Acta Biomed 2021; Vol. 92, N. 4: e2021410 DOI: 10.23750/abm.v92i4.11965 © Mattioli 1885 A dva n c e s i n h e mo g l ob i n opat h i e s ( e d i t or : A s h ra f T S ol i m a n ) Immigration and screening programs for hemoglobinopathies in Italy, Spain and Turkey Duran Canatan1, Joan Lluis Vives Corrons2, Giorgio Piacentini3, Fatih Kara4, Bekir Keskinkılıç4, Başak Tezel4, Aslıhan Külekçi Uğur4, Meliha Babayiğit4, Elena Krishnevskaya2, Giuseppe Millimaggi3, Ozlem Erinekçi1, Zekiye Özdemir1, Vincenzo de Sanctis3 1 Thalassemia Diagnosis Center of Mediterranean Blood Diseases Foundation, Antalya (Turkey); 2Red Blood Cell and Haema- topoietic Disorders Unit, Institute for Leukemia Research Josep Carreras (IJC) and University of Barcelona, Catalonia (Spain); 3 Private Accredited Quisisana Hospital, Ferrara (Italy); 4General Directory of Public Health of MOH of Turkey, Ankara (Turkey) Abstract. Sickle cell disease (SCD) and thalassemias are the most common monogenic diseases in the world. The number of migrants and refugees in Europe and Turkey, in the past decade, has increased dramatically due to war, violence or prosecutions in their homeland. Prevention and management of haemoglobin disorders is well established and managed in countries where these conditions were traditionally endemic or in countries that have a longstanding tradition of receiving migrants. Therefore, preventive and diagnostic programmes regarding hemoglobinopathies in immigrant populations have been implemented. The purpose of this paper it to report a summary of the experience gained in Italy, Spain and Turkey in migrants, asylum seekers and refugees. (www.actabiomedica.it) Key words: Hemoglobinopathies, migrants, refugees, Turkey, Spain, Italy, Equality Plus Project Introduction in or have origins in central Africa. The condition also affects people from Central and South America, the More than 270 million people worldwide are car- Arabian Peninsula, Middle East, India, and eastern riers of a clinically relevant hemoglobinopathy. One Mediterranean (4). percent of pregnancies are at risk for disease, resulting The thalassemias are caused by decreased or each year in 330, 000 affected births due to sickle cell absent production of otherwise normal a- or β-globin disease (SCD; 83%) or thalassemia (17%) (1). chains. β-thalassemia major occurs in individuals who Inherited hematologic disorders are common are either homozygous or compound heterozygous for among many immigrant and refugee populations and a β -thalassemia mutation. The phenotype of β -thalas- should be considered in any subject who has anemia semia major can also result from coinheritance of β detected on screening, even if other potential causes -thalassemia mutation with Hb E (Hb E/ β -thalas- exist. These disorders include thalassemias, SCD, semia) or with a large enzyme defects, and cell membrane defects (2,3). deletion in the β -globin gene locus (δβ -thalas- Perhaps the most widely known of these condi- semia) or in conjunction with a-globin gene duplica- tions is SCD, due to replacement of glutamic acid by tion (5). a valine at the sixth amino acid position of the beta Historically, the prevalence of β-thalassemia has chain. Globally, 80% of people affected by SCD live been highest in the Mediterranean region, the Middle 2 Acta Biomed 2021; Vol. 92, N. 4: e2021410 East, and Southeast Asia and lowest in Northern factors need to be considered. Such factors include the Europe and North America (4). Due to migration pat- permanency of the migration, whether it is a migration terns, β-thalassemia is increasingly more common in of single people or of families, whether the migrant will non-endemic regions, including Western Europe and marry locally or from the country of origin, whether North America (6). consanguineous marriage will still be practiced in the Screening programmes in the EU are determined host country, whether there will be free choice partner at national level, and therefore there are wide varia- or an arranged marriage, whether birth rate of immi- tions and disparities in practice between countries. The grant families will be that of the home or the host main objective of screening for hemoglobinopathies country and whether there is a second generation of is to improve outcomes for patients by detecting the migrants and the customs that they have adopted (10). disease early and allowing early intervention, and to allows the possibility of offering genetic counselling to The Italian screening programs for hemoglobinopathies parents of affected children (7,8). and their prevalence in immigrants The purpose of this paper it to report a summary of the experience gained in Italy, Spain and Turkey in Hemoglobinopathies are not strictly a ‘disease migrants, asylum seekers and refugees. of migrants’ in Italy; an extensive national popu- lation surveys for β-thalassemia begun in Italy in 1948 