The impact of migration on the prevalence of thalassemia in a cohort of pregnant women in Berlin: a retrospective analysis of blood count parameters

Einleitung: Die Thalassämie gehört zu den häufigsten monogenen Erkrankungen welt-weit. Laut Schätzung von Angastiniotis und Modell sind ca. 4,5% der gesamten Weltbevölkerung Anlageträger für eine Hämoglobinopathie (= Thalassämie-Syndrome oder anomale Hämoglobinvariante) mit heterogener geographischer Verteilung. In Deutschland wird die Trägerschaft von Hämoglobinopathien in der Bevölkerung mit ca. 0,48% als relativ gering eingestuft. Aufgrund der angestiegenen Zuwanderung in den letzten Jahren, insbesondere aus Ländern mit höheren Thalassämie-Prävalenzen, ist ein Anstieg der Thalassämie-Prävalenz in der Bevölkerung Deutschlands zu erwarten. Eine Einschätzung der Entwicklung der Thalassämie-Trägerschaftszahlen kann wichtige Erkenntnisse zur Verbesserung verfügbarer Versorgungsinfrastrukturen, wie z.B. die Einführung eines Screenings auf Hämoglobinopathien im Rahmen der Schwangerschafts-vorsorge, beisteuern. Methodik: In der vorliegenden Dissertation prüfte ich mit Hilfe einer prädiktiven Formel die Blutbilddaten von 35.717 Schwangeren, die in den Jahren 2013 bis 2020 in Berlin entbunden haben, auf eine mögliche Thalassämie-Trägerschaft. Die Auswahl der einge-setzten prädiktiven Formel erfolgte nach einer Vorprüfung in einer Vergleichskohorte. Außerdem analysierte ich die Asyl- und die Zuwanderungszahlen, um ihre Entwicklung in den letzten Jahren zu bestimmen und mögliche Zusammenhänge mit der Entwicklung der geschätzten Thalassämie-Trägerschaft unter den eingeschlossenen Schwangeren zu evaluieren. Ergebnisse: Unter 47 geprüften prädiktiven Formeln zeigte die Ravanbakhsh-Formel Nr. 4 die besten Eigenschaften zum Screening der Blutbilddaten der Schwangeren auf das Vorliegen einer Thalassämie-Trägerschaft. Die mithilfe dieser Formel geschätzte Tha-lassämie-Trägerschaft war in allen untersuchten Jahren deutlich höher als die bisher be-kannte Prävalenz in der Bevölkerung Deutschlands (Spannbreite: 2,4% - 5,1%). Die Da-ten verdeutlichten außerdem einen zeitlich versetzten Anstieg in der geschätzten Tha-lassämie-Trägerschaft unter den Schwangeren nach dem Anstieg der Asylzahlen in den Jahren 2015 und 2016. Die Aufarbeitung der Zuwanderungsdaten aus dem letzten Jahr-zehnt in Zusammenhang mit den Herkunftsländern und deren Prävalenzprofil für die Thalassämie-Syndrome legt eine Trägerschaft-Zunahme in der Bevölkerung Deutsch-lands nahe. Schlussfolgerung: Die vorliegende Dissertation präsentiert die ersten Indizien für eine Zunahme der Thalassämie-Trägerschaft bei schwangeren Frauen in Berlin im Zuge des jüngsten Anstiegs der Einwanderungszahlen. Diese Ergebnisse verdeutlichen die Notwendigkeit von prospektiven Studien zur Entwicklung und Prüfung eines pränatalen Screening-Algorithmus auf Hämoglobinopathien-Trägerschaft im Rahmen der Schwangerschaftsvorsorge. Hierdurch könnte die bisher empfohlene Bestimmung der Hämoglobinkonzentration (Hb) in der aktuellen Mutterschafts-Richtlinien des Gemeinsamen Bundesausschusses (G-BA) durch ein frühes und effizientes Stufendiagnostik-Verfahren ersetzt werden.Introduction: Thalassemia is one of the most common monogenic diseases worldwide. According to an estimate by Angastiniotis and Modell approximately 4.5% of the world’s population are carrier for a hemoglobinopathy (= thalassemia-syndrome or abnormal hemoglobin variant) with heterogeneous geographical distribution. In Germany, the carrier rate of hemoglobinopathies (0.48%) in the population is relatively low. Due to increased immigration in the recent years especially from countries with higher thalas-semia prevalence, an increase in thalassemia prevalence in the current population of Germany is expected. An estimation of its development can provide important insights into necessary improvements of available care infrastructures for patients with hemoglobinopathies, such as the introduction of a screening for hemoglobinopathies as part of prenatal care. Methods: In this doctoral thesis, blood count data of 35,717 pregnant women who gave birth in Berlin between 2013 and 2020 was screened for the presence of a possible thalassemia trait using a predictive formula. The predictive formula used was selected after preliminary testing in a comparison cohort. In a further step, asylum and immigration data was also analyzed to determine their evolution in recent years and to evaluate possible associations with the development of estimated thalassemia carrier rates among included pregnant women. Results: Among 47 predictive formulas studied, Ravanbakhsh formula No. 4 showed the best characteristics for screening the blood count data of pregnant women. The estimated thalassemia carrier rate using this formula was significantly higher than the previously known prevalence in the German population in all years studied (range: 2.4% - 5.1%). The data also highlighted a temporally offset increase in estimated thalassemia carriers among pregnant women following the increase in asylum numbers in 2015 and 2016. Reappraisal of immigration data from the past decade in relation to countries of origin and their prevalence profile for thalassemia syndromes also suggests an increase in carrier rates in the German population. Conclusion: This doctoral thesis presents the first evidence for a possible increase in thalassemia carrier rates among pregnant women in Berlin in the wake of the recent increase in immigration. These results highlight the need for prospective studies to develop and test a prenatal screening algorithm for hemoglobinopathy carriers in the context of prenatal care. Thus, the currently recommended determination of hemoglobin concentration in the current maternity guidelines of the G-BA (The Federal Joint Committee = Gemeinsamer Bundesausschuss) could be replaced with an early and efficient stepwise diagnostic procedure

