Original Title: Avis - Pertinence d’ajouter les variantes HbS/E, HbE/E et HbE/β-thal aux cibles primaires du test de dépistage néonatal des hémoglobinopathies

Authors' objectives: Hemoglobinopathies are a family of rare diseases transmitted in an autosomal recessive manner. They are characterized by defects in hemoglobin, a protein complex composed of α and β chains responsible for oxygen transport in the blood. Mutations that affect the structure of hemoglobin can cause sickle cell diseases, while those that lead to reduced α or β chain synthesis can cause thalassemia. Sickle cell diseases are characterized by hemolytic anemia and painful vaso-occlusive crises that can lead to ischemia-reperfusion injury and organ and tissue damage. Many forms of abnormal hemoglobin can result in sickle cell diseases, the most common of which is hemoglobin S (HbS). The β-thalassemias are characterized by anemia of varying severity, depending on the extent of lowered β- chain hemoglobin. Patients with more severe impairment require regular blood transfusions to limit their clinical symptoms. In both forms of hemoglobinopathy, symptoms will begin to appear a few months after birth. Sickle cell diseases mainly affect people from sub-Saharan Africa, the Caribbean, the Mediterranean, the Middle East and parts of India and South America. Thalassemias are particularly prevalent around the Mediterranean, the Middle East, the South Caucasus, Central Asia, and India. Newborn screening for hemoglobinopathies has been implemented in a few countries. The hemoglobinopathies targeted by this assessment: HbS/E, HbE/E and HbE/β- thal, have a prevalence ranging from 1 in 4,000 to 1 in 400,000 births. Managing patients with hemoglobinopathies has greatly improved over the past decades, improving patient prognosis, and significantly reducing mortality. In Quebec, an hemoglobinopathy assay was introduced in 2016, and the variants currently targeted by the Newborn Blood Screening Program are those with at least one allele that codes for HbS: HbS/S, HbS/C, HbS/β+-thal, HbS/β0 -thal, HbS/O-Arab and HbS/D-Punjab. However, hemoglobin E can be detected by this assay, although it is not currently included as a primary target by the Quebec Newborn Blood Screening Program. In addition, the carrier status of a major sickle cell disease can, according to the document Cadre de référence du Programme Québécois de Dépistage néonatal sanguin et urinaire, be disclosed to the child's parents, to the child him/herself when he/she is 14 years of age or older, or to the treating physician if they so request. In contrast, the ministère de la Santé et des Services sociaux’s Guide d’interprétation des résultats de porteurs de gènes d’hémoglobinopathies indicates that disclosure of carrier status is limited to those forms of hemoglobin targeted by the screening program. The Ministère de la Santé et des Services sociaux therefore questions the relevance of adding the HbE/E, HbS/E and HbE/β-thal variants to the primary targets of the Quebec Newborn Blood Screening Program in order to be able to harmonize the documentation of newborn screening for hemoglobinopathies and follow-up of hemoglobinopathy gene carriers.

