Indication - Sickling disorders
Sickle cell testing
First added in 2020
Screening, Aid to diagnosis
To screen for or to aid in the diagnosis of sickle cell disease, C trait (SCT) and other variant sickling disorders
Capillary whole blood, Venous whole blood
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 3A51.Z
Summary of evidence evaluation
The evidence base for these tests is in its infancy, with no systematic review available nor any studies of test impact. The primary studies provided indicate that the tests have very high sensitivity and specificity. The studies have generally been well done, recruiting appropriate populations. Many used discrepant analysis to resolve differences between the reference standard and the POC test; but the possible bias this will have introduced is small, as there have been very low numbers of discrepant cells. Several large, well-designed studies have shown the POC test for sickle cell disease and trait to have high accuracy, with sensitivities and specificities > 97% across newborns, children and adults. There is no evidence as yet of the impact of using the test. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3
Summary of SAGE IVD deliberations
SCD is a global health problem that contributes to excess mortality in children under 5 years of age; early recognition in infants is critical. Last year, sickle cell testing using electrophoresis was added to the EDL (EDL 2), and SAGE IVD requested the submission of a POC test. The type of POC test under consideration is a simple, accessible test that can be used in rural settings. It is cheaper compared with gold standard tests, such as electrophoresis. While there is no systematic review available for the products under this test category, there are sufficient large, well-designed studies to show that they are very accurate. SAGE IVD noted that no studies for implementing the tests were submitted but acknowledged that, as new tests, it is unreasonable to expect evidence on clinical impact. The group also noted that since the test category was submitted for consideration, the findings of a pilot implementation of one of these products in Nigeria have been published. Some concerns were raised about the tests’ lack of international regulatory approval, despite one of the commercially available tests holding a CE mark (in this case the CE mark is self-declared without any independent evaluation since the test is considered a low-risk IVD in the European context). Given the geographic distribution of the sickle cell gene, the test is unlikely to ever get stringent oversight from a regulatory authority in any of the founding members of the Global Harmonization Task Force (Australia, Canada, European Union, Japan or United States of America). One WHO expert also raised concerns about the potential for the addition of a POC RDT to the EDL to divert much-needed resources away from gold standard tests. But the recent report from Nigeria shows the tests can be procured for less than US$ 2. Some concerns were also raised about how the test could and should be used. Clarity of purpose was emphasized as important, especially given that some countries have high prevalence of both SCD and thalassaemia and need to be able to differentiate between the two. And SAGE IVD cautioned against using DBS as a specimen type because of a lack of evidence and regulatory oversight of the DBS protocol.
SAGE IVD recommendation
SAGE IVD recommended including the sickle cell testing test category in the third EDL: • as a disease-specific IVD for use in community settings and health facilities without laboratories (EDL 3, Section I.b, Sickling disorders); • using a rapid diagnostic test format; • to screen for or to aid in the diagnosis of sickle cell disease, sickle cell trait and other sickling disorders.
Details of submission from 2020
Disease condition and impact on patients SCD is a widely prevalent haemoglobinopathy in sub-Saharan Africa that is frequently deadly in early life, killing the majority of afflicted, undiagnosed children before their fifth birthday (1). In many high-income countries, universal newborn screening programmes coupled with prophylactic interventions and inexpensive treatment have dramatically reduced the mortality and morbidity of SCD during the first 20 years of life (2, 3). But in sub-Saharan Africa and central India, where more than 90% of annual SCD births occur, newborn screening programmes have not been universally implemented, if at all, largely because of the cost and logistical burden of laboratory diagnostic tests (4). Does the test meet a medical need? WHO estimates that early diagnosis and intervention would prevent 70% of existing SCD deaths. The main barriers to implementing newborn screening programmes at scale include the cost of diagnostic tests, lack of adequately distributed laboratory infrastructure and lack of adequate, sustained funding. Standard clinical laboratory methods to identify Hb variants include gel-based or capillary electrophoresis, isoelectric focusing (IEF), and high-performance liquid chromatography (HPLC). These methods require collecting a relatively large volume of whole blood, as well as uninterrupted electrical supply, highly trained and dedicated operating personnel, and the transport of blood samples from POC to possibly distant testing facilities (5). With emphasis on UHC, POC diagnostic tests can be deployed to rapidly evaluate acutely ill babies and children in high-prevalence regions and offer appropriate life-saving interventions once an SCD diagnosis is made. How the test is used For children born with SCD to survive into adulthood, they must be diagnosed as early in life as possible. Once the disease is diagnosed, the patient can be clinically managed with inexpensive and widely available drugs such as hydroxyurea (to elevate expression of fetal haemoglobin) and penicillin (to prevent SCD-related infections). The POC diagnostic test for sickle cell disease and trait provides a reliable result that supports a final diagnosis in newborns, children and adults without confirmation by a laboratory method. It can determine whether an individual is healthy, homozygous for SCD or is carrying the trait (heterozygous for SCD). It requires just a small droplet of blood as the sample input and, with minimal training, returns an accurate diagnostic result within 10–15 minutes. This test has been validated with high accuracy in multiple published field studies, conducted at both rural clinics and developed health centres. It requires no electricity or cold chain, and is stable for up to 2 years in temperatures of 15–40 °C and high humidity. In addition to widespread SCD diagnostic screening initiatives in maternity wards, enhanced population coverage can be obtained by screening children during visits to vaccination clinics, as well as screening all adults of marriage age. This three-pronged approach would be expected to increase the life expectancy of SCD patients, but also to decrease future disease incidence by allowing young adults to make informed parental and family planning choices based on the probability of passing on the sickle haemoglobin gene. The test is innovative and has the potential to address a clinical need that is not met by existing technologies. Existing diagnostic methods for SCD include large machines for HPLC and electrophoresis which require electricity, infrastructure, equipment, reagents and trained personnel. These technologies are also relatively expensive, cannot be easily scaled and are not easily deployed in rural environments. By contrast, the POC diagnostic test for SCD does not need electricity or refrigeration and can be run just as easily in a hospital ward or waiting room as in an outdoor rural clinic. Also, since the test delivers results in just 10–15 minutes, its use could significantly reduce the number of patients lost to follow-up.
