A Sample-to-Answer Point-of-Care Diagnostic for Recently Transfused Sickle Cell Anemia Patients in Low Resource Settings - Sickle cell disease (SCD) is the most common inherited hemoglobin disorder in the US. Approximately 100,000 Americans have SCD, and 2.5 million have sickle cell trait (SCT). Thanks to universal newborn screening and preventive treatments, most children with SCD in the US survive to adulthood. However, the average life expectancy for individuals with SCD is still 20 years less than that of the general population. The emergency department is the primary safety net for Americans with SCD; patients without accessible medical records can present with acute complications like severe anemia, pain crises, or sepsis. Because these patients often require emergency blood transfusions, protein-based point-of-care blood tests for SCD become unreliable, as they detect normal hemoglobin from the blood donor as well as sickle hemoglobin, thereby misdiagnosing patients as sickle cell carriers. This limitation means existing point-of-care tests cannot be used for up to three months in patients who have received a blood transfusion, resulting in significant delays in time to diagnosis and preventing treatment initiation. There is an urgent need for an inexpensive, easy-to-use test that targets the genetic basis of the disease and delivers results rapidly so that accurate treatment can be initiated immediately. Such a test could also help reduce the costs associated with universal newborn screening. To address this need, we will develop a rapid, inexpensive nucleic acid-based test to detect the common point mutations in the â globin gene that cause SCD: âS(Glu6Val) and âC(Glu6Lys). We propose a low-cost, painless test that can be performed with cheek cell scrapings and can differentiate the following genotypes: 1) SCD patients (âSâS: SS, âSâC: SC); 2) unaffected individuals (âAâA: AA); 3) SCT patients (âAâS: AS, âAâC: AC); and 4) Hemoglobin C disease (âCâC: CC). We aim to: (1) Design and validate the first genetic point-of-care nucleic acid amplification test for sickle cell disease that can be used in recently transfused patients; (2) Implement the test on a low-cost, manufacturable, fully integrated sample-to-answer platform; and (3) Evaluate sensitivity, specificity, and usability of the test in two pilot clinical studies. An inexpensive point-of-care test that allows rapid identification of patients with SCD and SCT would have significant impact in the US, including reducing the pain and cost of universal newborn screening. Despite universal newborn screening, only 16% of individuals of childbearing age in the US with SCT are aware of their status. A low-cost, painless cheek swab could be easily integrated into preconception visits to close this awareness gap. Moreover, SCT is a leading cause of exertional sudden death in the US among athletes (37-fold increase in risk) and military recruits (28-fold increase in risk). Mandatory screening has already reduced the risk of sudden death by 89%. A rapid, cheek swab test that could be performed on site would allow schools and military processing stations to identify atrisk individuals immediately. Finally, SCT carriers face cardiovascular and maternal health and risks that are often overlooked. SCT carriers have a higher incidence of venous thromboembolism and pregnancy-related hypertensive disorders (e.g., preeclampsia). Providing clinicians with a rapid genetic confirmation tool could allow for better surveillance and earlier intervention (e.g., aspirin prophylaxis in pregnancy) in these high-risk populations.