Authors' results and conclusions: RESULTS (#1 THE SEVERITY OF HBS/E, HBE/E AND HBE/ Β-THAL VARIANTS IS VARIABLE): Some patients with HbS/E, which is part of major sickle cell diseases, will be asymptomatic or have mild to moderate impairment. About one-third will have vaso-occlusive crises. Complications of the disease can lead to death. • The HbE/E form, a type β-thalassemia variant, is usually mild. • The severity of the HbE/β-thal β-thalassemia depends on the genotype. Patients typically have moderate to severe anemia, and the majority receive transfusions on a regular or occasional basis. (#2 THE PROGNOSIS FOR INDIVIDUALS WITH THE HBS/E, HBE/E, AND HBE/ Β-THAL FORMS IS GENERALLY GOOD): Patients with HbS/E appear to have a good prognosis. However, they are at risk of developing certain complications. • The prognosis of patients with HbE/E is good, and no data suggesting that severe complications may occur have been identified. • Some patients with HbE/β-thal require transfusions. This treatment improves their prognosis, but infections and complications associated with iron overload remain major causes of death. (#3 THE SCREENING TEST FOR HEMOGLOBINOPATHIES IS RELIABLE): In the literature, the assay's sensitivity and specificity are estimated at 100%. However, there are several limitations in the included studies. • The data reviewed suggest that the occurrence of false positives and false negatives is very rare in hemoglobinopathy screening. • The included studies observed reference rates between 0.05 and 23.44 per 100,000 newborns, which varied according to the prevalence of the study area. • Between 2017 and 2020, eight cases of HbE/E and fewer than five cases each for HbS/E and HbE/β-thal were identified and confirmed in Quebec. (#4 NEWBORN SCREENING FOR HEMOGLOBINOPATHIES APPEARS TO BE EFFECTIVE): No studies were identified that assessed the effectiveness of newborn screening for HbS/E, HbE/E, and HbE/β-thal variants. • Therefore, the effectiveness analysis was translated from data from other variants of sickle cell diseases or β-thalassemias. • Newborn screening may reduce hospitalizations and mortality associated with sickle cell diseases and may reduce growth failure in children with β- thalassemias. • The advisory committee members believe that screening has had the greatest impact on the natural history of hemoglobinopathies by preventing sepsis. Of the variants under study, they felt that the benefit of screening would be greatest for HbS/E and HbE/β-thal. (#5 CARRIER STATUS IS AN ISSUE IN NEWBORN SCREENING FOR HEMOGLOBINOPATHIES ): Carrier status is not readily disclosed to parents, but the Quebec Newborn Blood Screening Program can disclose carrier status to the family, the treating physician, or the individual tested who is 14 years of age or older who requests it, but this possibility seems to be little known by professionals and citizens. • Knowing one's carrier status for hemoglobinopathy could have advantages according to the members of the advisory committee as well as representatives of the Sickle Cell Anemia Association of Quebec. • Some carriers of hemoglobin S could, in very rare and particular situations, present symptoms. Knowing that they are carriers could therefore accelerate decisions regarding management and the initiation of appropriate treatments. (#6 SOCIO-CULTURAL ISSUES ARE INVOLVED): The prevalence of various forms of hemoglobinopathy varies according to ethnic origin. Variants are more specific to certain regions of the world and to certain immigration profiles of populations. • A certain stigma seems to accompany hemoglobinopathy, which can be improved by providing information to the various cultural communities and health care professionals. (#7 A CARE TRAJECTORY IS IN PLACE IN QUEBEC): Although not currently primary targets for newborn screening for hemoglobinopathy, HbS/E, HbE/E and HbE/β-thal variants are detected in Quebec because of the nature of the assay and patients are referred for diagnostic confirmation and management. • Even screening has improved the management of all children born in Quebec, generally limiting equity issues, unmet needs remain. Among these, access to specialists in the regions is still difficult for the medical and psychological follow-up of individuals with hemoglobinopathies. (#8 THE ECONOMIC IMPACT OF ADDING THE THREE VARIANTS APPEARS LIMITED): On the basis of the partial information available and the uncertainty that accompanies it, the results of the cost-effectiveness analyses selected are not transferrable to the Quebec situation, and the budgetary impact of maintaining screening for these variants was deemed to be low.