by Silvestroni Bianco. The Researches showed Italy that β-thalassemia was a social problem with about 2,500,000 heterozygous individuals and over 10,000 Around 5.1 million foreign citizens legally reside homozygous patients (11). in the country (Table 1). The first ten nationalities of The highest frequency of SCD has historically immigrated people, as of 1st of January 2018, living in been reported in Sicily. Chromosomal analysis sug- Italy are reported in Table 2 (9). gested that SCD originated from Northern Africa The majority are economic migrants and their (12,13). effects in terms of genetic disease, are difficult to esti- In 1998, a questionnaire, requesting information mate in terms of numbers with accuracy, since many about the cases of SCD was sent to all Italian centers of Table 2. First 10 nationalities of immigrated people, as of 1st of Table 1. Estimates of different categories of foreign population January 2018, living in Italy. in Italy in 2017. (Source: Caritas Italiana. Common home migration and develop- (Source: Caritas and Migrantes 2017/2018. Elaboration on ISTAT ment in Italy. May 2019.pp.1-30; by courtesy of Scripta Manent, data; by courtesy of Scripta Manent, Milan- Rivista Italiana di Milan- Rivista Italiana di Medicina dell’Adolescenza -2020) Medicina dell’Adolescenza -2020) Acta Biomed 2021; Vol. 92, N. 4: e2021410 3 Pediatrics and determined the distribution and sever- West African countries Senegal and Nigeria, as well ity of SCD in Italy. A total of 696 cases were reported. as Morocco, Egypt, and Tunisia in North Africa, and The distribution of registered patients showed that, Syria in the Middle East. Approximately two-thirds although the S gene originated mostly in Sicily, with of the 70 patients were diagnosed after an acute com- an estimated mean frequency of 2% and a peak of 13%, plication requiring emergency care and some of these and Southern Italy, 20% of patients with SCD lived in complications, likely preventable with early diagnosis Central and Northern Italy (14). and treatment, were life-threatening (16). To expedite According to 2019 data from the National Regis- the identification of SCD and mitigate complications, try of Thalassemia and Haemoglobinopathies, in Italy the same Researcher (17) undertook a pilot study in there are approximately 1,275 patients living with which they performed point-of-care screening of ref- SCD. The epidemiology of SCD has changed consid- ugees seen in a single refugee center during October erably in the country over recent years, in particular in 2017. Three percent were found to have SCD and 20% response to changes in migratory patterns and migra- were found to have the heterozygous AS genotype. tion from countries with high SCD prevalence (13). The majority of sickle hemoglobin (HbS) carriers were Therefore, implementation of screening programs from West Africa, and the authors noted that “none of for early detection of patients with SCD has become the newly identified SCD patients were aware of their necessary in Italy as a result of the high rate of migra- condition ”. These findings prompted the researchers tion from areas with a high prevalence of the disease (17) to propose several initiatives to improve screening (Sub-Saharan Africa, Middle East and the Balkans). of SCD among migrants arriving to Italy, in particular: A screening programs for early detection of • Routine screening for SCD in refugees from patients with SCD was conducted from 2014 to 2016. countries endemic for SCD within 10-14 days Samples from 17,077 new mothers were analyzed and from their arrival to identify potentially vulner- 993 showed alteration of Hb patterns (5.8%) (1.0% Hb able patients AS carriers); of the 1011 at-risk newborns, four (0.4%) • A structured, collaborative national network carried SCD and 90 (8.9%) were Hb AS carriers. The • Educating ED physicians to identify and treat Authors also detected 268 (32.1 %) β-thalassemia het- acute SCD-related events ( such as: SCD-related erozygous, 24 (2.9 %) δ thalassemia heterozygous, 6 acute vaso-occlusive events) (0.72 %) persistent HbF or δ/β thalassemia heterozy- • Rapid referrals of refugees with SCD or sympto- gous. Altered levels of HbA2 and HbF were also matic HbS-carrier genotype to a comprehensive reported: 103 women (12.35 %) showed decreased val- SCD reference center. ues of HbA2 (<2%), 32 (3.83 %) were identified to be • Earlier initiation of disease-modifying treatment carrier of HbA2 borderline (3.2-3.8%) and 156 (18.70 (e.g., hydroxyurea). %) had increased HbF levels. These data provided val- uable information on the frequency of these conditions Together, these data suggest that the increased in geographic areas in which the disease was histori- number of patients with SCD in Italy has mostly cally rare (15). resulted from migratory patterns of immigrants arriv- The experience on new cases of SCD and other