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Hemoglobin disorders inEurope: a systematic effort ofidentifying and addressingunmet needs and challenges bythe Thalassemia InternationalFederationMichael Angastiniotis,1 Lily Cannon,1Eleni Antoniou,1 Angelo Loris Brunetta,1George Constantinou,1 Eva Maria KnollKnoll,2 Dimitris Loukopoulos,3 AntonSkafi,1 Androulla Eleftheriou1

1Thalassaemia International Federation,Nicosia, Cyprus; 2Institute for SocialAnthropology, Austrian Academy ofSciences, Vienna, Austria; 3National andKapodistrian, University of AthensMedical School and BiomedicalResearch Foundation of the Academy ofAthens, Athens, Greece

AbstractHemoglobin disorders (thalassemia and

sickle cell disease) are a group of hereditaryanemias that today occur across the world.The recent population movement has led toa steady increase of carriers and patients inall countries of the European Union.Requiring complex monitoring and treat-ment and, as a consequence, well-organizedand nationally coordinated, supported andfunded services, these lifelong conditionsare now visible to healthcare services in theEU. The purpose of this study is to providean overview of the current situation pertain-ing to these disorders, as perceived by thepatient/parent community that theThalassemia International Federation (TIF)represents. The aim is to establish a com-prehensive understanding of the situationand unmet needs faced by migrants withthalassemia. The implementation of activi-ties by TIF in 2018-2020 to identify andaddress these challenges, paves the way toincreased awareness, education and policychanges building on international expertiseand knowledge that will enable the provi-sion of state-of-art clinical management ser-vices thus guaranteeing an improved qualityof life. A bird’s eye view of the prevalenceof these disorders is presented contributingto the further understanding of challengesmet by both patients and healthcare profes-sionals in the receipt and provision of qual-ity healthcare respectively.

IntroductionHemoglobin disorders are a group of

hereditary anemias caused by genetic muta-tions affecting the production of the globinchains of the hemoglobin molecule. Theirprevalence seems to be related to past orpresent prevalence of Plasmodium falci-parum malaria across the globe, since itappears that healthy carriers have a selec-tive advantage over non-carriers as far assurvival to malarial infection is concerned.There is a geographical coincidence ofhaemoglobinopathy prevalence, with thoseparts of Europe where malaria was rampantin the past.1 Cyprus is a primary example ofthis phenomenon, since until its eradicationin 1948, malaria was a major public healthproblem; the beta thalassemia carrier ratewas recorded to be 15-18%.2 Lowlandregions of Greece, Italy and Turkey weresimilarly affected.

Geographical distribution in EuropeHigh prevalence globally, for both tha-

lassemia and sickle cell disease (SCD),appears to range from the Mediterraneanbasin across Africa and the Middle East tothe Far East reaching the Pacific coast. Inthe European setting, the countries in whichthe indigenous population is most affectedare the South of France, Italy, Greece,Albania, Turkey and the Mediterraneanislands. Some countries to the north ofthese, such as the Balkans are less affectedas is the Iberian Peninsula. Southern Russiaand the Caucasus have a variable preva-lence, with the exception of Azerbaijanwhich has a high prevalence. North of theseareas are most European countries wherebeta and alpha thalassemia are extremelyuncommon (with around 0.1-0.2% of thepopulation being heterozygotes), whilesickle cell genes and other variants arealmost unknown in the indigenous popula-tions (Figure 1).

Historical population movements in theearly and mid-20th century from highprevalence countries have introduced thesedisorders to the countries of WesternEurope (e.g. UK and France) and theAmericas (e.g. USA, Canada and Brazil).Furthermore, more recent population move-ments to Europe, of different causality, vol-untary or forced, have changed theEuropean landscape in the area ofhemoglobin disorders, and have led to asteady increase of carriers and patients in allcountries of the European Union, includingformerly low prevalence countries such asScandinavian countries (viz. Denmark,Sweden) and Central European countries (v.Slovakia, Czech Republic).3,4 A migrationflow from the east has followed a transit

route through Turkey, Greece and theBalkans aiming to reach the countries ofWestern and Northern Europe (mainlyFrance, Germany and Sweden). FromAfrica, the origin of most sickle cell carri-ers, increasing numbers are entering theEuropean continent mainly across theMediterranean to Italy and Spain. Someamong of the persons originating from highprevalence countries of the Middle East,South East Asia and sub-Saharan Africa arelikely to be healthy carriers of these disor-ders or indeed patients. Likewise, personsfrom Afghanistan, Iraq, Syria, Thailand andTurkey, entering Europe from the Easternborders of Greece and the Balkans might becarriers of thalassemia or HbE genes. InGermany, only about 1000-1500 sickle cellpatients were recorded in 2014, while in2016 a neonatal screening study revealedthat 1 in 2385 newborns are SCD carriers,probably of Sub-Saharan ancestry.5,6 Thedocumented number of people settling inEurope until 2015 from high prevalenceareas and the subsequent estimated numberof carriers based on prevalence rates in theircountries of origin is demonstrated in Table1.8-14 In the absence of an internationallyaccepted definition of migrant, in this pub-lication the term will be used to define anyindividual who lives outside their country

Thalassemia Reports 2021; volume 11:9803

Correspondence: Androulla Eleftheriou,Executive Director, Thalassemia InternationalFederation; 31, Ifigenias Street, 2007Strovolos, Nicosia, Cyprus.Tel.: +35.722319129. E-mail: thalassaemia@cytanet.com.cy

Key words: Thalassemia; sickle cell disease;hemoglobin disorders; prevalence; migration;Europe.