Allogeneic hematopoietic stem cell transplantation from sibling and unrelated donors in pediatric patients with sickle cell disease—A single center experience

HSCT is curative in SCD. Patients with HLA-identical sibling donor have an excellent outcome ranging from 90%-100% overall and event-free survival. However, due to the lack of matched sibling donors this option is out of reach for 70% of patients with SCD. The pool of potential donors needs to be extended. Transplantations from HLA-matched unrelated donors were reported to be less successful with shorter event-free survival and higher incidences of complications including graft-vs-host disease, especially in patients with advanced stage SCD. Here we report transplantation outcomes for 25 children with SCD transplanted using HLA-matched grafts from related or unrelated donors. Overall survival was 100% with no severe (grade III-IV) graft-vs-host disease and a 12% rejection rate. Mixed donor chimerisms only occurred in transplantations from siblings, while transplantations from unrelated donors resulted in either complete donor chimerism or rejection. Despite the small patient number, overall and disease-free survival for unrelated donor transplantations is excellent in this cohort. The advanced disease state, higher alloreactive effect and stronger immunosuppression in unrelated donor transplantations raises patient risk, for which possible solutions could be found in optimization of transplant preparation, graft manipulation or haploidentical transplantation using T cell receptor α/β-depleted grafts

Introduction of universal newborn screening for sickle cell disease in Germany - a brief narrative review

Sickle cell disease (SCD) is a severe non-malignant disorder of hemoglobin and is inherited in an autosomal-recessive manner [...

Benefits of a disease management program for sickle cell disease in Germany 2011–2019: the increased use of hydroxyurea correlates with a reduced frequency of acute chest syndrome

Sickle Cell Disease (SCD) is the most common monogenic disorder globally but qualifies as a rare disease in Germany. In 2012, the German Society for Paediatric Oncology and Haematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. Besides other activities, this consortium issued treatment guidelines for SCD that strongly favour the use of hydroxyurea and propagated these guidelines in physician and patient education events. In order to quantify the effect of these recommendations, we made use of claims data that were collected by the research institute (WIdO) of the major German insurance company, the Allgemeine Ortskrankenkasse (AOK), and of publicly accessible data collected by the Federal Statistical Office (Statistisches Bundesamt, Destatis). While the number of patients with SCD in Germany increased from approximately 2200 in 2011 to approximately 3200 in 2019, important components of the recently issued treatment guidelines have been largely implemented. Specifically, the use of hydroxyurea has more than doubled, resulting in a proportion of approximately 44% of all patients with SCD being treated with hydroxyurea in 2019. In strong negative correlation with the use of hydroxyurea, the frequency of acute chest syndromes decreased. Similarly, the proportion of patients who required analgesics and hospitals admissions declined. In sum, these data demonstrate an association between the dissemination of treatment guidelines and changes in clinical practice. The close temporal relationship between the increased use of hydroxyurea and the reduction in the incidence of acute chest syndrome in a representative population-based analysis implies that these changes in clinical practice contributed to an improvement in key measures of disease activity

Sickle cell disease in Germany: Results from a national registry

Background Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. Procedure A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. Results Most patients had homozygous SCD (HbSS 75.1%, HbS/beta-thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6-4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/beta thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. Conclusion With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD