Screening For Sickle Cell Disease Research Articles

Health education to promote knowledge about sickle cell disease and newborn screening in pregnant women: a community-based pilot study using the healthy beginning initiative

BackgroundPregnancy presents a critical period for any maternal and child health intervention that may impact the health of the newborn. With low antenatal care attendance by pregnant women in health facilities in Nigeria, community-based programs could enable increased reach for health education about sickle cell disease (SCD) and newborn screening (NBS) among pregnant women. This pilot study aimed to assess the effect of education on the knowledge about SCD and NBS among pregnant women using the Healthy Beginning Initiative, a community-based framework.MethodsA pre-post study design was used to evaluate knowledge of SCD and NBS in a convenience sample of 89 consenting pregnant women from three communities. Participants were given surveys prior to and following completion of a health education session. McNemar’s test was used to compare the proportion of participants with correct responses. The level of significance was taken as p < 0.05.ResultsCompared to pre-test values, post-test values showed that participants understood that SCD is hereditary (93.3% vs. 69.7%), both parents must have at least one gene for someone to have SCD (98.9% vs. 77.5) and blood test is the right way to know if one has SCD (98.8% vs. 78.7%). Also, a large proportion of participants (post-test ~ 89.9%; compared to pre-test ~ 23.6%) understood that the chance of conceiving a child with SCD was 25% for a couple with the sickle cell trait (SCT). Knowledge of the possibility of diagnosing SCD shortly after birth was highly increased in the post test phase of the study when compared to the pre-test phase (93.3% vs. 43.9%, respectively). Concerning the overall knowledge scores, those with high level of knowledge significantly increase from 12.6% pretest to 87.4% posttest (p = 0.015).ConclusionThe health education intervention was associated with significant improvement on almost all measures of SCD knowledge. Focused health education for pregnant women using community structures can improve knowledge of SCD and NBS.

IJCM_364A: A Cross Sectional Study on Sickle Cell Disease awareness among adolescents in a tribal district of Maharashtra, India

Background: Sickle Cell Disease (SCD) poses a substantial health concern in India, especially among tribal populations. The Ministry of Health and Family Welfare’s Tribal Health Expert Committee has identified SCD as one of the top 10 challenges in tribal health. This study aims to assess the knowledge gap about SCD among school-going adolescents in a tribal district of Maharashtra. Objective: 1. To assess awareness of sickle cell anaemia among adolescents aged 12-18 years in a tribal district of Maharashtra 2. To provide recommendations based on study findings. Methodology: A cross-sectional study was conducted in a tribal district of Maharashtra, involving 394 school-going adolescents. Participant’s knowledge of sickle cell anaemia was assessed through face-to-face interview after obtaining necessary permissions from concerned authorities and assent from the participants. Data collection included information on general awareness, understanding of disease transmission, familiarity with sickle cell crisis, and preventive measures, with strict maintenance of data confidentiality. Results: Out of the 394 participants surveyed, 212 (53.8%) were females, and 182 (46.2%) were males. Only 19 students (5%) demonstrated awareness of SCD, with 16 (7.5%) females and 3 (1.6%) males out of the total. Surprisingly, none (0%) had knowledge of its transmission or had undergone screening for SCD. Within the aware subset, only 3 (15%) recognized Sickle Cell Crises, and a lone respondent (5%) was aware of its preventive measures. Conclusion: The study highlights a notable lack of sickle cell disease awareness among school-going adolescents in Maharashtra’s tribal district, posing a potential public health challenge. Urgent, tailored interventions are essential to sensitize the future generation, aligning with SDG 3, which aims for improved health and well -being through enhanced understanding and awareness.

Current Methods of Newborn Screening Follow-Up for Sickle Cell Disease Are Highly Variable and without Quality Assurance: Results from the ENHANCE Study.

Newborn screening (NBS) for sickle cell disease (SCD) has significantly improved childhood survival but there are still gaps resulting in delayed care for affected infants. As a state-run program, there are no national quality assurance programs to ensure each state achieves consistent, reliable outcomes. We performed this qualitative study of NBS follow-up practices to better evaluate and understand the multi-level, state-specific processes of how each state's public health department delivers the NBS results to families, how/if they ensure affected infants are seen quickly by sickle cell specialists, and to determine the close-out processes used in each state. This project used semi-structured interviews conducted with 29 participants across eight states to explore these NBS follow-up processes in each state. Participants included SCD providers, NBS coordinators, or personnel associated with state health departments and community-based SCD organizations (CBO). Our results show significant state-dependent variations in the NBS processes of information delivery and patient management. Specifically, programs differed in how they communicated results to affected families and which other organizations were informed of the diagnosis. There was also state-based (and intrastate) variation in who should assume responsibility for ensuring that infants receive confirmatory testing and are promptly started on penicillin prophylaxis. Case closure was also highly variable and poorly validated. Our results also yielded identifiable challenges and facilitators to NBS which were highly variable by state but potentially addressable in the future. This information suggests opportunities for systematic improvement in NBS follow-up processes.

Genetic Information to Share with Parents when Newborn Screening Reveals the Presence of Sickle Cell Trait.