Authors' recommendations: RESULTS (#1 THE SEVERITY OF HBS/E, HBE/E AND HBE/ Β-THAL VARIANTS IS VARIABLE): Some patients with HbS/E, which is part of major sickle cell diseases, will be asymptomatic or have mild to moderate impairment. About one-third will have vaso-occlusive crises. Complications of the disease can lead to death. • The HbE/E form, a type β-thalassemia variant, is usually mild. • The severity of the HbE/β-thal β-thalassemia depends on the genotype. Patients typically have moderate to severe anemia, and the majority receive transfusions on a regular or occasional basis. (#2 THE PROGNOSIS FOR INDIVIDUALS WITH THE HBS/E, HBE/E, AND HBE/ Β-THAL FORMS IS GENERALLY GOOD): Patients with HbS/E appear to have a good prognosis. However, they are at risk of developing certain complications. • The prognosis of patients with HbE/E is good, and no data suggesting that severe complications may occur have been identified. • Some patients with HbE/β-thal require transfusions. This treatment improves their prognosis, but infections and complications associated with iron overload remain major causes of death. (#3 THE SCREENING TEST FOR HEMOGLOBINOPATHIES IS RELIABLE): In the literature, the assay's sensitivity and specificity are estimated at 100%. However, there are several limitations in the included studies. • The data reviewed suggest that the occurrence of false positives and false negatives is very rare in hemoglobinopathy screening. • The included studies observed reference rates between 0.05 and 23.44 per 100,000 newborns, which varied according to the prevalence of the study area. • Between 2017 and 2020, eight cases of HbE/E and fewer than five cases each for HbS/E and HbE/β-thal were identified and confirmed in Quebec. (#4 NEWBORN SCREENING FOR HEMOGLOBINOPATHIES APPEARS TO BE EFFECTIVE): No studies were identified that assessed the effectiveness of newborn screening for HbS/E, HbE/E, and HbE/β-thal variants. • Therefore, the effectiveness analysis was translated from data from other variants of sickle cell diseases or β-thalassemias. • Newborn screening may reduce hospitalizations and mortality associated with sickle cell diseases and may reduce growth failure in children with β- thalassemias. • The advisory committee members believe that screening has had the greatest impact on the natural history of hemoglobinopathies by preventing sepsis. Of the variants under study, they felt that the benefit of screening would be greatest for HbS/E and HbE/β-thal. (#5 CARRIER STATUS IS AN ISSUE IN NEWBORN SCREENING FOR HEMOGLOBINOPATHIES ): Carrier status is not readily disclosed to parents, but the Quebec Newborn Blood Screening Program can disclose carrier status to the family, the treating physician, or the individual tested who is 14 years of age or older who requests it, but this possibility seems to be little known by professionals and citizens. • Knowing one's carrier status for hemoglobinopathy could have advantages according to the members of the advisory committee as well as representatives of the Sickle Cell Anemia Association of Quebec. • Some carriers of hemoglobin S could, in very rare and particular situations, present symptoms. Knowing that they are carriers could therefore accelerate decisions regarding management and the initiation of appropriate treatments. (#6 SOCIO-CULTURAL ISSUES ARE INVOLVED): The prevalence of various forms of hemoglobinopathy varies according to ethnic origin. Variants are more specific to certain regions of the world and to certain immigration profiles of populations. • A certain stigma seems to accompany hemoglobinopathy, which can be improved by providing information to the various cultural communities and health care professionals. (#7 A CARE TRAJECTORY IS IN PLACE IN QUEBEC): Although not currently primary targets for newborn screening for hemoglobinopathy, HbS/E, HbE/E and HbE/β-thal variants are detected in Quebec because of the nature of the assay and patients are referred for diagnostic confirmation and management. • Even screening has improved the management of all children born in Quebec, generally limiting equity issues, unmet needs remain. Among these, access to specialists in the regions is still difficult for the medical and psychological follow-up of individuals with hemoglobinopathies. (#8 THE ECONOMIC IMPACT OF ADDING THE THREE VARIANTS APPEARS LIMITED): On the basis of the partial information available and the uncertainty that accompanies it, the results of the cost-effectiveness analyses selected are not transferrable to the Quebec situation, and the budgetary impact of maintaining screening for these variants was deemed to be low.

Authors' methods: A rapid, thorough, and transparent literature review was conducted to document the parameters under investigation, including assay performance, efficacy, safety, and screening efficiency. Scientific and grey literature was identified from multiple databases and without limitation to study designs. Contextual and experiential data were collected from an advisory committee of hemoglobinopathy professionals and from the Sickle Cell Anemia Association of Quebec. All the data (scientific, contextual, and experiential) were presented to the members of the INESSS Comité délibératif permanent – Approches diagnostiques et dépistage, so that it could deliberate on the relevance of including the variants assessed in the primary targets of the Quebec newborn blood screening program in the current context.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/en/publications/publications/publication/pertinence-dajouter-les-variantes-hbs-e-hbe-e-et-hbe-b-thal-aux-cibles-primaires-du-test-de-depistage-neonatal-des-hemoglobinopathies.html

Year Published: 2023

URL for published report: https://www.inesss.qc.ca/en/publications/publications/publication/pertinence-dajouter-les-variantes-hbs-e-hbe-e-et-hbe-b-thal-aux-cibles-primaires-du-test-de-depistage-neonatal-des-hemoglobinopathies.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)