Public health relevance
Prevalence and socioeconomic impact Up to 90% of children with SCD in sub-Saharan Africa are thought to die, undiagnosed, before their fifth birthday, making SCD one of the leading causes of childhood deaths in the region (6–8). Individuals with SCD in these regions are commonly identified only after hospitalization for severe pain or other overt or life-threatening manifestations of the disease. Its effects on mortality and quality of life and its economic burden on regional health care systems have led SCD to be declared both a disease of public concern by the UN General Assembly and a priority noncommunicable disease by WHO. In 2015, McGann et al. called SCD a “tremendously under-recognized public health challenge” that may contribute up to 5% of under-5 deaths in Africa (9). The authors stated that universal public health efforts such as pneumococcal immunization would likely improve the survival of infants with SCD, but suggested that SCD’s contribution to childhood mortality remains largely unaddressed because the scale of the problem remains unrecognized. McGann et al. concluded that newborn diagnostic screening and preventive care for SCD in Africa is both feasible and highly cost-effective. And they recommended that both should be considered in the development of national health care strategies in the region. In 2019, Simpson et al. suggested that the impact of SCD on infectious disease deaths, poverty and economic growth is slowing sub-Saharan Africa’s progress towards key development indicators (10). The authors stated that technological, medical and systems innovation has made SCD more detectable, treatable and curable than ever before.
WHO or other clinical guidelines relevant to the test
Guidelines on the widespread clinical use of the POC test for SCD are being developed with reference to several key publications (4, 9–11).
Evidence for diagnostic accuracy
No systematic reviews of the test’s clinical accuracy exist yet, as the primary clinical studies are still very new (most were published in 2019). It is anticipated that such reviews will begin to be published in early 2020. A primary study by Mukherjee et al. evaluated the diagnostic accuracy of a POC test against automated HPLC in a newborn screening programme (12). It found the test to have a sensitivity of 98.1% and specificity of 99.1% for all possible phenotypes (HbAA, HbAS and HbSS) detected. Nankanja et al. designed a blinded, prospective diagnostic accuracy trial of a POC test for SCD as an investigational test compared with using capillary zone electrophoresis and found a sensitivity of 99.8% and specificity of 99.9% (13). The first multicentre, real-world assessment of a low-cost POC device was conducted in a low- income country (14). Between September and November 2017, 1121 babies were screened using both the POC test and HPLC, with discordant samples confirmed by molecular diagnosis. The sensitivity and specificity of the POC test were found to be 93.4% and 99.9%, respectively. Three further studies evaluated different products; all showed similar results, with the lowest sensitivity being 94.9% and specificity over 99% (15–17).
Evidence for clinical usefulness and impact
No systematic reviews of the test’s clinical usefulness or impact exist yet, as the primary study reports are still very new (most were published in 2019). It is anticipated that systematic reviews will begin to be published in early 2020. There are, however, two published reports with interesting findings about the test’s impact on patient care. The first is the Nankanja et al. study in south-eastern Uganda, which reported that the POC test detected a trace level of haemoglobin A in a recently transfused patient’s blood that the reference laboratory failed to detect (13). This makes the POC test more sensitive and more accurate than the laboratory test. This report was chosen to be presented as a late-breaking abstract at the 2018 American Society of Hematology conference, as one of only seven abstracts selected globally. The second study, by Steele et al., showed that the POC test could test whole blood samples obtained via heel prick from low-birthweight, premature babies, whereas the laboratory reference test could not be performed for these patients because insufficient blood volume was available (15). This means that the POC test enables even the youngest of patients to be screened, with much less pain and discomfort (to the child and parents) during the blood collection process.
Evidence for economic impact and/or cost–effectiveness
The cost of the POC diagnostic test for sickle cell disease and trait is projected to be approximately US$ 2 per test strip (delivered price to the end user), with additional cost savings possible when manufactured at a large scale. Early diagnosis and intervention programmes for SCD are projected to be cost-effective in sub-Saharan Africa and India (9, 18).
Ethical issues, equity and human rights issues
Potential ethical issues that must be considered involve the negative impact on reputation and societal value of individuals who are diagnosed as SCD positive. These individuals may experience stigma from peers or potential marriage partners; but they would also have increased quality of life and life expectancy. Use of the POC SCD test is projected to heavily reduce health care inequities and increase health care accessibility, as even individuals with very few resources who live in inaccessible and rural areas will receive enhanced clinical care relating to SCD. The test enables diagnosis early in life and in virtually any testing environment: even midwives working in rural villages could conceivably administer the test. All SCD-positive individuals could then be subject to early interventions with pneumococcal prophylaxis, oral penicillin, folic acid and hydroxyurea, which is also being made available to rural populations via drone delivery in Ghana (19). Rapid diagnosis and inexpensive treatment of rural and city populations alike will dramatically improve the penetration of quality health care throughout Africa and India.
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