Sickle Cell Disease Adolescents Research Articles

Cardiac Disease in Egyptian Thalassemia Major and Sickle Cell Disease Adolescents in relation to Vitamin D Status Using Echocardiogram & Ultrafast Magnetic Resonance Imaging

Abstract Background Cardiovascular complications are well recognized in patients with β-thalassemia major (β-TM) and sickle cell disease (SCD). Vitamin D deficiency is prevalent in patients with transfusion-dependent thalassemia and there is an association between vitamin D deficiency and both left ventricular function and iron overload in thalassemia. However, the relationship between vitamin D and cardiac iron is not well studied in Egypt and the role of vitamin D in cardiac disease in SCD and β-TM needs to be assessed. Aim To assess vitamin D status in children and adolescents with SCD and β-TM in relation to cardiac complications using echocardiography and cardiac magnetic resonance (CMR) T2*. Methods Forty-one patients with SCD and 35 patients with β-TM without symptomatic cardiac disease were studied stressing on history of splenectomy and transfusion history. Markers of hemolysis, serum ferritin and vitamin D levels were measured. Liver iron concentration (LIC) was assessed by magnetic resonance imaging (MRI). Screening for cardiovascular abnormalities was performed by the non-invasive Doppler echocardiography and CMR was used to assess myocardial iron overload. Results Echocardiography showed that cardiac functions were significantly impaired in β-TM patients compared with SCD while the frequency of pulmonary hypertension risk (elevated TRV ≥2.5 m/sec) was consistent between both β-TM and SCD groups. Cardiac T2* (which reflects cardiac iron overload) was significantly lower while myocardial iron concentration (MIC) was significantly higher in β -TM patients compared with SCD group. Vitamin D levels were decreased in both SCD and β-TM patients than control levels; however, SCD patients had significantly lower vitamin D levels. Low vitamin D levels were significantly associated withincreased risk of pulmonary hypertension in the SCD group while In β-TM group, vitamin D levels were significantly lower in patients with cardiac disease and those with serum ferritin levels ≥ 2500 µg/L. A significant evidence of diastolic dysfunction was found in SCD and β-TM patients who had low serum vitamin D level < 20 ng/mL. Vitamin D levels were negatively correlated to serum ferritin and LIC while positively correlated to cardiac T2*. Conclusion Low vitamin D levels were associated with cardiopulmonary dysfunction in adolescents with SCD and β-TM. Vitamin D deficiency in those patients was linked to cardiac iron overload leading to iron induced cardiomyopathy. Proper chelation therapy is mandatory to improve cardiac disease, iron overload and consequently, vitamin D status in β-TM patients.

5613260 A PHASE -- IIA-IIB, OPEN LABEL, SINGLE CENTER TRIAL TO STUDY SAFETY, TOLERABILITY AND EFFICACY OF MEMANTINE AS SUPPORTIVE LONG-TERM TREATMENT OF SICKLE CELL PATIENTS: TRIAL DESIGN AND ENROLLMENT

Background: Sickle cell disease (SCD) is a life-threatening hematological disorder with a high rate of long-term comorbidities and a significant socioeconomic burden. Anemia, vaso-occlusive and pain crises, infections, and a high rate of long-term comorbidities are hallmarks of SCD. The pathophysiology of SCD is due to a single point mutation (Glu6Val) that causes polymerization of the mutant hemoglobin (HbS), resulting in red blood cells (RBC) sickling. Inflammation, hemolysis, microvascular obstruction, and organ damage characterize the clinical expression of SCD. The standard of care includes Hydroxycarbamide, symptomatic treatment, blood transfusions, new drugs, and bone marrow transplant as curative therapy. Our recent findings showed that N-methyl D-aspartate receptors (NMDARs) are up-regulated SCD-RBCs and Ca2+ uptake via NMDARs affects SCD-RBC hydration, and hypoxia-induced sickling (Hanggi P. et al., 2014). Inhibition of NMDARs with Memantine, a drug used in Alzheimer’s disease, emerges as a novel treatment in SCD. Memantine administration in 6 SCD adults demonstrated safety (Hegemann I. et al., 2020); and suggested a reduction of RBCs irreversible sickling (Makhro A, et al., 2020). Aims: This phase IIa-IIb open-label, single-center trial aims to study the safety, tolerability, and efficacy of Memantine in adults and teenagers with SCD (NCT03247218). Methods: This trial enrolled 23 SCD (SS and Sβ Thalassemia) 17 patients received Memantine for at least one year period, Hydroxycarbamide was continued administered. Starting dose of Memantine was 5 mg/day with escalation every 3 months, up to 15 mg/day in teenagers and up to 20 mg/day for adults. Patients were followed up monthly, a total of 6762 patients/days of follow-up were summarized. Results: The only safety events reported were transient headache and constipation in two patients; no adverse side effects were noticed. Overall, the number of admission days and emergency room visits decreased compared to the pre-screen period. The hemoglobin and fetal hemoglobin levels remain stable despite less use of blood transfusions; based on preliminary laboratory analysis a trend of reduction in hemolytic and inflammatory parameters can be noticed. Conclusions: The results of this phase IIa-IIb trial suggested safety and probable clinical benefit in long-term treatment with Memantine in SCD adolescents and adults. Full results of this trial are anticipated at the end of 2022 and a phase III trial will be required for the final assessment of the clinical benefit of Memantine treatment in SCD.

5613512 ASSESSMENT OF CHRONIC PAIN IN CHILDREN AND ADOLESCENTS WITH SICKLE CELL DISEASE IN ITALY: PRELIMINARY RESULTS OF A PROSPECTIVE STUDY C.PIATTELLINI1, V.MUNARETTO2, G.REGGIANI2, I.BAIDO2, E.MARAN2, A.BIFFI2, F.BENINI1, A.ZANIN1 AND R.COLOMBATTI2

Context: Children with sickle cell disease (SCD) suffer from episodes of intense pain such as vaso-occlusive crisis (VOC) that can increase in severity throughout life, leading to a poor quality of life. In addition to epVOCs, patients with SCD can also report recurrent VOCs even on daily basis and chronic pain which can be defined as pain that presents on most days for over over six months. Chronic pain in SCD has profound consequences for the patient: it is often associated with depression and anxiety and can lead to challenges with sleep, and chronic fatigue that impair quality of life. In spite of its burden, chronic pain is difficult to diagnose early for several reasons. In Italy, there is no current data on the prevalence and characteristics of chronic pain in the pediatric population with SCD. Objectives: 1) To evaluate the prevalence and characteristics of chronic pain in a large pediatric, adolescent and young adult SCD cohort (6-24 years) using the American Pain Society Pain Taxonomy (AAPT) Diagnostic Criteria for Chronic Pain in SCD to standardize each patient’s clinical information and using also the PROMIS and PedsQL domains for investigating pain and its effects on health related quality of life (HRQOL); 2)To compare the PROMIS and PedsqL questionnaires to investigate how chronic pain affects quality of life (QoL).A secondary outcome will be to assess if these tools can help to identify potential patients with chronic pain. Methods: The process included multiphase qualitative methodology between the Pain Team and the sCD Team of the AOP. A literature review on SCD was conducted to generate domains of interest for the individual interviews. PROMIS questionnaire investigates Global Health of the patient(7 items),Pain Sensory (8 items),Affective (8 items), Behavior (8 items), Mobility upper extremity (8 items), Strength (4 items), Physical Activity (4 items),Physical stress (4 items), Psychological stress (4 items),Sleep Disturbance (4 items)Sleep Related Impairment (4 items),Anger (5 items) and PedsQL for sickle cell disease. Results: We evaluated 43 patients with SCD ages 6–24 years from May 2021 to September 2022 referred to the Padova SCD reference center.Patients were distributed in 3 classes according to their age (19 (44%) between 6-13 years, 14 (32%) between 13-18 years and 10 (24%) between 18-24 years, 44% were female and only 5 (12%) of them had bone marrow transplants (TMO).Hydroxyurea was treatment regimen of 37 patients, 7 patients among these were on crizanlizumab and 4 subjects in our cohort are on chronic transfusion therapy.According to the American Pain Society Pain Taxonomy (AAPT) criteria for chronic pain in SCD (tab below[1] 16 (37%) patients with presumed chronic pain were identified all between the ages of 13 and 24 years old.Following the scoring of dimensions of Pedsql 12 subjects belong to the category of “excellent quality of life”, 12 to “good quality of life”, 5 to “fair quality of life”, 3to “modest quality of life”, 11 to “poor quality of life. Of the entire patient cohort, 9 fall within the criteria defined by AAPT and thus can be considered to have chronic pain.Further analyses are underway for PROMIS. Conclusions: In our cohort a growing population of SCD adolescents present clinical features of chronic patin These data need to be investigated in further studies thanks a close and muldisciplinary collaboration between Pain services and SCD haematological centers.Reference 1. Dampier C, Palermo TM, Darbari DS, Hassell K, Smith W, Zempsky W. AAPT Diagnostic Criteria for Chronic Sickle Cell Disease Pain. J Pain. 2017 May;18(5):490-498. doi: 10.1016/j.jpain.2016.12.016. Epub 2017 Jan 5. PMID: 28065813.[1]

Successful HPV Vaccination in Adolescents with Sickle Cell Disease Following a Quality Improvement Bundle Intervention

