, incidence rate 2/100 person‐years, had clinical stroke recurrence, compared to 20/33 in the non‐HU group, incidence rate 29/100 person‐years (Hazard ratio (HR) 9.4 [95% Confidence interval (CI): 1.3–70.6]; P = 0.03). When the groups were compared, in the non‐HU group, four died (vs. zero), 13 (53% vs. 10%) had moderate–severe physical disability (P = 0.017), and 12 (44% vs. 20%) required special education or were too disabled to attend school. Our data support the role of HU as a useful intervention for prevention of stroke recurrence in SCD when transfusion programs are not available or practical. Am. J. Hematol., 2011.

A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.

Plasma Concentration of Platelet-Derived Microparticles Is Related to Painful Vaso-Occlusive Phenotype Severity in Sickle Cell Anemia

High plasma level of microparticles (MPs) deriving mainly from erythrocytes and platelets has been detected in sickle cell anemia (SCA) patients. Flow cytometry was used to determine the concentration of MPs in two groups of SCA patients exhibiting marked differences in painful vaso-occlusive crisis rates [a non-severe group (n = 17) and a severe group (n = 12)], and in a control group composed of healthy subjects (n = 20). A 3- to 4-fold increase of total MP plasma concentration was detected in SCA patients. Higher platelet-derived MPs concentration was detected in the severe SCA group while erythrocyte-derived MPs concentration was increased in the non-severe SCA patient group only. Our results suggest that plasma concentration of MPs shed by platelets is a biomarker of the vaso-occlusive phenotype-related severity.

Acute pulmonary complications of sickle cell disease.

Acute pulmonary problems in sickle cell disease (SCD) patients, in particular acute chest syndrome (ACS), cause significant mortality and morbidity. It is important to differentiate ACS from pneumonia to avoid inappropriate or inadequate treatment. Asthma may increase the risk of ACS and co-morbid asthma and SCD are associated with worse patient outcomes and, in preclinical models, more severe inflammation. Recurrent wheezing, however, can occur in the absence of a diagnosis of asthma; it is likely due to SCD related inflammation and additional therapies than those that treat asthma may be required. Further research is merited to clarify these issues.

Asthma and allergies in Jamaican children aged 2-17 years: a cross-sectional prevalence survey.

Objective To determine the prevalence and severity of asthma and allergies as well as risk factors for asthma among Jamaican children aged 2–17 years. Design A cross-sectional, community-based prevalence survey using the International Study of Asthma and Allergies in Childhood questionnaire. The authors selected a representative sample of 2017 children using stratified, multistage cluster sampling design using enumeration districts as primary sampling units. Setting Jamaica, a Caribbean island with a total population of approximately 2.6 million, geographically divided into 14 parishes. Participants Children aged 2–17 years, who were resident in private households. Institutionalised children such as those in boarding schools and hospitals were excluded from the survey. Primary and secondary outcome measures The prevalence and severity of asthma and allergy symptoms, doctor-diagnosed asthma and risk factors for asthma. Results Almost a fifth (19.6%) of Jamaican children aged 2–17 years had current wheeze, while 16.7% had self-reported doctor-diagnosed asthma. Both were more common among males than among females. The prevalence of rhinitis, hay fever and eczema among children was 24.5%, 25% and 17.3%, respectively. Current wheeze was more common among children with rhinitis in the last 12 months (44.3% vs 12.6%, p<0.001), hay fever (36.8% vs 13.8%, p<0.001) and eczema (34.1% vs 16.4%, p<0.001). Independent risk factors for current wheeze (ORs, 95% CI) were chest infections in the first year of life 4.83 (3.00 to 7.77), parental asthma 4.19 (2.8 to 6.08), rhinitis in the last 12 months 6.92 (5.16 to 9.29), hay fever 4.82 (3.62 to 6.41), moulds in the home 2.25 (1.16 to 4.45), cat in the home 2.44 (1.66 to 3.58) and dog in the home 1.81 (1.18 to 2.78). Conclusions The prevalence of asthma and allergies in Jamaican children is high. Significant risk factors for asthma include chest infections in the first year of life, a history of asthma in the family, allergies, moulds and pets in the home.

Hydroxyurea use in prevention of stroke recurrence in children with sickle cell disease in a developing country: A cost effectiveness analysis

We undertook a cost effectiveness analysis (CEA) of hydroxyurea (HU) in preventing stroke recurrence and/or death. We followed 43 children with sickle cell disease from 2000 to 2009 after having a first clinical stroke, of whom 10 opted for HU therapy. HU use led to decreased stroke recurrence and death without significantly increasing the annual cost of care per patient (J