Conflict of interests: the authors declare nopotential conflict of interests.

Novelty statement: An updated bird’s eyeview of the prevalence of hemoglobin disor-ders is presented following the recent migra-tion flow to Europe in 2015. Understandingthe distribution of carriers and patients acrossEurope, contributes to the further understand-ing of challenges met by both patients andhealthcare professionals in the receipt and pro-vision of quality healthcare respectively.Received for publication: 9 April 2021.Accepted for publication: 10 April 2021.

This work is licensed under a CreativeCommons Attribution 4.0 License (by-nc 4.0).

©Copyright: the Author(s), 2021Licensee PAGEPress, ItalyThalassemia Reports 2021; 11:9803doi:10.4081/thal.2021.9803

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of origin for whatever reason either volun-tary or forced (e.g. conflict, poverty, politi-cal unrest, natural disasters, etc.).5,6

Medical progress now allows for thesurvival of haemoglobinopathy patientswho would have passed away in early child-hood until a few decades ago. The increas-ing numbers of patients together with inten-sified population migrations from highprevalence countries today makehemoglobin disorders ‘visible’ to the healthservices of countries which previouslyregarded them as extremely rare, havingbrought new challenges to European healthservices.5 Persons born outside Europe aregenerally increasing in Europe, but in thecontext of hemoglobin disorders, it is thosemigrants that have arrived more recently(after 2012) from high prevalence countries,that are the focus of this study.

Figure 2 represents the number ofmigrants from high prevalence countries upto 2015. These estimates concern relativelyrecent migrations, while other second andthird generation migrants are not counted.Since then and up to the end of 2019, anoth-er 855,000 have arrived, mainly from highprevalence locations (IOM data).7 In addi-tion, unregistered/undocumented illegalentries are estimated to be high, especiallyfrom sub-Saharan Africa where the HbSgene is present in high prevalence. Frontex,the European Union frontier police15 esti-mate that from 2009 to mid-2020, 317,000such migrants were detected from Sub-Saharan African countries and another102,000 from the Maghreb countries andLibya. It is possible that many others maynot have been detected. Therefore, it isspeculated that as many as half a millionpeople from high prevalence of sickle cellcarriers may have entered Europe, withSpain, Italy, France, Germany and the UKbeing the main recipients. This means thatthere are around 20 million settlers inEuropean countries of low prevalence forhemoglobin disorders who may have abnor-mal hemoglobin genes (with the exceptionof Italy which has both indigenous andmigrant high risk populations). This isaround 5% of the total population of themost affected countries.

The increasing size of this public healthproblem with considerable socio-economicrepercussions in Europe is demonstrated bythese estimations. Registries, health recordsand other databases are essential tools forgathering information, which help to definethe epidemiology, clinical outcomes and thenatural history of these rare conditions,which have been on the rise in much ofNorthern and Western Europe for quitesome time now but the migration crisesplaying out since 2015 has made these dis-

orders more visible as numbers keep rising.Information from such healthcare tools willhelp to improve the much needed quality ofmultidisciplinary care and to plan services,as well as to assist in research initiativesincluding clinical trials. Thus, the develop-ment of an EU-wide comprehensive dis-ease-specific Registry is pivotal for moni-toring not only the spread of hemoglobindisorders in each country but as a healthplanning tool that informs national policy

for the development of targeted specializedcare services and allocation of appropriatefinancial and human resources (FarmakisD, Angastiniotis M, Eleftheriou A.Thalassemia registries - A call for action: Areport of the Thalassemia InternationalFederation; 2020 - undergoing peerreview).16

Services for hemoglobin disordersThese lifelong conditions require com-

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Figure 1. β-thalassemia carrier rates in the indigenous population of the WHO EuropeanRegion (2020).

Figure 2. Map showing migration flows into Europe.

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plex monitoring and treatment and, as aconsequence, well-organized and nationallycoordinated, supported and funded services.These services include the need for regularblood transfusions and iron chelation sup-ported by multi-disciplinary medical collab-orations in expert centres17 as described inthe International Guidelines for ClinicalManagement of Thalassaemia.18 Such orga-nized multidimensional care has beendemonstrated to have converted lethalchildhood disorders to chronic conditions ofadult life,19 allowing patients to achieve anear normal life. Scattered minority groupsin an environment in which these are rareconditions, may not have access to theexpert care that they need. Not being opti-mally treated will result in poor quality oflife, more complications and even moreexpert and expensive clinical management.In the north and western European settings,such services are available in academic and

other reference centers. The EuropeanCommission, in its rare disease policy andaccording to the Regulation 2011/24/EU onCross-Border Healthcare, has promoted inthe context of a specific legislation thedevelopment of a system of networking(European Reference Networks) so that apatient with a rare condition may be treatedin a local health facility, which is networkedwith a reference center, in a shared care sit-uation.20 In the case of blood disorders, suchas thalassemia and SCD, the Eurobloodnetconsortium is the responsible EuropeanReference Network21 created to put intopractice the proposed hub and spoke systemof service delivery to rare disease patients.

