Screening For Sickle Cell Disease Research Articles

Enablers and barriers to newborn screening for sickle cell disease in Africa: results from a qualitative study involving programmes in six countries

ObjectivesGiven the fundamental role of newborn bloodspot screening (NBS) to enable prompt diagnosis and optimal clinical management of individuals with sickle cell disease (SCD), we sought to systematically assess enablers...

Newborn Screening for Sickle Cell Disease Among Tribal Populations in the States of Gujarat and Madhya Pradesh in India: Evaluation and Outcome Over 6 Years.

Sickle cell disease (SCD) poses considerable public health problems in India. This study was undertaken to understand the clinical course of SCD among children identified during newborn screening programmes in Gujarat and Madhya Pradesh where the frequency of the HbS gene is high. A total of 8,916 newborn babies 8,411 from Gujarat and 505 from Madhya Pradesh were screened over 6 years (2010–2016) using HPLC and the diagnosis was confirmed by molecular analysis in a subset. A total of 128 babies (122 Gujarat, 6 Madhya Pradesh) were identified with sickle cell disease, of whom 87 (69 HbSS, 18 HbS-β thalassemia) from Gujarat were followed for 0.5–6.6 years. Acute painful events, severe anemia and fever with infections were the major complications and 23 babies required hospitalization. Severe to moderate clinical presentation was found in 13.8% babies with SCD whereas, 86.2% babies had a milder presentation. Presence of ameliorating factors (α-thalassemia and Xmn 1 polymorphism) did not have a discernible effect on the clinical severity. Parents of babies with SCD were educated and counseled for home care. Distribution of mobile phones to 44 families having babies with SCD was beneficial as it allowed regular contact with patients and their families. Genetic counseling to the affected families has increased the awareness and acceptance for prenatal diagnosis and 18 couples opted for prenatal diagnosis in subsequent pregnancies. SCD is not always mild among tribal groups in India. Therefore, facilities for early diagnosis and prophylactic treatment in the tertiary care centers should be made available. The difficulties in regular follow up of the babies in remote rural areas have also been highlighted.

Neonatal Screening for Sickle Cell Disease in Congo.

Introduction Sickle cell disease is an autosomal recessive inherited disorder due to the mutation of a gene coding for the globin beta chain. The aim of this study is to update the epidemiological data on hemoglobinoses, in particular sickle cell disease in newborns in Congo. Materials and Methods This was a descriptive cross-sectional study, conducted from October 1, 2019, to March 31, 2020, throughout the Congolese national territory. It involved all full-term newborns, without distinction of nationality, aged 5 days or less, and whose parents consented to participate in the study. The blood samples, taken at the heel and collected on Whatman blotting paper, were analyzed using the HPLC Variant NBS machine. Results In 2897 newborns (NN) screened, hemoglobin abnormalities were found in 603 NN (20.81%). The mean age of these newborns was 1 day (extremes 0 and 5 days). The male-to-female ratio was 1.03. Abnormal hemoglobins were mainly Hb S (n = 597 (97.71%)); Hb C (n = 5 (0.82%)); and variants (n = 7 (1.15%)). The national prevalence of major sickle cell (MSC) syndromes and sickle cell trait was 1.35% and 19.43%, respectively. The prevalence ranged from 1.77% to 2.56% for MSS in four departments and from 20.5% to 25.8% for the sickle cell trait in six other departments. Conclusion Data on homozygous sickle cell disease remain consistent with previous studies. However, further studies should clarify the molecular anomalies of the variants observed in our samples.

Premarital Genotype Screening for Sickle Cell Disease: Knowledge Gaps, Perception and Determinants of Uptake among Final Year Undergraduates of a Tertiary Institution in South-West Nigeria.

Strategies involved in the prevention and management of sickle cell disease include premarital genotype screening and counselling as well as efforts at increasing the knowledge of the population about the condition. This is a cross-sectional descriptive study which assessed the knowledge of sickle cell disease and premarital genotype screening, attitudes towards screening and factors associated with uptake of premarital genotype screening among 326 final year students at the University of Ibadan, Oyo State, Nigeria. Respondents were within the age range of 18-24 with a mean age of 23. Majority of the respondents had AA genotype (68.71%). Only 15.95% of the respondents had good knowledge of sickle cell disease. Mean knowledge score was 14 out of 26 with a standard deviation of 4.31. 75.77% of the respondents had good knowledge of premarital genotype screening. 76.07% of the respondents had good attitudes to premarital genotype screening. Mean attitude score was 9.5 out of 12 with a standard deviation of 2.15. Respondents' current level of study (P=0.000) and marital status (P=0.042) were significantly associated with knowledge of sickle cell disease. There was significant association between knowledge of sickle cell disease and knowledge of premarital genotype screening (Fisher's P= 0.000). Knowledge of premarital genotype screening was significantly associated with respondents' current level of study (P=0.004) and attitudes to premarital genotype screening (Fisher's P= 0.000). Significant knowledge gaps were identified in the study population. There is need for continuous assessment of knowledge gaps and educational intervention to decrease the incidence of sickle cell disease.