ing, in recent years, from countries in which there is hemoglobinopathies in refugees, between 2014 and a high disease prevalence (13). Comprehensive pre- 2017, at 13 Italian reference centers for hemoglobi- vention programs including public education, genetic nopathies was reported by De Franceschi et al. (16). counseling, and population screening, accompanied by A total of 70 patients with hemoglobin disorders were prenatal diagnostics are recommended. It is generally identified (61 new patients with SCD, 6 with transfu- recognized that registries are important tools for detect- sion- dependent thalassemia, and 3 with other hemo- ing demographic patterns, allocating resources, moni- globinopathies), the majority of whom were male. toring patient outcomes, and guiding decisions (18,19). Half were adults with the median age of 21 years The main challenges for physicians were lack of aware- and the other half were children. Most came from ness of the asylum seekers’ specific health care problems, 4 Acta Biomed 2021; Vol. 92, N. 4: e2021410 language and intercultural communication problems, as birthplace: 1) North Africa; 2) Sub-Saharan Africa; 3) well as access and integration of asylum seekers into the Asia, and 4) Central and South America. The preva- health care system, Language barriers and poor multi- lence of hemoglobinopathies and SCD was calculated cultural competencies should be also considered (16,17). for each category and are illustrated in table 3. After 2003, the increasing immigration flows, especially from Africa (Northern and Sub-Saharan Spain regions) led to the emergence of SCD as one of the most common hereditary disorders in Spain, with an As in other Mediterranean countries, the main impact on the burden of healthcare in several of its hemoglobin disorder in Spain is β-thalassemia. Until geographical regions. In these regions, 2003, however, the prevalence of hemoglobinopathies the prevalence of SCD was directly related to the in Spain was unknown, and only the establishment of impact of immigrant populations, mainly from sub- universal pilot screening programs of hemoglobinopa- Saharan Africa (29). The national consensus in Spain thies allowed to identify an overall incidence of 0.33% indicated that the number of African immigrants has (20,21). doubled in only 5 years. Furthermore, the distribu- The first study of hemoglobinopathies in Spain was tion of this immigrant African population was very carried out in 1981, in Barcelona by Baiget et al. (22). heterogeneous and differed widely from one region to The Authors reported a global prevalence of hemoglo- another (Table 4) binopathies of 0.14%, a value significantly lower value In conclusion, all the studies performed until than that reported by the WHO in 1995 (23). 2008, demonstrated that in Spain the prevalence of Although after this first publication, many stud- hemoglobinopathies was lower when compared to ies have been carried out to establish the prevalence other Mediterranean countries (30) or concerning the of β-thalassemia in Spain, in only one, the individu- European median (0.5 cases for thalassemia and 15 als included were representative of almost all Spanish for SCD per 100,000 inhabitants) (31). Moreover, the geographical regions (24). This study demonstrated prevalence of SCD was heterogeneous and strongly that β-thalassemia distribution was very heterogene- influenced by the migratory flows. ous with a prevalence ranging from 0.1% to 5% and After 2008, the most updated information on pointed out that most of the HbS, and also HbC and the current situation of hemoglobinopathies in Spain other hemoglobinopathies carriers, were from south- has been recently published by the Spanish Society ern and western geographical regions of Spain. Moreo- of Pediatric Hematology and Oncology (SEHOP) ver, control programs based on the screening of couples from a multicentric study with the participation of 51 at risk for thalassemia and the offer of antenatal diag- hospitals all over Spain in which 75 thalassemias (62 nosis resulted beneficial for reducing the frequency of thalassemia major), 826 SCD and 58 other hemoglo- β-thalassemia major (25). Noteworthy, some of the binopathies were registered (Table 5) (32). Spanish regions exhibited a significantly higher prev- A national registry of hemoglobinopathies was alence of both b- thalassemias and structural hemo- implemented in 2014. Fifty hospitals participated globinopathies, most probably due to the well known to the survey. Thalassemia was reported in 73 cases genetic influence of Arab populations in the past (26). and SCD in 615 cases. The incidence in 2014 was Between 2003 and 2008, a pilot study for neona- estimated at 4 cases of thalassemias and 14 cases of tal screening of hemoglobinopathies was performed in SCD among 426.303 live births (0.002 per 1.000 Catalonia by Man˜ú et al. (27,28) with the