The various issues faced by migrantsare, as yet, only partially met in Europe as isthe case with many other rare diseases.There are a variety of factors that influencethe access of migrants to optimal care: i)unfamiliarity with the health system and the

available services in the host country; ii)language barriers since most migrants donot speak the language and are often of apoor educational background; iii) difficultand delayed diagnosis, both because thelaboratories in the vicinity in which themigrants have settled may not be familiarwith complexity of diagnosis; iv) they maynot have a diagnosis or medical historyfrom their country of origin; v) families areconcerned with social issues, such as find-ing employment and housing as well as fac-ing prejudice and xenophobia, and thus maydelay any health concerns.

The purpose of this study is to providean overview of the current situation inEurope pertaining to thalassemia and SCD,as perceived by the patient/parent commu-nity that the Thalassemia InternationalFederation (TIF) represents. This investiga-tion has been undertaken in the context ofthe ‘Thalassemia In Action (THALIA)’

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Table 1. The prevalence of thalassemia and sickle cell disease in European countries affected by the migration crises based on data fromthe International Organization for Migration site.7

Country Carrier rate of β-thalassemia No. of accepted migrants No. of accepted migrants from Estimate of the patient and SCD in the from high prevalence areas high prevalence SCD areas population indigenous population with thalassemia and low (indigenous and migrant) prevalence of SCD

Austria 0.2% 311,000 14,000 60-79 BTS* 132 SCD*Belgium 0.28% 408,000 64,000 62 BTS* 358 SCD*Denmark 0.2% 171,000 16,000 83 BTS* 236 SCD*France 0.8% 3,993,000 511,000 666 BTS8,9 22,000 SCD10

Germany 0.2% 3,427,000 127,000 600-1600 BTS* 2000 SCD11

Netherlands 0.1% 748,000 71,000 350 BTS* 2000 SCD*Norway 0.1% 162,000 47,000 100 BTS* ? SCDPortugal 1.44% 16,000 75,000 40 BTS* 800 SCD*Serbia 1.2% Transit country - Transit country - 3-5 BTS* Migrants not settled Migrants not settled Spain 1.6% 1,032,000 228,000 100 BTS12,13 800 SCDSweden 0.3% 535,000 84,000 150 BTS* 584 SCDSwitzerland 0.4% 531,000 35,000 62 BTS* 194 SCDItaly 4.3% β-thalassemia 1,621,000 284,000 7044 BTS* 2.1% SCD 2000 SCDUK 0.1% 2,652,000 1,005,000 1564 BTS 14,000 SCD14

Total - 15,679,000 2,581,000 -SCD, sickle cell disease; BTS, β-thalassemia syndromes. *Information on the number of patients, where access to an updated registry is not available are derived from information provided by national experts,either during TIF visits or during the TIF European Symposium for Thalassemia and Sickle Cell Disease (December 2020).

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Framework Partnership between theFederation and the European Commission,initiated in 2018, focused on identifying andaddressing the unmet needs and challengesof patients living within the EU with a par-ticular emphasis on migrants with tha-lassemia and SCD in France, Germany andSweden (as host countries), and Austria andSerbia (as transit countries), known as‘THALIA countries of priority’.

MethodologyThrough the application of a mixed

methods approach, information has beenobtained by patients/parents and healthcareprofessionals working in the field ofhemoglobin disorders through a variety ofvehicles, as described below. The aim beingto establish a comprehensive understandingof the situation and unmet needs faced bythe thalassemia patient community living inFrance, Germany and Sweden, Austria andSerbia. Onsite visits were supplemented bya literature search concerning epidemiologyand service description.

Onsite delegation visitsIn each visit a delegation was composed

of medical specialists and/or patient advo-cates along with a local TIF member.

During each visit, the TIF delegationmet with medical specialists, health author-

ities and patient associations (if in exis-tence) and individual patients/parents tomap the situation and tailor the support (e.g.education, awareness raising, advocacy,etc.) provided by TIF accordingly. The TIFdelegation team, in collaboration with thelocal medical community and patients’association, observed a situation analysis.The COVID-19 pandemic has necessitatedin 2020 the transition to virtual delegationvisits.

Thalassemia-specific prevalencedatabase and literature findings

TIF maintains a thalassemia-specificprevalence database to monitor the geo-graphical distribution of patients throughoutthe EU and supports the improvement ofexisting, and the creation of new publichealth policies and legislations by nationalhealth authorities. This is largely based onpublished literature but also on locallyderived information particularly concerningpatient numbers. Although many publica-tions offer a significant contributiontowards understanding the epidemiology ofthese disorders, the lack of reliable andcomprehensive national registries for tha-lassemia and haemoglobinopathies at pre-sent suggests a gross underestimation oftheir prevalence in Europe. In addition,knowledge and understanding of the distri-bution of patients and prevalence of the dis-ease in each country is a huge contributing

factor to public health planning.Results

A total of 20 onsite TIF delegation visitswere conducted to the five THALIA coun-tries of priority (France, Germany, Austria,Sweden and Serbia), between January 2018- March 2020. In addition, 15 virtual meet-ings took place during 2020 withpatients/parents and treating physiciansfrom each of the aforementioned countries.The total number visits/virtual meetings andpersons (patients/parents and medical spe-cialists) which the delegation teams inter-acted per country with are shown in Table 2.