IntroductionHuman papilloma virus (HPV) infection can cause cervical, anal, penile, vaginal, and oropharyngeal cancer. The CDC recommends HPV vaccination as a 2 or 3-dose series at <15 or ≥15 years, respectively. Completion of the vaccine series decreases rates of cervical cancer in young women by 29%(Guo, F. et al. American Journal of Preventive Medicine 2018). For this reason, focus is currently on vaccinating younger patients to optimize benefit. Historically, adolescents have had low rates of completion of the HPV vaccine series. African Americans, in particular, have significantly lower rates than whites in receiving the full series (De, P. and H. Budhwani. Public Health 2017). Vaccine hesitancy in sickle cell disease (SCD) patients exists and is exemplified by a lower uptake in teenagers with SCD compared to non-SCD counterparts (Beverung, L. et al. American Journal of Hematology 2018). However, completion of 23-pneumococcal vaccine polyvalent (PPSV-23), which is routinely administered as a series during well-child visits, has notably been high. SCD programs serve as medical homes where primary care may also be provided. With this in mind, we introduced a quality improvement (QI) intervention to improve the uptake of HPV vaccination in the adolescent SCD clinic. A bundle intervention was developed including 1) provider education about HPV vaccination importance, 2) nurse review of each adolescent's vaccine records prior to clinic visit, 3) provider notification by the nurse regarding the need for HPV during the visit, 4) discussion of the vaccine benefits with the family, 5) provision of the vaccine in the SCD clinic after parent consent, and 6) offering of MOC points as incentive to providers for project participation. We sought to evaluate the impact of the QI bundle on completion of the HPV vaccine series. We hypothesized that implementation of the QI bundle would increase the rate of completion of the HPV vaccine series among adolescents with SCD. Secondary objectives included association between completion of the HPV vaccine series and frequency of outpatient visits to the SCD clinic, quality of life (QoL), SCD-specific knowledge, completion of the PPSV-23 series, and markers of socio-economic status (SES).MethodsRetrospective data was collected using the Sickle Cell Clinical Research and Intervention Program (SCCRIP) study database (Hankins JS, et al. Pediatr Blood Cancer 2018). Patients aged 12-18 years between October 1, 2018 and December 31, 2019 with any SCD genotype and who were enrolled on the SCCRIP study were included in analysis. The following variables were extracted: age, sex, race, ethnicity, age, economic hardship index (EHI), parental education level, household income, genotype, SCD-specific knowledge, and distance to healthcare facility. The prevalence of completed HPV series, defined as 2 doses ages <15 years and 3 doses ages ≥15 years, in the 12 months prior to implementation of the bundle vaccination program (before October 1, 2018) and after implementation of program (October 2, 2018 to December 31, 2019) was calculated using Fisher's exact. Demographic characteristics and QoL were compared between patients who completed the vaccine series and those who did not.ResultsIn total, 373 patients met inclusion criteria. Their median age was 15.2 (range 12-19), 50% were female, 225 (60.3%) had HbSS/Sβ 0-thalassemia, and 114 (29.7%) had HbC/Sβ +-thalassemia. The mean SES index was 70% (±27%) and the mean QoL score 73 (±14.6). HPV vaccine completion rates increased from 31% to 56.2% after the bundle implementation (Figure 1, p<0.01). Completion of the series was associated with higher SES index, completion of the PPSV-23 series, and higher frequency of outpatient visits. There was no significant association between completion of the vaccine series and QoL, distance from healthcare facility, and disease-specific knowledge (Table 1).DiscussionPrevention of communicable diseases such as HPV is imperative in the general population. However, baseline vaccination rates in adolescents with SCD is low. A QI intervention that includes provider education and incentives, active verification of HPV vaccination status, and promotes coordinated communication between the nurse, providers, and patients effectively increased completion of the HPV vaccine series among adolescents with SCD. Continued strategies are needed to further increase the rates of vaccine completion. [Display omitted] DisclosuresHankins: Vindico Medical Education: Consultancy; Global Blood Therapeutics: Consultancy; UpToDate: Consultancy; Bluebird Bio: Consultancy.

Caregiver Perceptions of Adolescent Self-Management Skills Predicts Higher Disease Knowledge Among Adolescents with SCD

Introduction: The increased survivorship of children with sickle cell disease (SCD) into adulthood requires sufficient readiness to transition to adult healthcare. Transition readiness encompasses the necessary skills to successfully transition to adult healthcare, including self-care, decision-making (i.e., self-management), and self-advocacy. Disease education improves self-management in populations with chronic illnesses, but the relationship between disease knowledge and self-management in the adolescent SCD population during healthcare transition is unknown. We hypothesize that disease knowledge is associated with self-management and engagement in adult healthcare.Methods: Adolescents with SCD and their caregivers completed a disease self-management skills checklist (SMSC) in early adolescence. The SMSC was modified from the validated Transition Readiness Assessment Questionnaire (J Pediatr Psychol. 2011 Mar; 36(2): 160-171.). The 21-item SMSC assesses perceived disease knowledge and self-management skills. At age 17, adolescents were invited to visit adult providers prior to leaving pediatric care (J Pediatr Health Care. 2012 Nov-Dec;26(6):e45-9.) At their last pediatric visit, adolescents completed the disease knowledge quiz, which tested their actual knowledge of SCD pathophysiology and complications. The disease knowledge quiz is a new instrument with 97% content validity as assessed by six pediatric and adult SCD experts. Association of SCD knowledge and perceived caregiver and adolescent self-management skills were evaluated by Pearson correlations if normally distributed; otherwise by Spearman correlation. Univariate linear regression tested associations between disease knowledge and SMSC. Univariate logistic regression tested associations between disease knowledge, visitation to adult provider, and completion of first adult visit.Results: Thirty-six African-American adolescents (18 males; 18 females) with SCD and their caregivers completed the SMSC at a median age of 16 years and actual disease knowledge 2 years later at the last pediatric visit. Thirty-two visited adult care prior to leaving pediatrics and thirty-two completed the first adult visit. Predictors of actual adolescent knowledge immediately prior to leaving pediatrics were caregiver's early perception of their adolescent's self-management skills (Figure). Disease knowledge associated with higher likelihood of meeting adult providers during pediatric care (Figure). Neither self-management assessments nor disease knowledge associated with completion of first adult visit (Figure).Conclusion: Caregivers are better evaluators of their adolescent's transition readiness than adolescent themselves, as demonstrated by a significant relationship between caregiver perceptions of their adolescent's self-management early in the transition process and adolescents' disease knowledge preceding departure for adult care. Adolescents' SCD knowledge level predicted future desire to engage in adult healthcare, demonstrated by the higher likelihood of visiting adult providers while in pediatric care. The lack of relationship between self-management and disease knowledge with completion of first adult visit indicates other possible barriers curtailing successful adult care transfer. Collectively, our findings support early engagement of caregivers in measuring adolescent transition readiness to guide subsequent transition programming in the SCD population. [Display omitted] DisclosuresPorter:NHLBI: Research Funding.

Social support networks of adults with sickle cell disease.