The primary purpose of newborn screening for sickle cell disease is to diagnose the disease before the appearance of symptoms and to initiate early treatment. To answer the question "What genetic information needs to be communicated to parents when newborn screening reveals the presence of a sickle cell trait," we conducted a survey using a self-administered online questionnaire. We received responses from 122 healthcare workers and members of sickle cell disease associations, in France and French overseas departments. Our results showed similar positions on this issue. The information conveyed is not consistent and is the result of grassroots initiatives. The negative consequences generated by this information could be reduced when this information is delivered by a multidisciplinary team, within the framework of a dedicated consultation. This information on sickle cell trait status should be given in at least three key periods: the neonatal period, early adolescence, and later adolescence, when reproductive implications become important. Neonatal screening programs should develop systems that allow referring physicians to easily access the results of neonatal screening electronically. Harmonization of practices should allow a better analysis of the consequences of this counselling on family projects.

MALDI-MS in first-line screening of newborns for sickle cell disease: results from a prospective study in comparison to HPLC.

Newborn screening (NBS) for sickle cell disease (SCD) requires a robust, high-throughput method to detect hemoglobin S (HbS). Screening for SCD is performed by qualitative methods, such as isoelectric focusing (IEF), and both qualitative and quantitative methods such as high performance liquid chromatography (HPLC), capillary electrophoresis (CE), and tandem mass spectrometry (MS/MS). All these methods detect HbS, as well as low-level or absent HbA, and also other variants of hemoglobin. HPLC is considered as a reference method for NBS, because of its high sensitivity and specificity in detecting HbS. NeoSickle®, a fully automated matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform, combined with automated sample processing, a laboratory information management system and NeoSickle® software for automatic data interpretation, has increased the throughput of SCD testing. The purpose of this study was to compare the performances of NeoSickle® and HPLC. A prospective study was conducted including 9,571 samples from the NBS program to compare MALDI-MS using NeoSickle® with an HPLC method. Correlation between the two methods was studied. For the MALDI-MS method, sensitivity, specificity, NPV, and PPV were calculated. We found over 99.4 % correlation between the HPLC and MALDI-MS results. NeoSickle® showed 100 % of sensitivity and specificity in detecting SCD syndrome, leading to positive and negative predictive values of 100 %. NeoSickle® is adapted to NBS for SCD, and can be used in first-line high-throughput screening to detect HbS, and beta-thalassemia major warning. When HbS is detected, second-line use of another specific method as HPLC is necessary.

Cost-effectiveness of newborn screening for sickle cell disease: a systematic review protocol.

The purpose of the systematic review is to assess the cost-effectiveness of targeted/selective newborn screening compared with universal screening for sickle cell disease across various countries and settings. The incidence of sickle cell disease is increasing worldwide and it is a widespread and potentially fatal hematologic disorder that affects thousands of newborns worldwide. The cost of newborn screening creates a burden on households and the economy. Studies will be eligible for inclusion in the review if they include cost-effectiveness studies of newborn screening for sickle cell disease comparing targeted/selective screening with universal screening. A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as sickle cell disease, newborn, and economic evaluations. Two reviewers will screen the titles, abstracts, and full text independently against the inclusion criteria. Disagreements will be resolved by discussion or with a third reviewer. To assess methodological quality, the JBI checklist for economic evaluation will be used. Data will be extracted by 2 reviewers using a modified JBI data extraction form. The JBI dominance ranking matrix for economic evaluations will be used to summarize and compare the results. Cost-effectiveness will be measured on the basis of cost per test/case detected, quality-adjusted life years gained, or disability-adjusted life years averted. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment will be conducted to evaluate the certainty of economic evidence, such as use of resources and expenditures, and to incorporate the results into the decision-making process. PROSPERO CRD42017057963.

Sickle cell disease in the Zanzibar Archipelago, the Republic of Tanzania.

Sickle cell disease (SCD) is one of the most severe haemoglobinopathies, a group of blood disorders, typically inherited. The condition affects over 7.7 million people globally and results in more than 370,000 deaths per year. The highest morbidity and mortality rates are seen in Africa and most children with SCD are born in Tanzania. The available literature on SCD morbidity in Tanzania focus primarily on the residents of the mainland, while there is little data available on SCD morbidity among residents of the Tanzanian islands in the Indian Ocean. The aim of the present study was to confirm the presence of sickle cell disease among residents of the Zanzibar Archipelago. The study group consisted of 27 people, residents of Pemba Island in the Zanzibar Archipelago, aged between 2 months and 26 years old, whose at least one parent has been diagnosed with sickle cell anaemia. Blood samples collected from the study participants were tested using HemoTypeSCTM, a rapid, point-of-care diagnostic test. The tests were performed at the Amal Hospital (Chake Chake town, Pemba Island) in June 2023. Sickle cell disease was diagnosed in 11 study subjects (40.7%); their haemoglobin concentration ranged between 6.6 and 8.5 g/dL. The presence of the sickle cell trait (HbAS phenotype) was confirmed in 14 patients (51.9%). Only two of the tested patients had normal haemoglobin phenotype. The results of the present study support the necessity to introduce large-scale population- -based screening for SCD in the Zanzibar Archipelago, especially in infants whose family members have sickle cell anaemia. The introduction of such a programme will help monitor the number of new SCD cases in the region and may potentially reduce infant mortality due to SCD as well as minimize complications from SCD in older children through the adoption of effective disease prevention measures.