An overview of the available infrastruc-ture including national policies for screen-ing and access to healthcare services formigrants, diagnostic competencies, treat-ment centers visited during the THALIAprogram with expertise in the clinical man-agement of hemoglobin disorders as well assupport groups for patients transpiredthrough efforts exerted in the context of thisstudy, as demonstrated in Table 3.

Onsite visits to hospitals, treating cen-ters, laboratories and patient support groupswere conducted in each of the delegationvisits, in order to engage in discussion withthe relevant stakeholders to obtain informa-tion about services provided (either at thespecific health providing unit or across thecountry; Table 4) and to map the epidemio-logical situation in each country (Table 5).

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Table 2. TIF Delegation Team interactions with stakeholders in the THALIA countries of priority.

France Germany Austria Sweden Serbia Total

No. of visits/virtual meetings 10 9 10 4 3 36No. of patients/parents 123 143 140 22 57 485No. of medical specialists 158 66 45 16 12 297

Table 3. Available infrastructure for patients in THALIA countries of priority.

Infrastructure Austria France Germany Sweden Serbia

National Screening Policy No No No No NoDiagnostic Laboratories Yes Yes Yes Yes YesTreatment Centres Visited 2 2 8 2 1Patient Support Group No Yes Yes No None(Disease-specific) (Created in 2019 (National and (Several with by TIF initiative) Local coverage) local coverage)Access to healthcare Insurance coverage Yes fully Yes fully Yes but several providers Yes fully Yes fullyservices for registered migrants with variable coverage Insurance coverage Covered by NGOs Scheme exists under Only for Children fully covered; Transient undocumented migrants State Med Aid emergency care adults subsidized migrants are supported

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Other findings and observationsThe dispersal of patients with

hemoglobin disorders across the entire hostcountry, as well as the historical settlementof migrants from high prevalence areas, hasnecessitated the development of centers ofexpertise in the management of thalassemiaand SCD. These centers, are mostly foundin urban areas of France and Germany.However, networking with treating physi-cians and centers in more rural areasappears to be limited. By contrast, inSweden and Austria services are located incapital cities where hematology depart-ments (pediatric and adult) are providingcare for these rare blood disorders but withlimited networking. Quality of care wasvariable in main cities, whilst in rural areasor peripheral towns knowledge on theappropriate clinical management of thesedisorders is severely limited due to rarity ofcases. Patients in Serbia are distinctly evenmore scarce in comparison to France,Germany, Austria and Sweden, for two rea-sons: i) migrant patients are sporadic andremain on Serbian soil for a very limitedamount of time, transiting to settle in otherEuropean countries; and ii) the patientsfrom the indigenous population are veryfew due to the low prevalence rate.

One striking feature, common to all

treating centers visited, is that because ofthe low numbers of patients, the vast major-ity of patients transfused in the same centerdo not know each other and never meet(even though they may be in the next room).This is in stark contrast to the sense of com-munity and belonging experienced bypatients in countries where there are signif-icant number of patients, even in Europe(e.g. Cyprus, Italy, Greece, UK). Therefore,patients with thalassemia have reportedthrough interviews feelings of isolation andsocial marginalization, sometimes to a larg-er extent than patients with SCD who seemto be generally more abundant. This is fur-ther evidenced by the absence of tha-lassemia-specific patient support groups(Table 3) in Sweden, Austria and Serbia; aswell as the existence of small number ofsuch groups in Germany and France.Indeed, in the case of the France andSweden, thalassemia patients appeared tobe supported in a limited fashion by theSCD federation and blood cancer associa-tion respectively. The efforts exerted in thecontext of this study since 2018 has seen ashift towards the defining of functional sup-port groups in Germany and Austria and thefurther empowerment of the patient com-munity in France and Sweden. Serbia, as atransient country for migrants and with

extremely low number of patients with tha-lassemia, necessitates an ad-hoc supportapproach for individual patients.

High quality laboratory servicesenabling the diagnosis of carriers, affectedpatients, prenatal diagnosis and neonatalscreening are available in all the THALIAcountries of priority. The rarity of encoun-tering these disorders requires furtherawareness among laboratory personnel topursue further investigation of low indices,to differentiate between other causes of ane-mia (e.g. iron deficiency) and betweenpatients and carriers. The provision of reli-able results using validated methods isimperative, notwithstanding the responsi-bility for their interpretation lies with theclinicians. Routine screening or geneticcounselling policies were not in effect inany country under study. The familiarity ofprimary care physicians with suggestivesymptoms or suspicion of carrier/patientstatus based on ethnic origin, and hence rec-ommendations for appropriate referrals,could not be assessed at this stage.

Universal health coverage allows forthe access of all thalassemia and SCDpatients (including documented migrants)to basic treatment (i.e. blood transfusionand iron chelation), as well as access to thecomplex monitoring required in these

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Table 4. Summary of Healthcare Services provided to patients with hemoglobin disorders as deduced from TIF Delegation Visits (2018-2020).