Sickle cell disease (SCD) can cause both physical and psychological complications, such as severe pain and depression. These effects often necessitate social and caregiving support. Few studies have assessed support networks within the adult SCD population. Here, we describe the support networks of adults with SCD and identify who in these networks (1) provides emotional support, (2) is dependable during crisis situations, including social and financial adversities, and (3) provides assistance in health crises. Forty-nine adults with SCD completed surveys and social network assessments through interview. Generalized mixed-effects linear regression models were fitted to investigate the composition of support provision within these personal networks. Our findings indicate that parents and 'other important people' (e.g., friends, spouses) play key roles in the support provided to those with SCD. Siblings with SCD appeared to be more emotionally supportive than unaffected siblings. With much research centered around the pediatric and adolescent SCD populations, focus needs to extend to adults and the individuals involved in their care and disease management. Understanding the flow of support within these networks can help genetic counselors and healthcare providers to better identify both social ties that serve as support resources and less supportive relationships for individuals living with SCD and other chronic genetic conditions that might be targeted for intervention.

Mechanisms of Bone Impairment in Sickle Bone Disease.

Sickle bone disease (SBD) is a chronic and invalidating complication of Sickle cell disease (SCD), a multisystem autosomal recessive genetic disorder affecting millions of people worldwide. Mechanisms involved in SBD are not completely known, especially in pediatric age. Among the hypothesized pathogenetic mechanisms underlying SBD are bone marrow compensatory hyperplasia and bone ischemic damage, both secondary to vaso-occlusive crisis (VOC), which leads to cell sickling, thus worsening local hypoxia with a negative impact on osteoblast recruitment. Furthermore, the hypoxia is a strong activator of erythropoietin, which in turn stimulates osteoclast precursors and induces bone loss. Hemolysis and iron overload due to a chronic transfusion regimen could also contribute to the onset of bone complications. Vitamin D deficiency, which is frequently seen in SCD subjects, may worsen SBD by increasing the resorptive state that is responsible for low bone mineral density, acute/chronic bone pain, and high fracture risk. An imbalance between osteoblasts and osteoclasts, with a relative decrease of osteoblast recruitment and activity, is a further possible mechanism responsible for the impairment of bone health in SCD. Moreover, delayed pubertal growth spurt and low peak bone mass may explain the high incidence of fracture in SCD adolescents. The aim of this review was to focus on the pathogenesis of SBD, updating the studies on biochemical, instrumental, and biological markers of bone metabolism. We also evaluated the growth development and endocrine complications in subjects affected with SCD.

Evaluation of Glomerular Hyperfiltration and Albuminuria in Sickle Cell Disease Adolescents: Cross-Sectional Retrospective Study

Background: Sickle Cell Disease (SCD) renal abnormalities commence early in childhood. The glomerular abnormalities, glomerular hyperfiltration and albuminuria are the most prevalent. However, these SCD glomerulopathies have not been considered exclusively in the adolescent age group. Objective: To determine the prevalence of glomerular hyperfiltration and albuminuria as well as identify the determinants for glomerular hyperfiltration in adolescents with SCD. Patients and Methods: The electronic patient records of 153 adolescents with SCD aged 10 - th to 23rd June 2019. Clinical information and laboratory parameters were obtained. The glomerular filtration rate was derived using the Bedside Schwartz’s method. Grouping of the adolescents was based on the presence and absence of glomerular hyperfiltration, which was defined as glomerular filtration rate > 140 ml/min/m2. The presence of albuminuria was defined as urine albumin-to-creatinine ratio > 3 mg/mmol or protein-to-creatinine ratio of >15 mg/mmol. The clinical and laboratory determinants of glomerular hyperfiltration in the total study population were investigated. Result: Prevalence of glomerular hyperfiltration was 33.3% in the adolescents studied, and that of albuminuria was 15.7% amongst the SCD adolescents studied, of which 13.7% of those with glomerular hyperfiltration also had albuminuria. On univariable analysis, the SCD adolescents with glomerular hyperfiltration had significantly lower weight (48.0 ± 18.0 versus 54.8 ± 17.0 kg; p = 0.02), height (155.1 ± 13.1 versus 160.6 ± 13.1 cm; p = 0.01), body mass index (19.4 ± 5.0 versus 21.0 ± 4.3; p = 0.04), haemoglobin level (88.7 ± 13.3 versus 98.1 ± 21.7 g/L; p = 0.001), and serum creatinine level (0.4 ± 0.1 versus 0.6 ± 0.2 mg/dl; p = 0.0001) as compared to those with no glomerular hyperfiltration. The SCD adolescents with glomerular hyperfiltration also had significantly higher lactate dehydrogenase levels (525.9 ± 180.3 versus 449.6 ± 170.3 IU/L; p = 0.01) than those with no glomerular hyperfiltration. But, multivariable analysis revealed no associations. Conclusion: This study revealed that the prevalence of glomerular hyperfiltration in SCD children in the adolescent age group is high, and the high glomerular filtration rates begin to decline toward normal values in middle adolescence.

Assessing the atria in pediatric sickle cell disease: Beyond the dilation.