Knowledge and utilization of premarital screening for sickle cell disease among residents of semi-urban community, Bauchi State, Nigeria

Background: Sickle cell disease is a major genetic disease that manifests early in life and may lead to significant morbidities. It is an inherited disorder resulting from an abnormality in the structure of a protein in the red blood cell called haemoglobin characterized by the presence of crescent-shaped erythrocytes. Sickle cell disease is one of the most prevalent genetic disorders among the African populations. This study assessed the knowledge and utilization of premarital screening for sickle cell disease among residents of semi-urban community of Bauchi State, Nigeria. Methods: A descriptive cross-sectional design was used for the study. A multistage sampling technique was used in selecting 308 participants and a semi structured questionnaire was used in collecting data for the study. Data was analyzed using SPSS version 26 at 5% significance level and 95% confidence interval and presented in tables of frequencies and percentages. Results: The result revealed that 73.1% of the participants had good knowledge of premarital screening for sickle cell disease and their commonest sources of information were family and friends (45.6%). More than half of the respondents (66.8%) had good utilization. Conclusions: Majority of the respondents had good knowledge and utilization of premarital screening for sickle cell disease. We recommend that there should be more emphasis on health education and awareness programmes at community level on premarital screening for sickle cell disease. Also, genetic screening services should be made available in all primary health care centers.  

Scalable noninvasive amplicon-based precision sequencing (SNAPseq) for genetic diagnosis and screening of β-thalassemia and sickle cell disease using a next-generation sequencing platform.

β-hemoglobinopathies such as β-thalassemia (BT) and Sickle cell disease (SCD) are inherited monogenic blood disorders with significant global burden. Hence, early and affordable diagnosis can alleviate morbidity and reduce mortality given the lack of effective cure. Currently, Sanger sequencing is considered to be the gold standard genetic test for BT and SCD, but it has a very low throughput requiring multiple amplicons and more sequencing reactions to cover the entire HBB gene. To address this, we have demonstrated an extraction-free single amplicon-based approach for screening the entire β-globin gene with clinical samples using Scalable noninvasive amplicon-based precision sequencing (SNAPseq) assay catalyzing with next-generation sequencing (NGS). We optimized the assay using noninvasive buccal swab samples and simple finger prick blood for direct amplification with crude lysates. SNAPseq demonstrates high sensitivity and specificity, having a 100% agreement with Sanger sequencing. Furthermore, to facilitate seamless reporting, we have created a much simpler automated pipeline with comprehensive resources for pathogenic mutations in BT and SCD through data integration after systematic classification of variants according to ACMG and AMP guidelines. To the best of our knowledge, this is the first report of the NGS-based high throughput SNAPseq approach for the detection of both BT and SCD in a single assay with high sensitivity in an automated pipeline.

Implementation of a Newborn Screening for Sickle Cell Disease, at the Hospital Materno Infantil Dr Manuel Pedro Azancot De Menezes, Angola

Sickle Cell Disease (SCD) is a hereditary disease, and a worldwide public health problem, with a higher incidence in sub-Saharan Africa, where the prevalence is very high (about 80%). SCD prevalence can reach 3,3 % in Angola, while carriers of the sickle cell trait account for more than 25% of the population. The early identification of patients and their follow-up in consultation are an added value for the reduction of morbidity and mortality of children with SCD. The implementation of early infant screening and follow-up programs for children with SCD showed excellent results in increasing the survival of these children. With this project we intend to implement a Newborn screening in Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes, a referral of the main maternity in Angola, located in Luanda, the country capital, that could be replicated in other hospitals, giving training to the health professionals, and to the laboratory technicians, in order to diagnose the SCD patients. The objective of this project is to establish a neonatal screening for SCD at a main Hospital in Angola, contributing to reduce the under 5 mortality, and to support for pediatric follow-up consultations of children diagnosed with SCD. Specific aims include: record the data and medical history of babies diagnosed with SCD up to 5 years of age at regular appointments; estimate the prevalence of SCD in the municipality of Camama, Luanda; and to evaluate the costs of neonatal screening and early interventions in Angola, by supporting a registry of SCD. The newborn screening has started in June 2023, with the training of the team at the hospital, and with the creation of all documents and forms needed. The project received ethical approval in June 2023. The study includes every child born in the maternity ward of the Hospital, and also every child that take vaccinations there (in this way we can include newborns delivered at home), that the legal guardians authorize the collection of blood sample by prick heel for screening for SCD. The samples of filter paper duly identified with the sample number and date of collection are being sent to Lisbon (Portugal), for hemoglobin electrophoresis by isoelectric focusing (IEF) carried out in the Migele equipment (acquired with the support of Perkin Elmer, and the ARISE project) (Figure 1). All SS samples are being genotyped for the HbS mutation by PCR-RFLP. Since the start of the newborn screening (June 28 th) we have collected 1000 samples in 4 weeks and have started the IEF analysis with MIGELE (Perkin Elmer). The preliminary results (221 samples, 177 AA, 41 AS and 3 SS) showed a 1.4% prevalence of SS, and 19.5% of AS, confirmed by PCR-RFLP (in all AS and SS). The frequencies were in Hardy-Weinberg equilibrium. Moreover, we are searching for other possible hemoglobinopathies. More results will be presented. All children diagnosed as SS (SCD) are being contacted by the Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes, Angola, to be followed in consultation. Newborn screening and early interventions for SCD should be a health priority and implemented at national level. It is our plan to catalyze progress toward this aim by demonstrating the high prevalence of neonatal SCD in the Luanda Hospital and demonstrate the feasibility of this screening in reducing under 5 mortalities. The present project has the support of ARISE project “African Research and Innovative initiative for Sickle cell Education: Improving Research Capacity for Service Improvement” project (GA 824021 - ARISE - H2020-MSCA-RISE-2018) by supporting the secondments of Angolan Laboratory technicians in Lisbon (Portugal) to perform the IEF and genetic analysis and be trained. Until now 5 Angolan secondees, and 3 Nigerian secondees have been trained in Lisbon. Perkin Elmer (Revvity) is giving llogistical support by kindly support the low-cost acquisition, installation and training in MIGELE equipment for IEF, and being always available to technical support. Figure 1 - Flow diagram of the methodology followed in the present study.