Services Austria France Germany Sweden Serbia

National registry No Yes Yes No No (separate for thalassemia (SCD registry is active; and SCD) thalassemia registry is under development)National guidelines for the No Yes Yes Yes Noclinical management (partial adherence) (only for thalassemia) Pre-transfusion Children 9-10 g/dL Reference centers: Reference centers: Reference centers: 9-10g/dLHb (for thalassemia Adults 6-8 g/dL 9-10 g/dL 9-10 g/dL 9-10g/dL patients) Peripheral centers: Peripheral centers: Peripheral centers: <9 g/dL Variable < 9g/dL Variable <9 g/dL MRI availability for iron Until 2019 only Limited to Reference Yes but not systematic Limited to Not availableoverload monitoring for children Centres referral in all centers Reference Centres Multidisciplinary care For adults: Limited to Reference Limited to Reference Limited to Reference On referral On referral Centres Centres but not Centres but not well established well established Networking Not official Not official Exists but variable Not official NoneGenetic counselling Not organized Not organized Organized processes Not organized Not organized (Lack of disease-specific knowledge) SCD, sickle cell disease; Hb, hemoglobin; MRI, magnetic resonance imaging.

Table 5. Estimated No. of patients in each of the THALIA countries of priority.

Austria France Germany Sweden Serbia

Thalassemia 60-79 666 600-1600 150 N/ASCD 132 22-28,000 2000 584 N/ASCD, sickle cell disease.

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chronic disorders. Affordability is an essen-tial requirement for patient outcomes.Undocumented migrants fall below thehealth systems radar, not being officiallyeligible for the receipt of care, often reach-ing emergency departments or health-relat-ed NGO’s, where they can receive treatmentfree-of-charge. Neither of which howeverpossessing the necessary expertise in themanagement of these complex diseases.Thus, it is more likely for such patients todevelop medical complications that withouttimely and appropriate management in anexpert multidisciplinary care setting, willquickly result in health deterioration.Moreover, specialized monitoring tests arevariably covered by the responsible payingbodies (e.g. insurance). For example, MRIfor the measurement of iron overload, anessential monitoring test for the early detec-tion and prevention of iron damage to vitalorgans with great impact on patient sur-vival22 is available in reference centers inAustria, Germany, France and Sweden butnot always reimbursed by paying bodies.Furthermore, the absence of the service inthe periphery makes the need for patients tovisit reference centers, at least annually,imperative.

National guidelines, developed basedon TIF’s International Guidelines for theClinical Management of TransfusionDependent and Non-TransfusionDependent Thalassemia, adapted to nationalcircumstances, exist in France, Germanyand Sweden. Furthermore, a shared lan-guage allows Austrian physicians to refer toGerman published guidelines. Nonethelessthere is diverse awareness about the exis-tence of national guidelines by treatingphysicians across each country. This is evi-dent by consistently lower than recom-mended pre-transfusion hemoglobin levelsin many patients, especially in adult clinics.Moreover, many patients transfused inperipheral centers, present for transfusionwhen they feel the need (pallor, fatigue)rather than in accordance to protocol. Inaddition, in some cases, wrong doses ofchelating agents were also reported bypatients.

Organized multidisciplinary follow upand management of complications is anessential component for the improved sur-vival of patients.18,23,24 In view of the life-long effects on the heart, liver, kidneys,endocrines and other organs, specialistsfrom several disciplines are expected tocontribute to the holistic care of patients byproviding both early detection and compli-cation management. This of course shouldbe done by specialists who have becomefamiliar with the hemoglobin disorders, andare in communication and complete collab-

oration with the hematology team, takingcommon and agreed upon therapeutic deci-sions and where possible sharing patientvisits and communication. In the centersvisited in the course of this study, such orga-nized teams were found in only in two adultcenters - one in France and one in Germany,and one pediatric center in Austria. In gen-eral, patients are referred to specialists oncethey have developed a complication, whilevisiting specialists from an early age andbefore a ‘fait accompli’ was found to berare. Even though the concept of referencecenters, as mentioned above is a recognizedconcept in Europe, actual networking in ashared-care relationship with the peripherywhere patients may be receiving their rou-tine care, has not been formalized. Despitethis, patients have mentioned to the TIFteams that on their initiative they do go tovisit a reference center occasionally.

Disease-specific registries, endorsed bythe national health authorities were identi-fied in France8 and Germany.11 More specif-ically, the French National Registry coversboth thalassemia and SCD whereas inGermany the registry is for SCD while forthalassemia it is in the early stages of func-tioning. The French National ThalassemiaRegistry constitutes a best-practice examplein Europe, demonstrating the value ofdeveloping national disease-specific reg-istries as a service planning tool, as it clear-ly shows the increasing numbers of tha-lassemia patients living in the country (andtherefore increasing requirements of thehealthcare system). Indeed a total of 287individuals were registered in 2008; 479 in2010; 515 in 2012 and 666 in 2019.9

Austria, Sweden and Serbia did not havenationally endorsed disease-specific reg-istries for hemoglobin disorders.

Notably early on in the study it becameapparent that health and other services pro-vided for thalassemia overlapped with thoseprovided for SCD, as both disorders are partof the haemoglobinopathy family.Therefore, recommendations and subse-quent actions included both disorders,which despite their distinct and differentpathophysiology are treated in the samecenters, often by the same physicians. Infact, this overlap in services leads patientswith both disorders also to face some of thesame challenges, as a result not only due totheir rarity in the specific countries whichare the focus of this study, but also as a con-sequence of the distinct difficulties faced bymigrant communities in general.