Diastolic dysfunction (DD) and pulmonary hypertension (PH) are common causes of mortality for sickle cell disease (SCD) patients in developed countries. We hypothesized that left and right atrial strain (LAS-Ɛ, RAS-rƐ) are decreased in SCD adolescents, and that worsening values correlate with laboratory markers of disease severity. Prospective cohort study of patients with HbSS genotype of SCD was compared with healthy controls. LAS and RAS were measured from 4- and 2-chamber views by a blinded reader. Peak strain and strain rate values were obtained for atrial contraction (ac), reservoir (res), and conduit (con) phases. Mitral/tricuspid Doppler velocities, left atrial volume, right atrial area were obtained. Laboratory variables were obtained from the electronic record with the three prior values being averaged. Differences in variables were assessed with Wilcoxon rank sum test, and correlations assessed with Spearman's coefficient. There were 33 SCD patients compared to 35 healthy controls of similar age, gender, and size. SCD patients had increased left atrial volume and right atrial area. For LAS, Ɛres was significantly lower in SCD patients. For RAS, RƐcon was significantly lower. Neither measurement correlated with clinical markers. The majority of SCD patients had relatively normal atrial strain values. Those with markedly lower values had similar atrial size. A sub-set of SCD patients have markedly low Ɛres and rƐcon. No correlation with clinical markers was identified. Larger, longitudinal studies may determine utility of atrial strain as a screening tool in this at-risk population.

Sexual health of French adolescents with sickle cell disease

Purpose Focussing on sickle cell disease (SCD), the objective of this study was to assess adolescents’ sexual heath experience in the context of their chronic illness. Materials and methods We included teenagers from 14 to 19 years old followed for SCD in a hospital located in Créteil (France) from March 2017 to February 2018. Their sexual health experience was assessed by a self-questionnaire with three key themes: contraceptive experience, awareness of sexuality with chronic disease and level of information on the genetic transmission of the disease. Results 99 questionnaires were analysed. Only six SCD adolescents (one girl and five boys) reported being sexually active. Despite a very regular follow-up of their illness, only 13% of the boys and girls had received information on contraception at the hospital. Most adolescents (85% of boys and 81% of girls) did not think that the disease would interfere with sexual intercourse. The genetic pattern was well known (85% of boys and 87% of girls). Conclusion Young people with SCD need more information on contraception. Clinicians caring for them should be aware of the need for sexual health information in order to propose prevention actions adapted to these young people with chronic disease.

Malocclusion and Craniofacial Characteristics in Saudi Adolescents with Sickle Cell Disease.

Background:Sickle cell disease can result in dentofacial abnormalities. However, in Saudi Arabia, there are limited data with respect to orthodontic manifestations in patients with sickle cell disease.Objective:To determine the malocclusion and craniofacial characteristics in sickle cell disease adolescents and compare them with that of controls from the Eastern Province of Saudi Arabia.Methods:This comparative cross-sectional study included 112 Saudi patients with sickle cell disease, aged 12–18 years, and 124 age-matched Saudi controls from three major hospitals in Al Khobar and Dammam, Saudi Arabia. The Dental Aesthetic Index was used to assess malocclusion and orthodontic treatment needs. Digital lateral cephalometric radiographs were recorded for each patient and control, and its analysis included linear and angular measurements.Results:The prevalence of malocclusion was 87.5% in sickle cell disease patients and 54% in controls (P = 0.0001). The percentage of sickle cell disease patients with severe malocclusion that required orthodontic treatment was higher than that of controls (37.5% vs. 26.6%). In the sickle cell disease cohort, incisal segment crowding (72.4%), overjet (67.3%) and maxillary misalignment in the anterior segment (56%) were the most prevalent types of malocclusions and were significantly higher than that of controls (P < 0.05). About 38% and 67% of the sickle cell disease patients had openbite and posterior crossbite, respectively, compared with 19.3% (P = 0.001) and 37.1% (P = 0.0001) of controls, respectively. Cephalometric analysis showed that SNA (86.7°) and ANB (9.9°) angles were significantly higher in sickle cell disease patients than in controls (81.5° and 2°, respectively). In addition, lower central incisor-to-Frankfort horizontal plane (55°) and interincisal angles (121.5°) were significantly lower in sickle cell disease patients than in controls.Conclusion:Adolescents with sickle cell disease had a higher prevalence of malocclusion and greater orthodontic treatment needs than controls. Similarly, they had greater incisal crowding, overjet, openbite and posterior crossbite and demonstrated higher SNA, ANB and lower interincisal angles than controls. The findings of this study suggest that adolescents with sickle cell disease should be provided frequent dental examinations and early orthodontic treatment to improve their oral health, and thus quality of life.

Erythrocyte membrane ATPase activity in Sickle cell crisis

Background: Sickle cell disease is a genetic disease caused by a point mutation in the beta globin gene on chromosome 11 leading to the substitution of valine in place of glutamic acid in beta subunit of globin molecule. The vaso-occlusive crisis, or sickle cell crisis, is a common painful complication of sickle cell disease in adolescents and adults. Many studies have suggested the alteration in intracellular concentration of various ions associated with sickle cell disease.Aims and Objectives: This study aims to evaluate the activity of red blood cell membrane ATPase activity of sickle cell crisis patients in comparison to sickle cell patients in steady state.Material and Methods: Twenty patients of sickle cell crisis were included in the study. Twenty sickle cell patients in steady state were also registered who served as controls. The RBC Membrane ATPase activity were estimated and expressed as μmol of Pi/μg of protein/hour.Results: The activity of membrane ATPase were found to be significantly high in patients of sickle cell crisis in comparison to steady state ones.Conclusion: Membrane ATPases play a crucial role in the pathophysiology of sickle cell crisis. This study can be a based upon for future studies to understand the pathophysiology of sickle cell crisis and development of diagnostic and treatment modalities for the same.Asian Journal of Medical Sciences Vol.8(5) 2017 27-30

The 10-Item Sickle Cell Disease Severity Measure (SCDSM-10): A Novel Measure of Daily SCD Symptom Severity Developed to Assess Benefit of GBT440, an Experimental HbS Polymerization Inhibitor

Introduction and Objective: GBT440 inhibits HbS polymerization and reduces hemolysis, and is a promising treatment for Sickle Cell Disease (SCD). The traditional clinical endpoint, vaso-occlusive crisis (VOC) requiring healthcare utilization, is not a sensitive measure of the daily burden of symptoms in patients (the "tip of the iceberg" of severe symptom exacerbations) and poses a barrier to development of new treatments for SCD.The objective was to develop a sensitive measure to detect treatment-related improvements in daily symptoms and exacerbations that define the disease. Existing SCD measures focus on distal impact, not on the core signs and symptoms of disease, and therefore not appropriate for meeting the regulatory standard to prove treatment benefit. Beginning with a hypothesized conceptual framework focused on pain and fatigue, rigorous qualitative and quantitative research was used to develop the content of the Sickle Cell Disease Severity Measure (SCDSM).Methods: The content of the new measure was derived from 1-on-1 open-ended concept elicitation interviews in 56 adults and 10 adolescents with SCD in the US and UK. Participants were aged 12-63 years, 64% female, 44% currently on hydroxyurea treatment, 86% had 1 to 42 VOC in the previous year requiring urgent care. During the interview, 74% reported having a typical or "good" day versus 26% having a crisis or "bad" day.Interview transcripts were coded to identify the most bothersome and frequently mentioned concepts related to both "good" and "bad" days. As hypothesized, patients reported having crisis days more frequently than those crises requiring healthcare utilization (traditional VOC endpoint). Interviews continued until saturation was demonstrated. How items worked individually and together were explored to quantify the full range of SCD severity. Both Classical Test Theory and Rasch Measurement Theory quantitative analyses supported the qualitative data to refine item content. To document content validity, the SCDSM content in its final electronic daily diary format will be evaluated in cognitive debriefing studies. Subsequently, longitudinal evaluation will occur in future clinical trials with GBT440. Translation and cultural adaptation is planned.Results: After eliciting an initial pool of items using open-ended interviews, the items were administered to a small cohort of SCD patients. After analyses of the response data and re-examination of the qualitative data, revisions were made. The revised set was re-administered to a cohort of 50 SCD patients. Qualitative and quantitative analyses provided evidence that a set of 10-items demonstrated content validity in adult and adolescent SCD patients to produce a score which can measure the full range of sickle cell disease severity. The mixed methods process enabled streamlined decision-making concerning measure content. The final content includes items specific to pain, fatigue, concentration and breathlessness. Evidence supports the derived estimate as a reliable and valid measure of SCD symptom severity covering a wide range of experience and providing the ability to differentiate baseline symptoms from severe symptoms. Patient responses to the 10 SCDSM items are combined to generate a single daily estimate of SCD symptom severity. Two "scores" can be computed: an ordinal-level total score can be computed by summing item scores; an interval-level (linear) measure can be derived from item responses using RMT analysis.Conclusions: SCD patients have a high burden of daily symptoms, with severe or "crisis" days occurring more frequently than traditionally defined VOC. The 10-item SCDSM is a promising new measure of daily SCD symptom severity developed to be fit for purpose in clinical trials to determine the treatment effect of new drugs on potential improvement in baseline symptoms and/or prevention of symptom exacerbations. SCDSM will soon be tested in a clinical trial setting to determine its longitudinal measurement characteristics, generate guidelines for measure interpretability, and to explore the clinical benefit of GBT440 in SCD. Qualitative and psychometric findings based on the SCD patient voice will be presented at the meeting to provide evidence of SCDSM validity, reliability, and usefulness in assessing symptom severity in a disease that has heretofore been poorly characterized on a daily basis. DisclosuresBurke:Lora Group: Employment; Global Blood Therapeutics: Consultancy. Hobart:Lora Group: Research Funding. Fox:Lora Group: Research Funding. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Bridges:Global Blood Therapetics: Employment, Equity Ownership. Kraus:Global Blood Therapeutics: Employment, Equity Ownership. Ramos:Global Blood Therapeutics: Employment, Equity Ownership.

Severe Anemia As an Early Predictor of Kidney Injury

Adult patients with Sickle Cell Disease (SCD) develop overt proteinuria; microalbuminuria precedes overt proteinuria in Pediatrics. Prior Pediatric cross-sectional studies have evaluated the prevalence and associations of laboratory variables with the presence of microalbuminuria (MiA). This study utilized a prospective SCD nephropathy cohort study to understand the incidence, risk factors, and predictors for the development of MiA. Then, we tested the hypothesis that severe anemia as an infant or toddler, independent of future blood counts, clinical course, or therapies, would be predictive of developing microalbuminuria during adolescence.Methods: We are conducting an IRB approved Pediatric SCD Nephropathy cohort of patients with HbSS or SB0 thalassemia (n=152). We record every standard of care urine albumin/creatinine level obtained since birth (n=595) for each participant in our cohort along with their blood pressure, SCD therapy, complete blood count, and estimated glomerular filtration (cystatin C) from that visit. Patients were classified as having microalbuminuria if their urine albumin/creatinine was ≥ 30 mg/g using a Siemens DCA Vantage Analyzer. T-tests and chi-squared tests were used to compare individual demographic and clinical characteristics for continuous and categorical, respectively, of those patients who developed at least one episode of MiA using SAS 9.4. Next, we used a combination of left, right and interval censored data in a time to development of MiA model. To examine the incidence of MiA and its predictors, we utilized univariate and multivariate parametric survival regression models assuming a logistic distribution. To examine the predictive ability of a single CBC early in life for the development of MiA, we utilized logistic regression and computed the area under the receiving operating characteristics curves (AUC). Based on Baby HUG data, we used a hemoglobin <8.0 g/dL on their earliest Hb after 9 months and prior to their 2nd birthday for our classification of severe anemia.Results: Among 152 participants in our prospective cohort, 48 (32%) developed at least one episode of MiA. The mean age of the 48 patients that developed MiA was 13.2 years (s.d 4.3) as compared to the mean age of 13.9 years (s.d 4.4) among 104 patients that have not yet developed MiA. Participants with lower hemoglobin (p<0.0001), higher reticulocyte percent (p=0.003), higher white blood cell (WBC) count (<0.0001), higher absolute neutrophil count (p=0.003) and higher platelet counts (p=0.03) were significantly more likely to develop MiA at an earlier age. Nineteen of 75 patients (25%) were on HU at the time of their first identified episode of MiA, 20 of 53 (37%) were on transfusion and 10 of 24 (42%) were on no SCD modifying therapy. No statistical difference in time to first MiA was identified based on SCD modifying therapy (p=0.08), abnormal systolic blood pressure (0.6), diastolic blood pressure (0.3), eGFR (0.6), or bilirubin (p=0.08). In multivariate analysis, patients that were more anemic (p=0.002) and had a higher WBC (p=0.01) were more likely to develop MiA at an earlier age. To determine if an early CBC could predict future development MiA, we evaluated each patient’s CBC by two years of age. Severe anemia (Hb<8 g/dL)(p<0.0001), but not WBC (p=0.2) or platelet count (p=0.2), was identified as a risk factor for progressing to MiA in our cohort. Thirty one of 50 participants (62%) with Hb<8g/dL at two years of age eventually developed MiA in our cohort. Seventeen out of 98 participants (17%) with Hb≥8g/dL progressed to MiA. The AUC for a model of severe anemia alone as a predictor of MiA was 0.7 which was statistically similar to the model for development of MiA using severe anemia, WBC, and platelets (AUC 0.75).Conclusion: This cohort supports the finding that at the time adolescent SCD patients are identified with microalbuminuria, they have a greater degree anemia and leukocytosis than adolescent patients without microalbuminuria. Of great importance, severe anemia identified prior to two years of age is predictive of patients that will develop MiA during adolescence. Additional research into the pathophysiology of kidney injury and its association with acute anemic events or hemolysis is vital to modifying the progression to CKD. DisclosuresLebensburger:NHLBI: Research Funding; American Society of Hematology, Scholar Award: Research Funding.

Increased rates of body dissatisfaction, depressive symptoms, and suicide attempts in Jamaican teens with sickle cell disease.

This study aims to examine the association of body image and weight perceptions with risk of depression and suicidal attempts in Jamaican adolescents with sickle cell disease (SCD). Adolescents with SCD and a national sample of Jamaican adolescents completed a questionnaire examining body image, weight perceptions, and risk for depression. Perceived and desired body images were similar for both groups. Adolescents with SCD had higher levels of "negative body satisfaction" (43.9% vs. 33.9%; P = 0.03), risk for depression (28.7% vs. 19.3%; P = 0.01), and attempted suicide (12.4% vs. 6.6%; P = 0.02) than national sample. Risk of depression was higher in those who perceived themselves to be over or underweight, and lower in those with more friends and attending school. Females and those with body image dissatisfaction were more likely to have attempted suicide. Within the SCD adolescents, girls were at greater odds of having mental health issues. Jamaican adolescents with SCD have significantly higher rates of negative body satisfaction and depressive symptoms, and nearly twice the rate of attempted suicide, compared with their healthy peers. This underscores the need for healthcare professionals to better explore and discuss healthy weight, body satisfaction, and coping with the demands and uncertainties of having a chronic illness with Jamaican adolescents with SCD, even while promoting body acceptance and good self-esteem. Screening for mood disorders is strongly recommended and gender-specific interventions should be developed. Healthcare professionals need to encourage positive social interactions that improve adolescents' mental health.

Caregiver Perspectives of Stigma Associated With Sickle Cell Disease in Adolescents

Patients and families affected by various medical conditions report experiencing health-related stigma, which contributes to detrimental physical, psychological, and social outcomes. Sickle cell disease (SCD) is a genetic disorder that affects 89,000 individuals in the United States and is often associated with negative stereotypes and incorrect assumptions. The present study explored the perception of stigma as reported by caregivers of adolescents with SCD. Focus groups were conducted with 20 caregivers of patients with SCD. Focus groups were audio recorded and transcribed. The data were coded independently by two authors, and then reviewed conjointly until consensus was reached. Caregivers reported the perception of stigma in academic, medical, community, and family settings. They also reported internalized stigma including negative feelings toward having a child with SCD, feeling upset with others, and seeing negative emotions in their child due to SCD. Caregivers reported a general lack of knowledge about SCD across settings. These results demonstrated that stigma may affect individuals with SCD across multiple settings. These results also highlighted areas for intervention, with a focus on increasing communication and education toward medical providers, schools, and communities. Interventions can utilize technology, social media, and advertisement campaigns. Additionally, support groups for patients with SCD may help decrease stigma and validate patients' experiences.

Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease.