support of live births and 0.03 per 1.000 live births, respec- a grant of the Spanish Ministry of Health. tively) (33). A total of 4696 newborns from at-risk ethnic In summary, the current influx of economic groups were studied using two different targeted neo- migrants and asylum seekers in Spain, from coun- natal screening approaches. Neonates were classified tries with a high prevalence of haemoglobinopathies, into four different categories according to mother’s creates new challenges for health care systems and Acta Biomed 2021; Vol. 92, N. 4: e2021410 5 Table 3. Number of births from African origin immigrants (and indigenous residents of African ethnicity) and estimation of SCD prevalence in different Spanish regions (2006) ( by courtesy of Scripta Manent, Milan- Rivista Italiana di Medicina dell’Adolescenza -2020). diagnostic laboratories. The incidence of hemoglobi- Turkey nopathy is lower in Spain than in other Mediterranean countries, with a prevalence of approximately 1.5 cases Turkey is located in the intersection point of Asia, per 100.000 people. Pediatricians and pediatric soci- Europe and Africa and Turkey is a bridge between eties should work to improve the sensitivity of their economically and politically underdeveloped states respective populations towards migrants, asylum seek- and rich Western countries. ers, and refugees. Turkey is at the centre of refugee movements due to historical and geographical reasons. Turkey did not have a specific refugee policy until the 1950s and did 6 Acta Biomed 2021; Vol. 92, N. 4: e2021410 Table 4. Distribution of African immigrants and indigenous residents of African ethnicity in the different regions of Spain (2008) (by courtesy of Scripta Manent, Milan- Rivista Italiana di Medicina dell’Adolescenza -2020). * Regions in the north of the African continent. not have a strategy for the social inclusion of migrants of United Nations Turkey signed the 1951 convention and therefore was not ready for the recent high influx of and its 1967 protocol with a geographical restriction. migration. The first policies to be implemented regard- In April 2014, the Law on Foreigners and International ing migration and refugees came with the establishment Protection (LFIP) established a proactive migration Acta Biomed 2021; Vol. 92, N. 4: e2021410 7 Table 5. Characteristics of the registered 959 patients with hemoglobinopathy in Spain (Medicina Clinica. 2020; 155:95-103; by courtesy of Scripta Manent, Milan- Rivista Italiana di Medicina dell’Adolescenza -2020) policy to cope with migration influxes, without infring- to Turkey and Turkey has welcomed asylum seekers in ing fundamental human rights of asylum seekers (34). a difficult situation as a consequence of its historical Since the beginning of the Syrian civil war, started ties and its sense of obligation. After 1980s, Turkey has in March 2011, millions of refugees immigrated mostly become not only immigrant sending country but also to neighbouring countries. According to the Turkish immigrant receiving country. Conflict, violence and report of Health Services on Temporary Protection of persecution worldwide force due to the number of peo- General Directory of Public Health of MOH, in 2019 ple displaced by Turkey reached record levels, the high- approximately 3.6 million of immigrants were under est number in the world continues to host refugees. temporary protection (35). Turkey already serves to host 3.4 million regis- Turkey has also been receiving migrants form some tered Syrian refugees and about 370.000 people from African countries, such as Eritrea, Somalia, Egypt and other nations (37). In Turkey, an estimated 3.4 million Sudan. These migrants usually consider Turkey not as Syrian refugees have entered the country since 2011, the final destination of their travel, but rather a transit with 276. 158 babies being born to Syrian couples country. The official total number of irregular migrants living in Turkey between 2011 and 2017 (38). These who passed through Turkey to Europe between 2009 couples were not covered by the premarital screen- and 2013 was 225,590 (36). ing program that was widely implemented in Turkey Irregular migrants consider Turkey as a transit in 2002. In 18 pediatric hematology/ oncology cent- route. In addition, Turkey has rising power in its region ers throughout Turkey, 318 children from 235 refugee and this makes Turkey a destination country instead of families had β-thalassemia (mean age 8.1 years); most transit country for third country nationals. Besides, the of these patients presented with an inadequate transfu- turmoil which has continued for years in the Middle sion and chelation history. A total of 72 of 318 affected East, Caucasus and the Balkans has led to a mass influx children from refugee families were born in Turkey, 8 Acta Biomed 2021; Vol. 92, N. 4: e2021410 Table 6. Foreign Nationals Polyclinics (YUP) data for immigration in Turkey (From: www.goc.gov.tr. Directorate General of Migra- tion Management of Ministry of Interior of Republic of Turkey; by courtesy of Scripta Manent, Milan- Rivista Italiana di Medicina dell’Adolescenza -2020). indicating an urgent plan to screen refugee couples at In 1971, Cavdar and Arcasoy reported that the overall risk for hemoglobinopathies (39). incidence of β-thalassemia was 2.1% (41,42). In order to provide preventive health services and Altay published abnormal hemoglobins in Turkey basic health services to Syrians in our country more in different years. Forthy-two abnormal hemoglobins effectively and efficiently, to overcome the problems were identified in the Turkish population. The most arising from the language and cultural barrier, and to frequently observed abnormal hemoglobins were: Hb increase access to health services, the immigrant health S, Hb D, Hb C, HbE and Hb O Arab. HbS was the centers (GSM) are established. most common abnormal hemoglobin in Turkey (43). Currently, 780 migrant health units have been The Ministry of Health (MOH) established established in 180 migrant health centers in 29 prov- thalassemia centers in Antalya, Antakya, Mersin and inces and continue their activities. Mugla, the southern provinces of Turkey, after the “Syrians Temporary Protected Health Status and law named ‘‘Fight Against Hereditary Blood Dis- Development of the Republic of Turkey presented ease (FAHBD’’) was accepted in 1993.The Turkish by Related Services Project (Feelings)” framework; National Hemoglobinopathy Council (TNHC) was Efforts are being made to support the currently oper- installed to combine all centers, foundations and ating GSM’s, to create new GSM where needed, and associations into one organization together with the to employ Syrian health workers to provide services MOH in 2000. The written regulations of FAHBD in these centers. The number of Syrian physicians were published in 2002.Thirty-three provinces situ- employed in GSM is 694, the number of Syrian aux- ated in the Thrace, Marmara, Aegean, Mediterra- iliary health personnel is 954, the number of patient nean and South Eastern regions were selected for the referral personnel is 1,121, the number of support ser- Hemoglobinopathy Prevention Program. (HPP) by vices personnel is 399, the number of social workers is MOH and TNHC. A premarital hemoglobinopathy 11 and the number of psychologists is 12. test is mandatory and free of charge in this program. Increasing the service capacity for migration The number of newborn with thalassemia and hemo- health by training TSM personnel working in these globinopathies were 272 in 2002 and dropped to 25 centers on migration and migrant health is among the in 2013. There has been a 90.0% reduction in affected goals (40) (Table 6). newborns as the results of educational and preven- Hemoglobinopathies are a very important health tion in the last 10 years. This program has been run problem in Turkey. In 1958, the first clinical and as successfully in 41 provinces by the MOH till to hematological studies were published by Aksoy et al. 2013.(44,45) Acta Biomed 2021; Vol. 92, N. 4: e2021410 9 As of November 1, 2018, the hemoglobinopathy to develop diagnostic pathways for hemoglobinopa- Control Program has been implemented in 81 prov- thies, in order to plan interventions, including prenatal inces covering whole country, under the name of “Pre- diagnosis and cure. The absence of national registries Marriage Hemoglobinopathy Screening Program” (46). makes essential to identify ways and tools to better Mediterranean Blood Diseases Foundation describe the extent of the problem in terms of numbers (AKHAV), the European Network for Rare and and distribution across each country (48,49). Congenital Anaemias (ENERCA) and the Interna- tional Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET- Conflicts of interest: Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity A) through the Equality Plus project of the EU have interest, patent/licensing arrangement etc.) that might pose a con- planned a common response to the rising number flict of interest in connection with the submitted article. of SCD patients in Italy, Spain and Turkey with the objectives to create a national working group focused Acknowledgement: The Equality Plus project is supported and on subjects with hemoglobinopathies and to develop Co-Funded by the Erasmus and Programme of the European tailored guidelines and algorithms for the manage- ­Union ment of SCD that could be accessed and practiced by those involved in the care of these patients in order to improve their specific knowledge and their ability of communication with different cultures and to deal References with the medical needs of patients with hemoglobi- nopathies, considering the insufficient level of knowl- 1. 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