Systematic, Point-of-Care Newborn Screening and Treatment for Sickle Cell Disease in Rural Mali, West Africa: Results from an Ongoing Implementation Project

Introduction: Sickle cell disease (SCD) is highly prevalent across sub-Saharan Africa and is a significant source of under-5 mortality. Accurate characterization of the disease prevalence is difficult to determine due to the absence of systematic newborn screening in most African countries. Mali is a land-locked West African country with a high burden of sickle cell disease. Despite the critical need for early diagnosis of SCD to improve survival, wide scale diagnostic efforts utilizing IEF or HPLC in sub-Saharan Africa have been limited by a paucity of laboratory equipment and trained personnel, unreliable supply chain for consumables, and overall expense. Point-of-Care (POC) testing for SCD is advancing rapidly and has the potential to reduce these barriers. This analysis will review the results of an ongoing POC newborn screening program for SCD at a single rural hospital in Mali and will evaluate the acceptance rates and basic outcomes of resource-adapted treatment. Methods: Between March 2019 and March 2023, all newborns at Koutiala Women's and Children's Hospital in Koutiala, Mali were offered screening for SCD with the HemoTypeSC ™ POC test kit (Silver Lake Research, California, USA). After verbal consent, heel-stick samples were procured within the first 24 hours of life. The samples were processed according to the package insert. The results were available within 10 minutes and were provided to the caregiver prior to discharge. Newborns who were found to have sickle cell disease were referred to the SCD treatment program where they were offered ongoing access to basic treatment measures such as antibiotic prophylaxis, malaria prevention, and hydroxycarbamide therapy. Parents of infants with HbSS who had not been seen in the clinic for follow-up within at least 6 months were contacted by phone at the time of this analysis to provide an update on their clinical status. Families of infants with HbS trait or HbC trait received appropriate genetic counseling. Statistical analysis was performed using a paired t-test. Results: 11,938 infants were born over the study period and 11,818 (99%) received POC screening. Screening results revealed Hb S trait; n=1,119 (9.47%), Hb C trait; n=1,285 (10.87%), Hemoglobin SS; n=81 (0.69%), Hemoglobin SC; n=100 (0.85%), and homozygous C; n=20 (0.54%). In all, 181 infants (1.54%) were found to have sickle cell disease and were offered follow-up care in the SCD treatment program at Koutiala Hospital. In addition, 2,404 infants (20.34%) were found to be carriers of either HbC trait or HbS trait. The mean age of those children diagnosed with HbSS and HbSC at the time of this analysis was 22.20mo (3-42mo) and 21.46mo (4-37mo), respectively. 89% (n=72) of the infants with HbSS received ongoing disease management. Penicillin prophylaxis was accepted in 82% (n=59) of the children in this cohort. Additionally, 44% (n=32) were started on hydroxycarbamide at a low, fixed dose (20ml/kg/day) based on disease severity parameters. Mean MCV for those children receiving hydroxycarbamide was 89.06fL (+/- 9.5fL) and for the non-hydroxycarbamide group was 79.83fL (+/- 14.3fL) (p= 0.025). While the most common reason for clinical follow-up was routine treatment, patients were also seen for fever, malaria treatment, and bone pain episodes. Based on clinical records and phone follow-up, there were two confirmed deaths (2.5%) in the HbSS cohort. One infant died of non-SCD complications on the first day of life and the other died at 6 months of age without returning to the clinic for follow-up treatment. Conclusions: This program is the first to examine the impact of systematic POC infant screening and treatment for SCD in rural Mali, West Africa. The low cost and rapidity of POC testing resulted in a high rate of newborns screened and positively impacted the success of clinical follow-up. POC testing results were comparable when reviewed alongside historical IEF-based screening at Koutiala Hospital (Table 1). The higher percentage of infants screened by POC when compared to IEF may have been slightly affected by an increase in the general awareness of SCD amongst the regional population. There was a high acceptance rate of ongoing clinical care (89%) and low death rate (2.5%) within the HbSS cohort which may be attributable to early access to diagnosis and treatment. Results from a larger patient size and longer treatment duration will provide more insight into the benefits of POC screening in this setting.

Sickle Cell Disease Births and Social Vulnerability (2016-2020): A Report from the Sickle Cell Data Collection Program

Introduction Despite national implementation of universal newborn screening for sickle cell disease (SCD) since 2006, data on the prevalence of SCD births in the United States are scarce. Updated prevalence data by geographic location are needed to guide the allocation of resources and to connect newborns to comprehensive SCD care. The purposes of this study were to describe the 1) crude and race-adjusted SCD birth prevalence and 2) crude SCD birth prevalence by quartiles of the social vulnerability index (SVI, CDC, 2020) in 11 Sickle Cell Data Collection (SCDC) program states (Alabama, California, Colorado, Georgia, Indiana, Michigan, Minnesota, North Carolina, Tennessee, Virginia, and Wisconsin). Methods This retrospective cohort study used newborn screening (NBS) records from 2016 to 2020. Births were included if they were confirmed SCD births and the mother's county of residence at the time of birth was in an SCDC state. Mother's county and newborn's race, ethnicity, sex, date of birth, and genotype were extracted from NBS records or birth certificates, if available. Crude SCD birth prevalence per 10,000 was calculated by dividing the cumulative number of SCD births by the cumulative number of all live births from 2016 to 2020 and multiplying by 10,000. Race-adjusted SCD birth prevalence was calculated by dividing the cumulative number of Black SCD births by live non-Hispanic Black (NHB) births from 2016 to 2020 and multiplying by 10,000. Frequency of all births and NHB births were obtained from each state's health department. County characteristics were quantified by the SVI using the 2020 state-ranked CDC/ATSDR SVI datasets (CDC, 2020) and were matched to mother's county of residence at birth. SVI ranks counties on 16 social factors, including unemployment, minority status, and disability. Ranks were grouped into SVI quartiles: low (0 ≤ SVI ≤ 0.25), medium (0.25 &amp;lt; SVI ≤ 0.5), high (0.5 &amp;lt; SVI ≤ 0.75) and very high (0.75 &amp;lt; SVI ≤ 1.0) vulnerability. Crude SCD birth prevalence was calculated for each SVI quartile. Results From 2016 through 2020, there were 3,305 newborns with SCD across 11 SCDC states [ 49.6% male, 89.8% Black]. Georgia had the highest number of births (n=758) followed by North Carolina (n=435), California (n=419), and Alabama (n=386). The majority (57.0%) had Hb SS or Hb S Beta 0 thalassemia, 27.9% had Hb SC, and 9.6 % had Hb S Beta + thalassemia or other SCD type. The crude SCD birth prevalence ranged from 1.22 to 13.22 per 10,000 live births. The race-adjusted SCD birth prevalence for SCDC states was 28.55 per 10,000 or 1 in every 350 NHB births. Race-adjusted birth prevalence varied among states ranging from 19.53 to 34.11 per 10,000 NHB births (Table 1). Overall, the majority (67%) of mothers of newborns with SCD resided in high or very high social vulnerability counties (Figure 1). Except for Colorado, where the highest crude SCD birth prevalence was among mothers residing in medium social vulnerability counties, the remaining 10 SCDC states had the highest prevalence among mothers residing in high or very high social vulnerability counties. Limitations include using the mother's reported race for all births to calculate race-adjusted birth prevalence. Additionally, because of missing data on ethnicity for SCD births, we used all Black SCD births, rather than non-Hispanic Black SCD births, to calculate the race-adjusted SCD birth prevalence. Despite the limitations, the study provides crude and race-adjusted SCD birth prevalence data from 11 states in the South, Midwest, and Western United States, covering an estimated one third of the SCD population in the United States. Furthermore, providing the crude prevalence of SCD births by SVI quartile adds valuable information on county-level characteristics that might influence health outcomes for newborns with SCD. Conclusions The race-adjusted birth prevalence for SCD remains stable from previous estimates at 1 in every 350 BNH births. The finding that most mothers of newborns with SCD reside in high and very high social vulnerability counties at the time of birth underscores the importance of assessing social determinants of health (SDOH) that may impact health outcomes for newborns with SCD. Findings from this report can be used to guide state- and county-level programs that address SDOH for people with SCD and have implication for clinicians who must incorporate screening for SDOH in their practice and refer families to community resources as needed.

Non-Invasive Screening for Sickle Cell Disease Using Only a Smartphone Application

Introduction Pediatric mortality due to Sickle Cell Disease (SCD) remains high and often occurs prior to diagnosis in most black and brown low- and middle-income countries (LMICs), due to the high prevalence of SCD and limited resources in these countries.To that end, we developed a low-cost non-invasive screening tool that can be widely available at the point of need. Our screening tool utilizes the power of both image analysis and predictive algorithms as a novel approach to SCD screening and diagnostics. In this new app, we have combined the quantitative analysis of fingernail pallor, an adaptation of our previously described smartphone app for estimating blood hemoglobin levels using smartphone images of the nail beds, with qualitative symptom and medical history data to compute an SCD Likelihood Score (SLS) that provides an individual's pre-diagnostic test potential for disease, a key metric in the disease screening and diagnostic process. Methods 417 subjects ages 0.5-20 years old were enrolled from Children's Healthcare of Atlanta (CHOA) hematology/oncology clinic; of these patients, 219 patients had SCD, and 198 did not. Pediatric patients were screened because they best simulated the target populations aimed for the app's use. Our analysis was restricted to the presence of specific pain, past stroke history and/or symptoms, splenic crises, neurodevelopment disorder, family history of SCD, due to their specificity to SCD and their ability to be answered without the need for resource-intensive diagnostics. The SLS was calculated by determining the presence of these medical history items and the patient's anemia status informed by the patient's most recent CBC. For each symptom a weighted score was generated by finding the difference between the percentage of subjects with SCD and those without SCD, who experienced the symptom. The presence of symptoms was binarized with 1 indicating the presence of a symptom and 0 indicating the absence of a symptom. The binary value of the symptom was then multiplied by the symptom's respective weighted value. These values were totaled and normalized to give the overall clinical profile-weighted score with the same weight as the anemia status. A receiver operating characteristic analysis was conducted to select a threshold for the SLS that provided the most accurate diagnosis in our training dataset. We incorporated this SLS model into our lab's previously described smartphone app predictive algorithm . Results A clinical assessment of the screening app was conducted at CHOA and enrolled 68 participants from both in-patient and out-patient settings. Patient hemoglobin measurements were obtained using our previously described hemoglobin screening app and patients (and their parents for those needing their assistance) were asked to provide responses to the symptom survey. Of the five medical history items queried, family history and a history of splenic crisis when present was found to contribute to 30% and 41%, respectively, of the overall clinical profile score. Whereas the presence of a history of pain, stroke history, and learning difficulties made up smaller portions of this portion of the SLS. The app performed with a sensitivity of 100% and a specificity of 75% in screening for SCD in patients &amp;lt;5 years of age, the target demographic for early screening. Conclusion This SCD screening application has the potential to expand and improve SCD outcomes in LMICs where access to the gold standard or any accurate diagnostic tools is limited. The app's non-invasive and easy-to-use nature and the ubiquity of smartphones globally make this screening tool a practical and feasible mode of screening. Early disease screening is paramount to survival for children with SCD and if this tool proves to be accurate in these settings, can be lifesaving for the hundreds of thousands of infants with SCD born in LMICs per year. Non-invasive modalities such as our SCD screening application can enable resource allocation and cost reduction by identifying those patients who do and do not have a high likelihood of disease, thus reserving tests for those who are high risk.

Understanding Gaps in Current Practices of Newborn Screening Follow-up for Sickle Cell Disease in the United States

Introduction: Newborn screening (NBS) for sickle cell disease (SCD) has significantly improved childhood survival. However, gaps remain in follow-up after NBS as demonstrated by poor implementation of penicillin prophylaxis and stroke risk (TCD) screening. It is unknown how time to initial engagement with SCD specialist may impact long-term patient engagement. Currently, there are no standardized follow-up requirements for NBS across the United States; each state can decide how they inform families of diagnoses and initiate follow-up. The average time to the initial follow-up with a SCD specialist is not currently evaluated as a measure of quality assurance. Semi-structured interviews were conducted with 19 participants across 11 states to explore NBS processes. Participants included health care providers (n = 7), and stakeholders (NBS health department employees and community based SCD organization representatives (CBO); (n = 12). Data were analyzed using directed content analysis, informed by the SCD care continuum model, which outlines how newborns with SCD should proceed from diagnosis to initial and ongoing care engagement with a SCD provider. We examined how families were informed of abnormal results, how newly-diagnosed children were referred to SCD specialists, and when cases were closed. Results Representatives from 11 states including AL, AK, CA, GA, LA, MI, MS, MO, NY, SC, TN were included in this study (Table 1). Initial Notification: In all 11 states, the physician of record (on the NBS bloodspot card) is notified of abnormal results and expected to communicate results to families. This physician of record is not necessarily the child's actual pediatrician. In 2 states, a letter is sent to families at the same time as physicians are notified, but the letter does not convey screening results. In 1 state, the CBO NBS coordinator is responsible for communicating results to the family. Referral to a SCD specialist: There was substantial variability in referral practices. In most states, infants with positive SCD screens were referred to a SCD specialist by the pediatrician. In some states, the public health department refers infants with positive screens directly to the SCD center. In 2 states, the decision to refer an infant to a SCD center is left to the family, NBS coordinator or CBO. Timing of first visit: Most states intend infants with positive SCD screens to follow-up with the SCD clinic in &amp;lt; 2 months; however, some states do not require the initial visit until 6 months. Notably, most states do not track whether children with a positive SCD screen ever see a SCD specialist, Instead, cases are closed once the physician of record is informed. Facilitators and Barriers: The most common facilitators for communicating NBS results were having the correct physician of record on the blood spot card, the physician's knowledge of SCD, or the use of state-based immunization databases to track children with missing demographic information. Key facilitators for linkage to care included partnerships with SCD CBOs and/or having designated NBS follow up coordinators that offer ongoing family education and appointment reminders. Other facilitators included families with extended support and those who already had a child with SCD. The most common barriers to communicating NBS results were difficulty locating or reaching families, families moving out of state, insufficient contact information, and/or having the wrong physician of record. The main barriers to linkage to care included lack of insurance, lack of transportation, families who have difficulty accepting the SCD diagnosis, immigrant or refugee families with language barriers and other conflicting social/life demands. Conclusion The results of our study demonstrate wide variability in NBS follow-up for SCD with limited quality assurance to ensure newborns see a SCD specialist. These findings indicate a large multi-level intervention trial is needed to identify best practices for systematic improvement in NBS follow up process and ensure all infants are seen by a SCD specialist.

National Long-Term Follow-up of Children with Sickle Cell Disease Diagnosed By Newborn Screening in the Netherlands: Overview of the Morbidity and Mortality

Background: Sickle cell disease (SCD) is a genetic red blood cell disorder associated with increased morbidity and mortality. Newborn screening for SCD was introduced in January 2007 in the Netherlands to enable early diagnosis and initiation of preventive measures. The objective of this study was to assess the effect of newborn screening on the morbidity and mortality of children living with SCD in the Netherlands, 16 years after its implementation. Methods: In this national cohort study all children with SCD diagnosed by newborn screening were included. Patients were followed between 1 January 2007 and 31 March 2023 until end of follow-up, death or successful stem cell transplantation. Following informed consent, data were collected from medical files on SCD genotype, treatment, mortality and development of SCD-related complications. The incidence rate of SCD-complications was presented as lifetime-event per 100 person-years for the total duration of follow-up and for the age categories: 0-4, 5-11, and 12-16 years. Results: In total, 391 out of 540 eligible patients (72%) with SCD were included in all hospitals with patients with SCD under treatment, accounting for 3047 person-years. The mean age at the end of follow-up was 7.8 years (SD±4.5). The majority of patients had SCD genotype HbSS (58%), followed by HbSC (28%). As for the mortality, five patients died during follow-up, primarily at or below the age of 2 years (4/5, 80%). In three patients, the cause of death was related to SCD, including infection (n=2; aged 1.2 and 2.0 years) and acute splenic sequestration (n=1; 2.0 years). The SCD-related complications are presented in Table 1. The most common SCD complication in this cohort was vaso-occlusive crisis (including dactylitis) with hospitalization. SCD-related complications that mainly developed within the first 4 years of life, were vaso-occlusive crisis, acute hemolytic crisis, aplastic crisis, severe infections, splenic sequestration and ischemic cerebral infarction. Acute chest syndrome occurred equally in all age categories. Other SCD-related complications developed to a lesser extent in our cohort, and at a later age in adolescence or adulthood. Conclusion: In this cohort of neonatally screened children with SCD, a substantial number of SCD-complications occurred in the first 4 years of life. This study underlines the importance of parental education and 24/7 availably, high level acute specialized clinical care for these children from birth on. Further analysis to identify risk factors at young age for a severe phenotype will be conducted, to enable more targeted interventions in a timely manner. Hopefully, this will lead to reduction of disease burden, improving the quality of life in children living with SCD in the Netherlands.

Strengthening Health System and Community Mobilization for Sickle Cell Disease Screening and Management among Tribal Populations in India: An Interventional Study

Sickle cell disease (SCD) affects 5% of the global population, with over 300,000 infants born yearly. In India, 73% of those with the sickle hemoglobin gene belong to indigenous tribes in remote regions lacking proper healthcare. Despite the prevalence of SCD, India lacked state-led public health programs until recently, leaving a gap in screening and comprehensive care. Hence, the Indian Council of Medical Research conducted implementation research to address this gap. This paper discusses the development and impact of the program, including screening and treatment coverage for SCD in tribal areas. With a quasi-experimental design, this study was conducted in six tribal-dominated districts in three phases – formative, intervention, and evaluation. The intervention included advocacy, partnership building, building the health system’s capacity and community mobilization, and enabling the health systems to screen and manage SCD patients. The capacity building included improving healthcare workers’ skills through training and infrastructure development of primary healthcare (PHC) facilities. The impact of the intervention is visible in terms of people’s participation (54%, 76% and 93% of the participants participated in some intervention activities, underwent symptomatic screening and demanded the continuity of the program, respectively), and improvement in SCD-related knowledge of the community and health workers (with more than 50% of net change in many of the knowledge-related outcomes). By developing screening and treatment models, this intervention model demonstrated the feasibility of SCD care at the PHC level in remote rural areas. This accessible approach allows the tribal population in India to routinely seek SCD care at their local PHCs, offering great convenience. Nevertheless, additional research employing rigorous methodology is required to fine-tune the model. National SCD program may adopt this model, specifically for community-level screening and management of SCD in remote and rural areas.

Screening for haemoglobin disorders: One size may not fit all.

Accurate laboratory screening for sickle cell disease and other haemoglobin disorders is expanding worldwide. Two new reports describe different methods and strategies for screening in Mali and Denmark, respectively, and their encouraging results suggest that countries should tailor their screening programmes according to local needs, resources and opportunities. Commentary on: Guindo et al. Potential for a large-scale newborn screening strategy for sickle cell disease in Mali: a comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood. Br J Haematol 2024;204:337-345 and Gravholt et al. The Danish national haemoglobinopathy screening programme: report from 16 years of screening in a low-prevalence, non-endemic region. Br J Haematol 2024;204:329-336.

Implementation of hospital-based sickle cell newborn screening and follow-up programs in Haiti

AbstractOne in 120 children are born with sickle cell disease (SCD) in Haiti. However, health care challenges include isolated newborn screening (NBS) activities and lack of transcranial Doppler (TCD) ultrasound to assess stroke risk. The implementation activities of the Comparative Study of Children in Haiti and Miami with Sickle Cell Disease involved both NBS and TCD ultrasound implementations at 4 Haitian clinical sites. We hypothesized that hospital-based newborn SCD screening and follow-up programs would be feasible at Haiti. A traditional NBS laboratory method with dried blood samples was performed at 3 Port-au-Prince sites, and the traditional method plus point-of-care (POC) testing was used at the 2 northern sites. The rate of clinical follow-up for newborns with SCD as the outcome for the NBS intervention was compared with that of the NBS method. The NBS programs identified SCD in 0.77% of 8224 newborns over a 24-month period. In the rural hospital assigned to the combination screening, 56% of newborns identified with POC testing returned for follow-up, compared with 0% when POC was not available (P = .044). Newborns who tested positive for SCD and children aged <6 years with SCD at the clinical sites were eligible for study follow-up. Accrual was successful: 165 participants (mean age, 42 months; 53% males; 93% hemoglobin SS) were recruited and received oral penicillin. TCD ultrasound screening was hampered by poor internet connections and trained staff leaving Haiti, with only 1 active site conducting screening. Despite challenges, the implementation of NBS and sickle cell programs in Haiti is feasible. We are in the process of understanding how to mitigate implementation limitations.

A Newborn Screening Program for Sickle Cell Disease in Murcia (Spain).

Sickle cell disease (SCD) is an inherited autosomal recessive hemoglobin disorder caused by the presence of hemoglobin S, a mutant abnormal hemoglobin caused by a nucleotide change in codon 6 of the β-globin chain gene. SCD involves a chronic inflammatory state, exacerbated during vaso-occlusive crises, which leads to end-organ damage that occurs throughout the lifespan. SCD is associated with premature mortality in the first years of life. The process of sickling provokes asplenia in the first years of life with an increased risk of infection by encapsulated germs. These complications can be life-threatening and require early diagnosis and management. The most important interventions recommend an early diagnosis of SCD to ensure that affected newborns receive immediate care to reduce mortality and morbidity. The newborn screening program in the region of Murcia for SCD began in March 2016. We aimed to determine the incidence of sickle cell anemia and other structural hemoglobinopathies in the neonatal population of the region of Murcia, an area of high migratory stress, and to systematically assess the benefit of newborn screening for SCD, leading to earlier treatment, as well as to offer genetic counseling to all carriers. The prevalence of SCD in our region is similar to others in Spain, except for Catalonia and Madrid. The newborns with confirmed diagnoses of SCD received early attention, and all the carriers received genetic counseling.

High Throughput Newborn Screening for Sickle Cell Disease - Application of Two-Tiered Testing with a qPCR-Based Primary screen.

Sickle cell disease (SCD) is a group of hemoglobinopathies with a common point mutation causing the production of sickle cell hemoglobin (HbS). In high-throughput newborn screening (NBS) for SCD, a two-step procedure is suitable, in which qPCR first pre-selects relevant samples that are differentiated by a second method. Three NBS centers using qPCR-based primary screening for SCD performed a laboratory comparison. Methods using tandem MS or HPLC were used for differentiation. In a benchmarking test, 450 dried blood samples were analyzed. Samples containing HbS were detected as reliably by qPCR as by methods established for hemoglobinopathy testing. In a two-step screening approach, the 2nd-tier-analyses have to distinguish the carrier status from pathological variants. In nine months of regular screening, a total of 353,219 samples were analyzed using two-stage NBS procedures. The 1st-tier screening by qPCR reduced the number of samples for subsequent differentiation by>99.5%. Cases with carrier status or other variants were identified as inconspicuous while 78 cases with SCD were revealed. The derived incidence of 1:4,773, is in good agreement with previously published incidences. In high-throughput NBS for SCD, qPCR is suitable to focus 2nd-tier analyses on samples containing HbS, while being unaffected by factors such as prematurity or transfusions. The substantial reduction of samples numbers positively impacts resource conservation, sustainability, and cost-effectiveness. No false negative cases came to attention.