DiscussionMigration has changed the local preva-

lence of both inherited and acquired dis-eases,25 and the chronic disorders are a par-ticular challenge. The countries selected forthe purposes of the THALIA program wereselected as representing the effects of recentmigrations and to explore the questionwhether Europe is ready to meet the medi-cal, social, economic and public healthchallenges associated with hemoglobin dis-orders. Acknowledging robust health infras-tructure in most of the EU countries, theconcept of chronicity with multiple andcumulative organ damage and the need forsecondary prevention has not entered theclinical practice of managing these patientswho after all are suffering from rare condi-tions, little known in the host country.However, many other rare congenital redcell disorders are managed by hematolo-gists in Europe, which are met in the indige-nous populations that they serve. Is themanagement of Diamond-Blackfan syn-drome, for example, so vastly different fromthat of beta thalassemia? Could the weak-nesses that healthcare systems demonstratenot be due to the sudden increase in cases,but a result of a general weakness in theattention given to the so-called ‘benign’ asopposed to malignant blood disorders?Could the issue of ethnicity be an additionalfactor in the provision of expert care?

Europe has long recognized the needsof rare diseases, developing policies andservices, such as the creation of registriesand the development of EuropeanReference Networks (ERNs).26,27 In addi-tion, there are numerous centers of excel-lence and pioneers in research in manyEuropean countries. Experts are aware andare considering improvements and actionsin critical areas.28 Despite this,haemoglobinopathy patients do not, inmany cases, benefit from the expert carethat their new place of residence can pro-vide, thus achieving maximal survival andquality of life. Experience from the visits ofTIF teams, indicates an uneven availabilityof expert help. This is less related to the pro-vision of adequate and safe blood transfu-sion and the availability of essential medi-cations, but to expertise in their appropriateand timely use. As a consequence, low pre-transfusion hemoglobin and high iron loadswere observed. Likewise worrying was thepoor performance in providing timely andcoordinated multidisciplinary care. Thesenegative impressions were confirmed bypatients who generally felt isolated, with lit-tle support from organized support groups.These findings are in line with other rarediseases, which face similar issues in theprovision of early diagnosis and optimalcare.

Hemoglobin disorders however are dis-

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tinguished from other rare diseases only inthat they are more recently imported bymigrations. The conclusion then is that theyshould be provided with all European provi-sions for rare diseases with the addition ofmore intense awareness raising and moreeducation of healthcare professionals andthe migrant families. In addition, thesocioeconomic problems that arise when afamily arrives in a new environment, a newculture and a health system that has intrica-cies to which they must become familiarwith, deserves particular attention.Furthermore, the creation and empower-

ment of patient groups in these countries inan effort to provide peer-to-peer support,present their own distinct challenges direct-ly related to the heterogenous cultural, lin-guistic, religious, social, educational back-grounds of the migrant communities inwhich these disorders are found within thehost country. This is a stark difference to thehomogenous communities that set up pow-erful patient groups in EU countries with ahigh prevalence in the indigenous popula-tion (e.g. Cyprus, Greece, Italy).

The onus of providing quality care restswith healthcare authorities as well as the

treating physicians, since chronic and rareconditions require organization of services.The requirement is not necessarily to createspecialized haemoglobinopathy clinicswhere few patients exist, but to incorporatethem into benign hematology clinics includ-ing day transfusion units, separate frompatients with malignant conditions receiv-ing chemotherapy for obvious reasons.Moreover, networking, with adequate plan-ning and support, does not seem to be effec-tive as yet, and the referral relationshipbetween the expert and the physician whosees one or two cases, is not yet an estab-

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Table 6. Actions taken in the THALIA Work Program (2018-2020) for meeting challenges and unmet needs of hemoglobin disorders.

1. Policy-Makers:

- Thalassemia EU Health Record: Continuing to monitor the epidemiology of hemoglobin disorders in Europe, an example of which is the Italian WEBTHALclinical database.30

- Advocating for the rights of patients with thalassemia and migrants in the EU through meetings with the EU Health Commission and health authorities ofGreece, Cyprus and Italy (2020).

- Connecting with international bodies, national health authorities and foreign relations envoys to highlight the relation of thalassemia in the EU and migra-tion (2018-2020).

- EU Policy Recommendation & National Charter of Priorities: Comprehensive documents outlining the challenges faced by patients and identifying oppor-tunities for policy changes at the EU and national levels.

- Participation in EU Health Program High Level Conference (2019) to inform and raise awareness about THALIA, thalassemia, SCD, migration and theimpact on health infrastructure.

2. Patients & Families:

- Thal e-course: an online interactive educational platform providing disease-specific information as well as information on relevant policies and recom-mendations for advocacy purposed. Available in English, French, German, Greek, Italian, Arabic and Turkish.