Newborn Screening and Clinical Profile of Children With Sickle Cell Disease in a Tribal Area of Gujarat

To present the result of newborn sickle cell disease (SCD) screening and clinical profile of SCD newborns in a tribal area of Gujarat. We screened all newborns of sickle cell trait (SCT) and SCD mothers for SCD using high-performance liquid chromatography (HPLC) within two days of birth at a secondary care hospital in a tribal area in Gujarat from 2014 to 2019. Newborns with SCD were registered under an information technology based platform for hospital-based comprehensive care. Neonates were followed prospectively every 3 months. If they missed the clinic visit, a medical counsellor visited them at home to collect the required information. Out of 2492 newborns screened, 87 (3.5%) were diagnosed with SCD. Among the 67 newborns screened for alpha-thalassemia deletion, 64 (95.4%) of babies had alpha-thalassemia deletion. We recorded total 554 clinic visits over the period of 221.5 person-years. The rates of acute febrile illness, painful crisis, hospitalization and severe anemia were 42.9, 14.9, 14.9 and 4.5 per 100 person-year, respectively. Two deaths were recorded, and 5 babies (5.7%) had severe SCD. We found a high prevalence of alpha thalassemia deletion among newborn SCD cohort in tribal area of Gujarat, and 70% babies had atleast one clinical complication on follow-up.

S126: AN EU -- ARISE INITIATIVE GAP ANALYSIS APPROACH TO IMPROVING THE QUALITY OF LABORATORY SYSTEMS IN SUB-SAHARAN AFRICA.

Background: Accurate and reliable laboratory results are critical to diagnostics in sickle cell disease (SCD) newborn screening. In sub-Saharan Africa, due to neglect of some national health laboratories, there has been persistently high levels of laboratory error, lack of functioning quality management systems and laboratory accreditation. ARISE (African Research and Innovative Initiative for Sickle Cell Education) is a research project funded by the EU. It involves a secondment plan across 8 work packages between institutions in EU (Italy, France, UK and Cyprus) and non-EU (Nigeria, Lebanon, Kenya and USA) countries, creating an interagency and multidisciplinary staff exchange programme to share best practices in newborn screening, diagnosis and treatment of SCD, leading to improved disease outcomes. Secondments include medical, nursing, laboratory, administrative, academic and research professionals. Led by the RCPath and INSERM, WP3 is tasked with improving laboratory diagnostics, capacity, and quality assurance systems for population screening, diagnosis, treatment and monitoring of SCD through assessments, training and mentoring of laboratory health professionals. This is facilitated by baseline, interim and final gap assessments Aims: To compare a baseline gap analysis at the commencement of the project in 2019 with an interim gap assessment 2 years into the project, following secondments to UK laboratories from Nigeria To identify areas of increased focus and support during planned secondments, workshops, and virtual lectures Methods: 6 partner organisation laboratories participated in the baseline gap assessment in 2019, while 10 laboratories participated in the interim gap assessment in 2021, due to new institutions joining the ARISE initiative. An electronic online questionnaire (40 questions) was sent to each laboratory lead. Results: Survey results of the 6 laboratories that undertook both the baseline and interim gap assessment were analysed. A sample of comparative results between 2019 and 2021 include the following: Working towards accreditation - 2/6 versus 3/6: There is the need for each laboratory to progress towards an application for accreditation. SOP’s available for tests and processes - 38 versus 32: This might suggest standardisation and rebranding of documents previously labelled as SOP’s. No schedule of SOP revisions in 0/6 laboratories versus 4/6 laboratories: This clearly demonstrates an understanding that SOP’s need to be updated via a document management system. Scientist certified competences - 22 versus 22. Self -assessed improvement targets - 18 versus 15. Laboratory lead for QA - 3/6 versus 6/6: The importance of QA leadership for each laboratory identified prior to interim assessment. Summary and Recommendations: Early evidence suggests that ARISE secondments have facilitated improved approaches to laboratory governance procedures and QA. Mentoring by EU partner laboratories will further enhance this. ARISE related workshops and train - the- trainer programmes will support capacity building and skills transfer. A final assessment will be undertaken at the end of the ARISE initiative. Conclusion: The ARISE initiative will build on the early success of improvement in laboratory systems, to further support service development and capacity building. The target for each partner laboratory will be a timeline of application to full accreditation

S117: LONG-TERM FOLLOW UP OF DUTCH PATIENTS WITH SCD DIAGNOSED BY NEONATAL SCREENING -- EFFECT ON THE MORBIDITY AND MORTALITY IN THE NETHERLANDS.

Background: Newborn screening for sickle cell disease (SCD) has been introduced in January 2007 in the Netherlands. The objective of this study is to assess the effect of this neonatal screening for SCD by describing the residual risks of death and major disease-related events during the first fourteen years of life in children diagnosed with SCD at birth in the Netherlands. Aims: The objective of this study is to assess the effect of this neonatal screening for SCD by describing the residual risks of death and major disease-related events during the first fourteen years of life in children diagnosed with SCD at birth in the Netherlands. Methods: Here we report the first data of one center (Amsterdam UMC) of this prospective, national multicenter study. Following informed consent data were collected from medical files of all children born after 1 January 2007, diagnosed by neonatal screening. Descriptive data on SCD genotype, occurrence of major disease-related events (hospitalization for vaso-occlusive crisis (VOC), acute chest syndrome/pneumonia, severe infections and neurological complications) are presented. Overall survival and survival without specific SCD-related complications were analyzed by Kaplan-Meier curves. Results: Up until now, 98 (56%) out of 174 eligible subjects from this institution were included, with a total follow-up of 805 patient-years. This concerns approximately 35% of the national number. The majority (55%) had the severe genotype (HbSS/ beta0-thalassemia), the remainder had the milder genotype (HbSC or HbS/beta+-thalassemia). Survival by the age of 14 was 98.9%, with 1 death at the age of 1 years due to sepsis. Seven patients (7.1%) had a severe infection (meningitis, sepsis, osteomyelitis) caused by Streptococcus Pneumoniae in 3/7 cases. Two patients experienced a symptomatic cerebral infarction at the age of 11 months and 1.5 years. At the age of 10 years the survival without hospitalization for vaso-occlusive crisis was 27% (95% CI: 12.7 – 43.14%) and 51% (25.3 – 72.0%) for the SS/Sβ0 and SC/Sβ+ genotype respectively. Conclusion: In this cohort of neonatally screened patients with SCD, the SCD-related mortality and morbidity is still impressive with 1% mortality, 3 severe infections caused by Streptococcus Pneumoniae, and 2 patients with neurological complications. A final analysis of the effect of neonatal screening for SCD will follow after completion of data collection in all participating centers in the Netherlands.

Burden of sickle cell disease in tribal students in Maa-Baadi institutions in southern Rajasthan - A pilot study.

Sickle cell disease (SCD), an inherited disorder of erythrocytes, is highly prevalent in the tribal population of India. The tribal population of India is approximately 100 million and it is necessary to identify the magnitude of this problem. Furthermore, the prevalence of the disease is unknown among the five million tribal people of southern provinces of Rajasthan. In this study, we intended to determine the prevalence and characteristics of sickle cell disorder among the tribal inhabitants of southern Rajasthan. This cross-sectional study was conducted among the tribal students of the Maa-Baadis and hostels situated in the five tribal sub-plan districts of Rajasthan. Maa-Baadi centres are located in every village, whereas for every four to five villages, one hostel is allocated to accommodate the tribal students. The screening for SCD was done by solubility test and electrophoresis was used for confirmation. A total of 36,752 tribal students were screened from 1,006 Maa-Baadi centres and 243 hostels. The prevalence of SCD among the tribal students was 5.8 per cent. The prevalence of heterozygous and homozygous conditions was 5.61 and 0.17 per cent, respectively. Among the five sub-plan districts, the highest prevalence was observed in Sirohi district (10.5%) followed by Banswara (7.42%), Udaipur (6.53%), Pratapgarh (5.51%) and Dungarpur (1.89%). Among the four major tribes belonging to these districts, the highest prevalence was recorded in Garasia tribes (13.81%). The history of leg ulcers and the mean pulse rate were significantly high in SCD individuals. SCD is a significant problem among the tribes of southern Rajasthan, with the highest prevalence among the Garasia tribe. The present study recommends that a structured screening programme targeting the entire tribal population with appropriate counselling as well as providing treatment through the existing health system is the need of the hour.

Newborn Screening Practices for Beta-Thalassemia in the United States.

Beta-thalassemia, a heritable condition of abnormal hemoglobin production, is not a core condition on the United States Recommended Uniform Screening Panel (RUSP) for state and territorial newborn screening (NBS) programs. However, screening for sickle cell disease (which is on the core RUSP) also detects reduced or absent levels of hemoglobin (Hb) A and certain other Hb variants associated with beta-thalassemia and, thus, allows for a timely referral to appropriate healthcare to minimize sequalae of the disease. The Association of Public Health Laboratories’ Hemoglobinopathy Workgroup administered a comprehensive survey of all U.S. NBS programs to assess beta-thalassemia testing methodologies, the cutoffs for defining beta-thalassemia major, and the reporting and follow-up practices. Forty-six (87%) of the programs responded. Thirty-nine of the 46 responding programs (85%) report some form of suspected beta-thalassemia; however, the screening methods, the percentage of Hb A used as a cutoff for an indication of beta-thalassemia major, and the screening follow-up vary widely. The standardization of technical and reporting procedures may improve access to specialty care prior to severe complications, increase genetic counseling, and provide data needed to better understand the public health impact and clinical outcomes of beta-thalassemia in the United States.

Co-occurrence of sickle cell disease and oculocutaneous albinism in a Congolese patient: a case report

BackgroundSickle cell disease and oculocutaneous albinism are rare autosomal recessive disorders both related to mutations on chromosome 11. The diagnosis of patients suffering from both pathologies is necessary to enable dedicated monitoring of any complications at the ophthalmic and skin level. However, few cases are described in the literature.Case presentationA 14-month-old Congolese male child affected by oculocutaneous albinism, presented with pallor and jaundice. Blood indices revealed severe hemolytic anemia, which led to the diagnosis of sickle cell disease. The patient received a blood transfusion and close follow-up.ConclusionsThe co-inheritance of sickle cell disease and oculocutaneous albinism is a reality in the Democratic Republic of Congo, although it is rarely described. Given the current state of our knowledge, specific surveillance, specifically regarding cutaneous and ophthalmological complications, should be offered in this particular population. To enable this dedicated follow-up, sensitization to screening for sickle cell anemia in albino individuals should be carried out.

The Alberta Newborn Screening Approach for Sickle Cell Disease: The Advantages of Molecular Testing.

Sickle cell disease (SCD), a group of inherited red blood cell (RBC) disorders caused by pathogenic variants in the beta-globin gene (HBB), can cause lifelong disabilities and/or early mortality. If diagnosed early, preventative measures significantly reduce adverse outcomes related to SCD. In Alberta, Canada, SCD was added to the newborn screening (NBS) panel in April 2019. The primary conditions screened for are sickle cell anemia (HbS/S), HbS/C disease, and HbS/β thalassemia. In this study, we retrospectively analyzed the first 19 months of SCD screening performance, as well as described our approach for screening of infants that have received a red blood cell transfusion prior to collection of NBS specimen. Hemoglobins eluted from dried blood spots were analyzed using the Bio-Rad™ VARIANT nbs analyzer (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Targeted sequencing of HBB was performed concurrently in samples from all transfused infants. During the period of this study, 43 of 80,314 screened infants received a positive NBS result for SCD, and of these, 34 were confirmed by diagnostic testing, suggesting a local SCD incidence of 1:2400 births. There were 608 infants with sickle cell trait, resulting in a carrier frequency of 1:130. Over 98% of non-transfused infants received their NBS results within 10 days of age. Most of the 188 transfused infants and 2 infants who received intrauterine transfusions received their final SCD screen results within 21 ± 10 d of birth. Our SCD screening algorithm enables detection of affected newborns on the initial NBS specimen, independent of the reported blood transfusion status.

Clinical Utility of the Addition of Molecular Genetic Testing to Newborn Screening for Sickle Cell Anemia.

Sickle cell disease (SCD) is a group of related yet genetically complex hemoglobinopathies. Universal newborn screening (NBS) for SCD is performed in the United States and many other nations. Classical, protein-based laboratory methods are often adequate for the diagnosis of SCD but have specific limitations in the context of NBS. A particular challenge is the differentiation of sickle cell anemia (SCA) from the benign condition, compound heterozygosity for HbS and gene-deletion hereditary persistence of fetal hemoglobin (HbS/HPFH). We describe a sequential cohort of 44 newborns identified over 4.5 years who had molecular genetic testing incorporated into NBS for presumed SCA (an “FS” pattern). The final diagnosis was something other than SCA in six newborns (12%). Three (7%) had HbS/HPFH. All had a final, correct diagnosis at the time of their first scheduled clinic visit in our center (median 8 weeks of age). None received initial counseling for an incorrect diagnosis. In summary, genetic testing as a component of NBS for SCD is necessary to provide correct genetic counseling and education for all newborns' families at their first visit to a sickle cell center. Genetic testing also permits the use of early, pre-symptomatic hydroxyurea therapy by preventing infants with HbS/HPFH from receiving unnecessary therapy. We argue that genetic testing should be incorporated into contemporary NBS for SCD.

Sickle Cell Screening in Children in a Resource Constrained Environment: Diagnosis and Follow up

Introduction: Sickle cell disease (SCD) is the most common hemoglobinopathy in the world and it disproportionately affects population in tropical, resource-constrained regions where there is a high prevalence of malaria. Efforts to screen for SCD have been highly prioritized in these areas despite limited resources. However, follow up after diagnosis remains a challenge. Counterintuitively, many of those diagnosed with SCD are lost to follow up after screening while others lack access to treatment that would otherwise prevent them from developing adverse health effects of SCD which is the primary reason for screening for the disease.Objectives: To determine the rate of enrollment of children with sickle cell disease into comprehensive sickle cell clinic and initiation of sickle cell treatment after screening positive for SCD.Methodology: This is a cross sectional study. Families of children aged 5 years and below who screened positive for SCD as part of a validation of point of care test between 2017 and 2018 in Homabay County Referral Hospital in Kenya were contacted by phone and an inquiry was made on their health status, clinic visits and treatment for SCD. Five attempts were made at reaching the families within a period of one week. Data were analyzed using frequency tables.Results: Seven hundred children under 5 years were screened for SCD between 2017 and 2018 at Homabay County Referral Hospital and 34 were found to have sickle cell disease by screening and confirmatory testing. The mean age at the time of testing was 24 months (range 4 to 59 months). Mean follow up time was 33 months after diagnosis(range 32-35 months). Twenty-seven participants were reachable on phone and 8 could not be traced. Out of those contacted three had died from possible infectious diseases and one had stopped attending sickle cell clinic for unclear reasons. Twenty-three children were consistent with clinic attendance and were taking folic acid, and proguanil for malaria prophylaxis. Eight had not been started on hydroxyurea because they were asymptomatic for sickle cell. Fifteen patients who had been started on hydroxyurea had already experienced at least 3 or more painful crises, hospitalizations, febrile illness, or more than 1 blood transfusions within a year. These criteria are used to initiate hydroxyurea because of limited supply. In a setting where typically more than 50% of children screened for SCD are lost to follow up, 77% of the children were traceable and of those alive 96% were enrolled to comprehensive sickle cell clinic. Preliminary results from screening with point of care test permitted intensive education of families with a child highly likely to have SCD. This likely contributed to the high proportion of children attending SCD clinic. Relocation of families and unreliable phone contacts may have contributed to cases of lost to follow up.Conclusion: While screening for SCD is crucial for timely diagnosis and prevention of life-threatening complication of SCD, establishing consistent follow-up of patients is challenging. Timely screening results and education based on these results is an effective strategy to increase SCD clinic attendance, treatment adherence, and improve outcomes in children with SCD. DisclosuresStrouse: Takeda: Consultancy.

Comparison of Sickle SCAN and Hemotype SC As Point-of-Care Newborn Screening Diagnostics for Sickle Cell Disease in Luanda, Angola

Background: Sickle cell disease (SCD) is among the most common, lethal and poorly recognized diseases globally. Over 300,000 children are born each year with SCA and most die by five years, primarily due to the lack of timely and accurate diagnosis. In high-resource countries, early identification of SCD through newborn screening (NBS) is routine and subsequent delivery of preventive measures and comprehensive care is highly effective in reducing morbidity and early mortality. In lower-resource settings, where the incidence of SCD is much higher, NBS is limited to only a few pilot programs. Despite the proven efficacy of NBS, large-scale implementation remains infeasible in many sub-Saharan countries due to inadequate financial, laboratory, and technical resources. In the pilot NBS program in Angola, only 56% of infants with SCD were able to be contacted to relay results due to delays in traditional laboratory diagnostic methods, lack of traditional mailing system or primary care providers, and inconsistent telephone numbers. The development and deployment of low-cost, rapid, user-friendly, and accurate diagnostic testing for SCD is imperative.There are two promising point-of-care (POC) tests (Sickle SCAN and HemoTypeSC) that may allow for a simplified approach to newborn screening for SCD. There have been few real-world studies that compare these tests head to head, particularly in the setting of NBS, where accurate diagnosis amidst high levels of fetal hemoglobin is critical. We performed a study at maternity centers and immunization centers in Luanda, Angola to evaluate the real-world accuracy of these tests.Methods: The study was a prospective evaluation of two rapid, POC tests (Sickle SCANÔ or HemoTypeSCÔ) ain Luanda, Angola, with laboratory confirmation using a dried blood spot (DBS) by isoelectric focusing (IEF), defined as the gold standard. To evaluate the real-world feasibility and accuracy, with the guidance of the Angolan Ministry of Health, we selected 10 sites, including both birth hospitals and vaccination sites, to screen infants < 6 months of age. Due to the complexity of performing more than one POC at once, we focused on one POC test at a time and planned to test 100 infants with each test at each site, for a total of 2,000 infants tested overall. The study was designed to mimic a real-world setting with all POC testing performed and interpreted by local healthcare staff (nurses, students, and laboratory technicians) with basic instructions as to the use of each test.Results: Blood samples were collected from 2,000 infants from age 0 to 6 months of age, including 1,000 with Sickle SCAN and 1,000 with HemoTypeSC. 42 HemoTypeSC samples (4.2%) and 6 Sickle SCAN results (0.6%) were not included in the final analysis, as results were not interpreted in the recommended time frame (5 minutes for Sickle SCAN an 10 minutes for HemoTypeSC). Consistent with prior studies in Angola, the burden of sickle cell trait (AS, 21.9%) and sickle cell anemia (HbSS, 1.7%) was high. 63% of the tests were performed in maternity wards at the time/day of birth and 37% were performed in immunization centers through the first 6 months of life. The HemoTypeSCÔ took an average of 15 minutes to obtain a result, was repeated 68 times (6.8%) due to invalid results, and was read incorrectly 4 times (0.4%). The SickleScanÔ took an average of 7 minutes to run, was repeated 2 times (0.2%) due to invalid results, and read incorrectly 11 times (1.1%). All results were compared to the gold standard IEF and both tests correlated perfectly (100%) with the IEF results, excluding 12 samples that had inconclusive IEF results.Conclusions: This study demonstrates the feasibility and accuracy of both HemoTypeSC and Sickle SCAN for diagnosing SCD in newborns in a limited-resource setting of Luanda, Angola. Given the complexities of testing in the newborn period at busy maternity hospitals, it appears that testing at immunization centers may be a more practical solution to early infant diagnosis programs for SCD. While both HemoTypeSC and Sickle SCAN were accurate, Sickle SCAN was preferred by local staff likely due to the shorter time to interpretation and reduced need for repeating the test. Further implementation studies are needed, including careful analysis of end-user cost, to determine the appropriate strategy for these POC tests in low-resource setting of sub-Saharan Africa. DisclosuresNo relevant conflicts of interest to declare.

Multispectral Imaging for Microchip Electrophoresis Enables Point-of-Care Newborn Hemoglobin Variant Screening

Introduction: Hemoglobin (Hb) disorders are among the world's most common monogenic diseases. Nearly 7% of the world's population carry Hb gene variants. Sickle cell disease (SCD) arises when hemoglobin variant mutations are inherited homozygously (HbSS) or paired with another β-globin gene mutation. Epidemiological modeling shows that universal screening could save the lives of up to 9.8 million newborns with SCD by 2050 with 85% born in sub-Saharan Africa (SSA). The World Health Organization (WHO) estimates that early diagnosis of SCD coupled with intervention programs would prevent 70% of existing SCD mortality. SCD newborn screening performed in centralized laboratories has dramatically reduced SCD mortality in resource-rich countries. SCD newborn screening requires sensitive detection of low levels of certain Hb variants (i.e., sickle Hb, HbS) in the context of high levels of expression of other Hb variants (i.e., fetal Hb, HbF). The current centralized tests used for newborn screening for SCD are high performance liquid chromatography (HPLC) and isoelectric focusing. However, in SSA and central India, where >90% of annual SCD births occur, newborn screening programs have not been implemented universally due to the cost and logistical burden of laboratory diagnostic tests. As a result, there is a need for affordable, portable, easy-to-use, accurate, point-of-care (POC) tests to facilitate decentralized hemoglobin testing in low-resource settings to enable nationwide newborn screening.Methods: We have leveraged the WHO listed Hb electrophoresis test and developed a POC electrophoresis microchip, Gazelle-Multispectral (Fig. 1A) that enables sensitive detection and identification of Hb types under both white and ultraviolet (UV-410nm) light illumination. We hypothesized that the high absorbance of Hb at UV wavelength would enhances the limit of detection and allow the detection of Hb types at low concentrations thus enabling SCD screening in newborns. To test this hypothesis, we have conducted clinical testing of over 321 subjects under the age of 6 months many with Hb variants including HbA (normal hemoglobin), HbF, HbS, and HbC (hemoglobin C variant) at Korle Bu Teaching Hospital, the largest public hospital in Ghana, under IRB-approved protocol.Results and Discussion: Separated Hb variants are imaged under both white light illumination (Fig. 1B) and UV light illumination (Fig. 1C). The acquired data under white light illumination demonstrates the natural red color of hemoglobin but does not have good enough sensitivity to detect low concentration Hb types (Fig. 1B). The acquired data under UV light illumination is used for sensitive and accurate identification and quantification of Hb variants (Fig. 1C&D), and to automatically generate report for result interpretation (Fig. 1E). Following the Standards for Reporting of Diagnostic Accuracy Studies guideline, 294 out of 321 (91.6%) tests were recognized as ‘Valid’, while 27 out of 321 (8.4%) tests were recognized as ‘Inconclusive’. Gazelle-Multispectral determined Hb variant levels demonstrated high association with Person Correlation Coefficients of 0.97, 0.97, 0.89, and 0.94 for Hb A, Hb F, HbS, and HbC compared to HPLC. Bland-Altman analysis demonstrated high reproducibility with mean bias±1.96×standard deviation of 2.3%±11.4%, -2.7%±-13.3%, 0.8%±6.2%, and -0.3%±2.7%, for HbA, HbF, HbS, and HbC, respectively. Subjects with disease were identified at 100% sensitivity and specificity from normal subjects and subjects with trait. Additionally, subjects with trait were identified at 98.1% sensitivity and 97.0% specificity from normal subjects (Fig 1. Table).Conclusion: In summary, Gazelle-Multispectral imaging enables affordable and rapid identification of common Hb variants in newborns at the point-of-need. The Gazelle-Multispectral reader provide animated on-screen instructions with step-by-step guidance for test procedures to minimize user errors. The internally integrated data analysis algorithm automatically reports Hb type identification and quantification results in an objective and easily understandable manner. Gazelle-Multispectral is a versatile, mass-producible, multispectral detection-based electrophoresis platform for affordable, rapid, and accurate diagnostic and newborn screening programs for SCD at the POC in low resource settings where the prevalence of SCD is high. [Display omitted] DisclosuresAn: Hemex Health: Consultancy, Patents & Royalties. Rocheleau: Hemex Health: Current Employment. Avanaki: Hemex Health: Current Employment. Thota: Hemex Health: Current Employment. Odame: Novartis: Other: Steering Committee; Global Blood Therapeutics: Other: DSMB; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Gurkan: Hemex Health, Inc.: Current Employment, Patents & Royalties; Biochip Labs: Patents & Royalties; Dx Now Inc.: Patents & Royalties; Xatek Inc.: Patents & Royalties.

Time trends, sociodemographic and health factors associated with discharge and length of stay of hospitalised patients with sickle cell disease in Ghana: a retrospective analysis of national routine health database

ObjectivePatients with sickle cell disease (SCD) are prone to multiple episodes resulting in frequent hospital visits. We determined the time trends, sociodemographic and health factors associated with length of stay...

Gene Therapy for Sickle Cell Disease: Start of a New Era

This manuscript reviews treatment of Sickle Cell disease over time. The application of allogeneic stem cells proved the sickle cell disease could be permanently corrected and cured but limited to those with a compatible donor. The use of autologous cells for therapy is the dawn of a new era where the need for a third party is remove and eliminates that ethical issue. With sickle cell disease screening for the most high-risk patients is now available. The use of autologous genetically modified cells is equally as effective as those treated with allogeneic cells and makes it possible for the first time to treat all symptomatic children and adults suffering from sickle cell disease. This is the beginning of a new era for the treatment of hemoglobinopathies.

Community based screening for sickle haemoglobin among pregnant women in Benue State, Nigeria: I-Care-to-Know, a Healthy Beginning Initiative

BackgroundHaemoglobin genotype screening at prenatal care offers women an opportunity to be aware of their genotype, receive education on sickle cell disease (SCD) and may increase maternal demand for SCD newborn screening. In developed countries, most pregnant women who access prenatal care and deliver at the hospital receive haemoglobin genotype screening. In settings with low prenatal care attendance and low hospital deliveries, community-based screening may provide similar opportunity for pregnant women. We assessed the feasibility and acceptability of integrating haemoglobin genotype screening into an existing community-based HIV program.MethodsOnsite community-based integrated testing for HIV, hepatitis B virus and haemoglobin electrophoresis, were conducted for pregnant women and their male partners. Community Health Advisors implementing the NIH and PEPFAR-supported Healthy Beginning Initiative (HBI) program provided education on SCD, collected blood sample for haemoglobin electrophoresis and provided test results to participants enrolled into the HBI program. We concurrently conducted a cross-sectional study using a pretested, semi-structured, interviewer administered questionnaire to collect demographic data and assess awareness of individual haemoglobin “genotype” among HBI pregnant women participants.ResultsIn this study, 99.9% (10,167/10,168) of pregnant women who received education on SCD accepted and completed the survey, had blood drawn for haemoglobin electrophoresis and received their results. A majority of participating pregnant women (97.0%) were not aware of their haemoglobin “genotype”. Among the participants who were incorrect about their haemoglobin “genotype”, 41.1% (23/56) of women who reported their haemoglobin “genotype” as AA were actually AS. The odds of haemoglobin “genotype” awareness was higher among participants who were in younger age group, completed tertiary education, had less number of pregnancies, and attended antenatal care. Overall prevalence of sickle cell trait (AS) was 18.7%.ConclusionsIt is feasible to integrate haemoglobin “genotype” testing into an existing community-based maternal-child program. Most pregnant women who were unaware of their haemoglobin “genotype” accepted and had haemoglobin genotype testing, and received their test results. Increasing parental awareness of their own haemoglobin “genotype” could increase their likelihood of accepting newborn screening for SCD.

Health services use by children identified as heterozygous hemoglobinopathy mutation carriers via newborn screening

BackgroundNewborn screening (NBS) for sickle cell disease incidentally identifies heterozygous carriers of hemoglobinopathy mutations. In Ontario, Canada, these carrier results are not routinely disclosed, presenting an opportunity to investigate the potential health implications of carrier status. We aimed to compare rates of health services use among children identified as carriers of hemoglobinopathy mutations and those who received negative NBS results.MethodsEligible children underwent NBS in Ontario from October 2006 to March 2010 and were identified as carriers or as screen-negative controls, matched to carriers 5:1 based on neighbourhood and timing of birth. We used health care administrative data to determine frequencies of inpatient hospitalizations, emergency department (ED) visits, and physician encounters through March 2012, using multivariable negative binomial regression to compare rates of service use in the two cohorts. We analyzed data from 4987 carriers and 24,935 controls.ResultsAdjusted incidence rate ratios (95% CI) for service use in carriers versus controls among children < 1 year of age were: 1.11 (1.06–1.17) for ED visits; 0.97 (0.89–1.06) for inpatient hospitalization; and 1.02 (1.00–1.04) for physician encounters. Among children ≥1 year of age, adjusted rate ratios were: 1.03 (0.98–1.07) for ED visits; 1.14 (1.03–1.25) for inpatient hospitalization and 0.92 (0.90–0.94) for physician encounters.ConclusionsWhile we identified statistically significant differences in health services use among carriers of hemoglobinopathy mutations relative to controls, effect sizes were small and directions of association inconsistent across age groups and health service types. Our findings are consistent with the assumption that carrier status is likely benign in early childhood.

Prospective Newborn Screening for Sickle Cell Disease and Other Inherited Blood Disorders in Central Malawi.

Objectives: Newborn screening in the United States and Europe allows early identification of congenital disorders but does not yet exist in most low-resource settings, especially in sub-Saharan Africa. Newborn screening can identify multiple inherited hematological disorders, but feasibility and effectiveness for Africa are not fully determined. Methods: Surplus dried blood spot collected in Central Malawi through the HIV Early Infant Diagnosis surveillance program were repurposed and tested by isoelectric focusing for sickle cell disease and trait. Additional genetic testing identified G6PD deficiency and alpha thalassemia. Results: Testing of 10,529 cards revealed an overall sickle cell trait prevalence of 7.0% (range 3.9–9.7% by district); 10 of 14 infants identified with sickle cell disease (prevalence 0.1%) were located and received care at a specialized clinic. Subsequent testing of 1,329 randomly selected cards identified alpha thalassemia trait in 45.7% of samples, and G6PD deficiency in 20.4% of males and 3.4% of females, with 29.0% of females as heterozygous carriers. Conclusion: Inherited hematological disorders are common in Central Malawi; early identification through newborn screening can improve clinical outcomes and should be supported throughout Africa.