The first description of newborn screening was published in Pediatrics >50 years ago1 and ushered in an era of opportunity to identify infants with underlying medical conditions before they developed signs and symptoms of disease. Although the index medical condition was phenylketonuria, Robert Guthrie (developer of this system and originator of the eponymous Guthrie card) recognized that sickle cell disease (SCD) was also well suited to neonatal screening using dried blood spots2 because normal adult hemoglobin could be separated by simple gel electrophoresis from both abnormal sickle hemoglobin (HbS) and fetal hemoglobin (HbF).
The technical aspects of hemoglobin separation have improved over the years with the advent of high-performance liquid chromatography and isoelectric focusing (IEF), but newborn screening for SCD has essentially remained the same as it was originally envisioned. The United States now enjoys universal screening for SCD and other inherited hemoglobin disorders, and >2000 affected infants are identified annually.3
Despite these successes in the United States and other high-income countries, standard sickle cell screening techniques do not lend themselves well to low-resource settings. In many low-income countries, infants are often born outside of traditional hospitals; distances and transportation of samples to laboratories are challenging; costs of equipment, reagents, and electricity are prohibitive; trained personnel are scarce; and the ability to locate and retrieve affected infants reliably is limited. As an alternative, point-of-care (POC) testing for SCD has generated interest over the past decade and was accelerated by the National Institutes of Health Small Business Innovation Research Program.4
Because of the unique biochemical and physical characteristics of HbS compared with adult hemoglobin, it should be straightforward to distinguish these 2 important hemoglobins and correctly distinguish individuals with normal hemoglobin from those with sickle cell trait or SCD. However, the real-world testing environment is complex because of SCD having numerous genotypes, including homozygous sickle hemoglobin S, compound heterozygous sickle hemoglobin C, HbS β0 thalassemia, HbS β+ thalassemia, sickle hemoglobin D, and other rarer variants. High HbF levels among infants pose an additional challenge to early accurate diagnosis. A variety of techniques have been proposed for POC diagnosis of SCD, including immunoassays, paper diffusion, and electrophoresis.5
In this issue of Pediatrics, Alvarez et al6 report on the accuracy, utility, and value of a POC immunoassay for the rapid detection of SCD among newborns in Haiti and further suggest this approach can be adapted to other low-resource settings in the Caribbean with a high sickle cell burden. When the authors tested >1200 dried blood specimens from infant heel sticks collected over a 1-year period, POC had high sensitivity (97%) and good specificity (90%) compared with concurrent IEF. Notably, however, the test did not correctly distinguish HbS β+ thalassemia from sickle cell trait. Beyond accuracy, other important findings related to practicality and utility; Haitian infants who screened positive for SCD by POC testing had better health care delivery outcomes, as evidenced by a higher rate of confirmatory testing, as well as earlier pneumococcal immunization and penicillin initiation compared with infants diagnosed solely by IEF.
Based on the work of Alvarez et al6 and others using POC devices, where do things stand in 2019? We believe that POC testing for SCD is here to stay and will be useful in many low-resource settings. We propose that ideal POC devices should have the following characteristics: low cost, compact and portable, rapid results, high sensitivity even with HbF present, good specificity, accuracy for all sickle genotypes, user-friendly design and interpretation, simple storage requirements, and ability to operate in extreme temperature and humidity. Among these characteristics, ultimately, POC devices will be judged by accuracy, robustness, and cost.
Even if these characteristics are met, we also wish to raise important concerns about widespread newborn POC testing for SCD in low-resource settings. Most birthing facilities will lack adequate resources (trained nurses and time) for efficient high-volume testing, have little privacy or opportunity for counseling, struggle to find nonpaper solutions to record results and avoid repeat testing, and have limited means to deal with the psychological impact on parents of diagnosing SCD at birth in an otherwise healthy-appearing infant. All of these issues should be addressed before POC screening becomes standard of care.
The ability to provide appropriate follow-up care will perhaps be the greatest challenge of POC testing. Because POC diagnosis of SCD yields rapid results directly at the time of testing, it is critically important that appropriate services be available regarding the diagnosis and management. Particularly for low-resource settings, we suggest it would be advantageous to integrate POC screening into existing immunization programs that deliver a package of services, including breastfeeding and nutritional-education settings, in which counseling can also be more effectively delivered. The high levels of immunization coverage (>90% in most countries) could thereby be exploited to ensure access to early diagnosis and intervention in most infants, including those delivered outside hospitals. Such partnerships with public health systems will serve as a catalyst for implementing sustainable screening programs for SCD in low-resource settings.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2018-4105.
POTENTIAL CONFLICT OF INTEREST: Drs Ware and Odame have tested and published results using donated point-of-care devices for the diagnosis of sickle cell disease.
FINANCIAL DISCLOSURE: Other than what is described in the Potential Conflict of Interest section, the authors have indicated they have no financial relationships relevant to this article to disclose.