- Train-the-Trainers Capacity Building Workshop for Patients’ and Patient Associations (Thessaloniki, 2018; Hamburg, 2019; Virtual, 2020) - THALIA Mobile Application: launched in 2020, aiming to improve self-management. - Exchange of best practices through twinning programs (Cyprus/France, 2018; Greece/Germany, 2019). - Educational webinars (4 in total) on disease-specific issues for thalassemia and SCD. - Creation of TIF’s European Patient Advocacy Group for Thalassemia & Sickle Cell Disease. Total meetings organized: 3.- Clinical Trials Update: A digest provided to patients/parents every two months on the latest developments regarding clinical trials in the field (2018-2020). - Support and provision of technical expertise to patient organizations through empowerment (v. France, Germany), establishment (v. Austria) and mobi-

lization (v. Sweden).- Publication of brochures on Gene Therapy, Bone Marrow Transplantation & Prevention of Inherited Disorders (2018-2019).- Thalassemia from A-Z: a comprehensive e-glossary for patients with thalassemia (2019).- Development of resources for COVID-19 and hemoglobin disorders including information about the effects of SARS-CoV-2 on patients, blood transfusion,

Sickle Cell Disease, Vaccines and Therapeutic Drugs, etc. (2020). 3. Healthcare professionals:

- eThalEd e-course: an online course on the clinical management of thalassemia. Available in English, French and Arabic. - e-SCD course: an online course on the clinical management of SCD (2020). - Guidelines for the Clinical Management of Non-Transfusion Dependent Thalassemia. Available in English and French (2018). - Guidelines for the Clinical Management of Transfusion Dependent Thalassemia. Updated 4th edition (In print). - Short Guide for the Clinical Management of Transfusion Dependent Thalassemia. Distribution across Europe.- High Level Summit for Healthcare Professionals (Thessaloniki, 2019).- Symposium for Healthcare Professionals in Europe (Virtual, December 2020).- Renzo Galanello Fellowship. Training of 5 physicians (2018-2020).- Educational webinars (7 in total) on various aspects of thalassemia clinical management (2020).- Development of resources for COVID-19 and hemoglobin disorders including a Haemoglobinopathy Patient Pathway (Available in English and Greek) and

Risk Classification (2020). - Raising awareness among EU health professionals through participation in Annual Congress of European Hematology Association (2018-2020),

International Society for Blood Transfusion (2018), European Association for the Study of Liver (2019). 4. General Public:

- Publication and dissemination of awareness raising posters on Migration and brochures on Prevention of Inherited diseases: -thalassemia. - Articles in press and interviews regarding thalassemia, migration and Europe. - TIF website: Updating daily with news. Available in English, French, German, Greek, Italian, and Arabic. - Training of European Solidarity Corps volunteers from Germany, France and Italy about hemoglobin disorders and the migration of populations from high prevalence areas to Europe as refugees, political asylum seekers and economic migrants (2019-2020).

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lished practice in many locations. Thebeliefs by many hematologists that theseblood disorders, due to their benign nature(as opposed to malignant hematological dis-eases) are simpler in their management, andmerely entail the provision of blood andmedications, is an unfortunate common per-ception.

A country that stands out in theEuropean setting is the UK. In this countryfor many decades populations from thecommonwealth countries have been settlingand are now in second and third generation.This has led to planning of reference centersand commissioning, especially located inareas where these communities live, net-working, quality control of centers withannual reviews, registries, research, nation-al guidelines on all aspects of clinical man-agement, including psychosocial support.Finally, a national prevention programbased mainly on antenatal clinic and neona-tal screening, prenatal and pre-implantationgenetic testing.29 This kind of comprehen-sive planning is expected be followed by allEuropean health services as these condi-tions become more visible.

The THALIA Work Program (2018-2020) has enabled, as demonstrated in thisstudy, to identify the location of patientswith hemoglobin disorders as well as to fur-ther understand the challenges met by bothpatients and healthcare professionals in thereceipt and provision of quality healthcarerespectively. In addition to this situationanalysis, the THALIA Work Program facil-itated the implementation of correctivemeasures to alleviate the challenges identi-fied through activities listed in Table 6.30

ConclusionsImproving case management and devel-

oping a culture to focus on rare and chronicdisorders, which are recently appearing inthe spectrum of clinical experience of localspecialists, is a challenge. The organizationof healthcare services for unfamiliar condi-tions to the authorities, raising awareness toa health burden which is now increasing,requires a resilience in health service man-agement, when concerns over adequacy ofbudgetary support are paramount. The factthat poor monitoring and treatment nowwill increase complications and costs overtime is not known to many services. Changein some settings takes time, especiallywhere a culture of networking and collabo-rative care is a necessity. Such networkingis possible because centers of expertise doexist in most European countries. The man-agement of hemoglobin disorders shares thesame difficulties with other rare conditionsin Europe. Additional issues arise because

the conditions are recently imported, andthe social considerations of immigrant pop-ulations. Nonetheless, there is ample inter-national expertise and knowledge to beoffered for the appropriate clinical manage-ment and care of patients with hemoglobindisorders, that would guarantee animproved quality of life.

References1. Piel FB, Patil AP, Howes RE, et al.

Global distribution of the sickle cellgene and geographical confirmation ofthe malaria hypothesis. Nat Commun2010;1:104.

2. Plato CC, Rucknagel DL, GershowitzH. Studies on the distribution of glu-cose-6-phosphate dehydrogenase defi-ciency, thalassemia, and other genetictraits in the coastal and mountain vil-lages of Cyprus. Am J Hum Genet1964;16:267-83.

3. Modell B, Darlison M, Birgens H, et al.Epidemiology of hemoglobin disordersin Europe: an overview. Scand J ClinLab Invest 2007;67:39-69.