Environmental variations have strong influences in the etiology of type 2 diabetes mellitus. In this study, we investigated the genetic basis of diabetes in patients with sickle cell disease (SCD), a Mendelian disorder accompanied by distinct physiological conditions of hypoxia and hyperactive erythropoiesis. Compared to the general African American population, the prevalence of diabetes as assessed in two SCD cohorts of 856 adults was low, but it markedly increased with older age and overweight. Meta-analyses of over 5 million single-nucleotide polymorphisms (SNPs) in the two SCD cohorts identified a SNP, rs59014890, the C allele of which associated with diabetes risk at P = 3.2 × 10(-8) and, surprisingly, associated with decreased APOB expression in peripheral blood mononuclear cells (PBMCs). The risk allele of the APOB polymorphism was associated with overweight in 181 SCD adolescents, with diabetes risk in 592 overweight, non-SCD African Americans ≥ 45 years of age, and with elevated plasma lipid concentrations in general populations. In addition, lower expression level of APOB in PBMCs was associated with higher values for percent hemoglobin A1C and serum total cholesterol and triglyceride concentrations in patients with Chuvash polycythemia, a congenital disease with elevated hypoxic responses and increased erythropoiesis at normoxia. Our study reveals a novel, environment-specific genetic polymorphism that may affect key metabolic pathways contributing to diabetes in SCD.

Adolescents with sickle cell anaemia: Experience in a private tertiary hospital serving a tertiary institution.

Background:Many adolescents with sickle cell disease (SCD) have adjustment difficulties in the transition period from paediatric care to the adult system because they find themselves in unfamiliar waters where they have to learn to manage themselves. The aim of this study is to evaluate the prevalent crises and morbidities associated with SCD in adolescents in Babcock University Teaching Hospital (BUTH), to also assess the level of knowledge of these adolescents about SCD and to determine their emotional response to the disease.Materials and Methods:This was a retrospective review of case notes of adolescents with sickle cell anaemia that were seen in BUTH, from May 2013 to April 2014. Data extracted from the case notes was entered into a Microsoft (MS) Excel and analysed using descriptive statistics. Results were presented in tables.Results:A total of 50 subjects were seen in the department during this study period. Vaso-occlusive crises in the form of bone pains (93.1%) were the commonest crises encountered. Associated morbidities were malaria 34 (85%), tonsilitis 1 (2.5%), pneumonia 1 (2.5%), leg ulcer 1 (2.5%), azotaemia 1 (2.5%) and subarachnoid haemorrhage 2 (5%). Majority (88%) had adequate knowledge about general health maintenance while knowledge on nutrition and appropriate analgesia use is still inadequate. Eleven (22%) had symptoms of depression, four (8%) had suicidal ideation while one (2%) had a history of attempted suicide.Conclusion:This study emphasizes the importance of psychosocial intervention as part of a comprehensive health management for people with SCD.

Risky behaviours of Jamaican adolescents with sickle cell disease

ObjectivesTo describe the risky behaviours of Jamaican teens with sickle cell disease (SCD) and compare them to a national sample of Jamaican youth.MethodsOne hundred twenty two SCD adolescents, 15–19 years old, completed the standardized questionnaire used in the Jamaican Youth Risk and Resiliency Behaviour Survey (JYRRBS), which was a nationally representative survey of 1317 Jamaican youths. Information was obtained on socio-demographics, smoking, alcohol use, and sexual activity. Secondary data from the JYRRBS were extracted to measure the difference in risky behaviours between the groups.ResultsAlmost 50% of SCD and 58% of national teens reported having had sexual intercourse. More SCD teens used alcohol (77.7% vs. 60.7%; P value = 0.001). Risky behaviours tended to coexist and living with a parent (odds ratio: 0.62, P value <0.01) and currently attending school (odds ratio: 0.43, P value <0.001) lowered the likelihood of having had sex.DiscussionSCD teens engage in many risky behaviours and health care professionals should screen and counsel them at each visit.

Platelet Activation and Inhibition iN Sickle cell disease (PAINS) study

Platelet activation/aggregation in sickle cell disease (SCD) may promote tissue ischemia, suggesting that antiplatelet therapy may be useful. However, the assessment of platelet function and the effect of antiplatelet therapy in blood from SCD patients may be confounded by hemolysis with the release of adenosine 5′-diphosphate (ADP). Here we evaluate the levels of platelet activation markers in SCD adolescents vs. normal controls and compare, by multiple methods, the effect of in vitro blockade of the platelet ADP receptor P2Y12 by prasugrel's active metabolite, R-138727. Platelet activation markers in blood from SCD adolescents (n = 15) and healthy adults (n = 10), and the effect of R-138727 (0.1–10 µM) added in vitro, were evaluated with and without ADP stimulation. The circulating levels of platelet–monocyte and platelet–neutrophil aggregates were significantly higher (p < 0.01) in SCD patients than in healthy controls. R-138727, in a concentration-dependent manner, inhibited platelet function in both SCD patients and healthy subjects as judged by ADP-stimulated light transmission aggregation, VerifyNow® P2Y12 assay, multiple electrode aggregometry, and flow cytometric analysis of platelet vasodilator-stimulated phosphoprotein, activated GPIIb-IIIa and P-selectin. The R-138727 IC50s for each assay were not significantly different in SCD vs. healthy subjects. In summary: (1) The high circulating levels of platelet–monocyte and platelet–neutrophil aggregates demonstrate in vivo platelet activation in SCD and may be useful as markers of the in vivo pharmacodynamic efficacy of antiplatelet therapy in SCD. (2) The similar in vitro R-138727 IC50s in SCD and healthy subjects suggest that the prasugrel dose-dependence for platelet inhibition in SCD patients will be similar to that previously observed in healthy subjects.