4. Aguilar Martinez P, Angastiniotis M,Eleftheriou A, et al.Haemoglobinopathies in Europe: health& migration policy perspectives.Orphanet J Rare Dis 2014;9:97.

5. Grosse R, Lukacs Z, Cobos PN, et al.The prevalence of sickle cell diseaseand its implication for newborn screen-ing in Germany (Hamburg MetropolitanArea). Pediatr Blood Cancer2016;63:168-70.

6. Hunter P. The refugee crisis challengesnational health care systems: Countriesaccepting large numbers of refugees arestruggling to meet their health careneeds, which range from infectious tochronic diseases to mental illnesses.EMBO Rep 2016;17:492-5.

7. International Organization forMigration (IOM). Migration data -Europe. Available from: https://migra-tion.iom.int/europe?type=arrivals

8. Thuret I, Pondarré C, Loundou A, et al.Complications and treatment of patientswith β-thalassemia in France: results ofthe National Registry. Haematologica2010;95:724-9.

9. Agouti I, Thuret I, Bernit E, et al. Datafrom the French registry for beta-tha-lassemia patients. EHA LearningCenter. Badens C 2019;266587.

10. Global Blood Therapeutics. Overviewof the sickle cell disease environment inselect European countries; October2020. Available from:https://ir.gbt.com/static-files/29a0775c-

ed27-4778-8c10-90dbb9ae1f09 11. Kunz JB, Lobitz S, Grosse R, et al.;

German Sickle Cell Disease Registry.Sickle cell disease in Germany: Resultsfrom a national registry. Pediatr BloodCancer 2020;67:e28130.

12. Cela E, Bellón JM, de la Cruz M, et al.;SEHOP-Hemoglobinopathies StudyGroup (Sociedad Española deHematología y Oncología Pediátricas).National registry ofhemoglobinopathies in Spain(REPHem). Pediatr Blood Cancer2017;64:26322.

13. Bardón Cancho EJ, García-Morín M,Beléndez C, et al. Update of the Spanishregistry of haemoglobinopathies in chil-dren and adults. Med Clin (Barc)2020;155:95-103.

14. National Health Service. NHSHaemoglobinopathy Annual report for2018-9. Available from:h t t p s : / / n h r . m d s a s . c o m / w p -content/uploads/2019/06/NHR_AnnualReport201819.pdf

15. Frontex. Migratory map - Europe.Available from:https://frontex.europa.eu/along-eu-bor-ders/migratory-map/

16. Nelson EC, Dixon-Woods M, BataldenPB, et al. Patient focused registries canimprove health, care, and science. BMJ.2016;354:i3319.

17. Taher AT, Weatherall DJ, CappelliniMD. Thalassemia. Lancet2018;391:155-67.

18. Cappellini MD, Cohen A, Porter J, etal., eds. Guidelines for the managementof transfusion dependent thalassemia(TDT) [Internet]. 3rd ed. Nicosia (CY):Thalassemia International Federation;2014.

19. Farmakis D, Giakoumis A,Angastiniotis M, Eleftheriou A. Thechanging epidemiology of the ageingthalassemia populations: A positionstatement of the ThalassemiaInternational Federation. Eur JHaematol 2020;105:16-23.

20. Aymé S, Rodwell C. The EuropeanUnion Committee of Experts on RareDiseases: three productive years at theservice of the rare disease community.Orphanet J Rare Dis 2014;9:30.

21. EuroBloodNet. Available from:https://eurobloodnet.eu/

22. Modell B, Khan M, Darlison M, et al.Improved survival of thalassemia majorin the UK and relation to T2* cardio-vascular magnetic resonance. JCardiovasc Magn Reson 2008;10:42.

23. Noronha SA, Sadreameli SC, StrouseJJ. Management of sickle cell disease inchildren. South Med J 2016;109:495-

Article

Non-co

mmercial

use o

nly

502.24. Powell RE, Lovett PB, Crawford A, et

al. A multidisciplinary approach toimpact acute care utilization in sicklecell disease. Am J Med Qual2018;33:127-31.

25. European Centre for Disease Preventionand Control (ECDC). Assessing theburden of key infectious diseases affect-ing migrant populations in the EU/EEA.Stockholm: ECDC; 2014.

26. Baldovino S, Moliner AM, Taruscio D,

et al. Rare diseases in Europe: from awide to a local perspective. Isr MedAssoc J 2016;18:359-63.

27. Moliner AM, Waligora J. The EuropeanUnion Policy in the field of rare dis-eases. Adv Exp Med Biol2017;1031:561-87.

28. Iolascon A, De Franceschi L,Muckenthaler M, et al. EHA researchroadmap on hemoglobinopathies andthalassemia: an update. Hemasphere2019;3:e208.

29. Weil LG, Charlton MR, Coppinger C, etal. Sickle cell disease and thalassemiaantenatal screening programme inEngland over 10 years: a review from2007/2008 to 2016/2017. J Clin Pathol2020;73:183-90.

30. Longo F, Corrieri P, Origa R, et al.Changing patterns of thalassemia inItaly: a WebThal perspective. BloodTransfus 2020. [Epup ahead of print].

Article

[Thalassemia Reports 2021; 11:9803] [page 21]

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