Die Digitalisierung der medizinischen Versorgung hat auch für Kinder- und Jugendärzte große Bedeutung. Wissenszuwachs in der klinischen Forschung, frühzeitige Entlassungen aus der stationären Behandlung und der Wunsch des Patienten bzw. seiner Sorgeberechtigten, gerade im Fall chronischer Krankheiten wohnortnah versorgt werden zu können, stellen den Allgemeinpädiater vor Herausforderungen. Im vorliegenden Beitrag wird ein Konzept vorgestellt, das speziell den Bedürfnissen der ambulanten Betreuung, der niederschwelligen Hinzuziehung von Experten, der beschleunigten Diagnosefindung und der Stärkung des Therapiebündnisses zwischen Arzt und Patient Rechnung trägt. Somit kann sich jede Kinder- und Jugendarztpraxis ein digitales Expertennetzwerk einrichten und die Praxisverwaltung durch eine bundeseinheitliche Praxis-App entlasten. Über diese beiden Grundpfeiler lassen sich barrierefrei Therapie-Apps freischalten, mit denen insbesondere Jugendliche und chronisch Kranke ihre Therapie- und Krankheitsdaten an die Praxis senden. Über die vorhandene Technik (Praxis-App auf Smartphone) kann eine Videosprechstunde vereinbart werden, in der der Arzt den Therapie- und Heilungsverlauf mit seinem Patienten abstimmt. Sämtliche virtuellen Unterstützungen erfolgen mit geringem technischen Aufwand (1. Download von PädExpert® für die Praxis, 2. Installation der Praxis-App „Mein Kinder- und Jugendarzt“ auf dem Smartphone des Patienten). Die digitale Technik unterstützt die persönliche Beratung des Allgemeinpädiaters und trägt zur Stärkung des Therapievertrauens bei. Gleichzeitig gewährleistet sie eine Qualitätsverbesserung für die ambulante Versorgung, etwa durch Zurverfügungstellung von leitlinienbasierten Computeralgorithmen und der Expertise virtuell hinzugezogener Spezialisten.

In Deutschland ist der Eisenmangel die häufigste Anämieursache. Die Erkrankung tritt v. a. bei Kleinkindern und in der Adoleszenz bei menstruierenden Mädchen auf. Bei typischer Ernährungsanamnese (verminderter Fleischverzehr) ist die Diagnose einfach zu stellen. Die wichtigsten Differenzialdiagnosen des Eisenmangels sind die heterozygoten α- und β-Thalassämien. Durch die Zuwanderung von Mitbürgern aus Risikogebieten für Hämoglobinopathien (v. a. Afrika, Südostasien, Mittelmeeranrainerstaaten) nimmt auch in Deutschland die Bedeutung der Sichelzellerkrankung, Hämoglobin(Hb)-E-Thalassämie und anderer Hämoglobinopathien zu. Unter optimaler Behandlung erreichen 85–90 % der Kinder mit Sichelzellanämie und 100 % der Kinder mit Thalassämie das Erwachsenenalter. Allerdings wurden diese Hämoglobinopathien noch nicht als Gesundheitsproblem in Deutschland erkannt. Um ein besseres Bewusstsein für Patienten mit Hämoglobinopathien zu schaffen, werden im vorliegenden Beitrag die klassischen Symptome, Diagnosekriterien, Differenzialdiagnosen und Therapieoptionen behandelt. Kinder mit Sichelzellerkrankung und rezidivierenden Schmerzkrisen profitieren vom frühen Beginn einer Hydroxycarbamidtherapie. Wichtig ist, dass auch in Deutschland ein Screening bei Neugeborenen auf Sichelzellerkrankung eingeführt wird. Dies ermöglicht eine antibiotische Prophylaxe mit Penizillin bis zum 5. Lebensjahr. Familien mit Herkunft aus einem Risikoland sollte eine Hb-Analyse mit dem Ziel der pränatalen Diagnostik im Fall der Trägerschaft für eine Hämoglobinopathie beider Eltern angeboten werden. Die dominant vererbte hereditäre Sphärozytose ist bei der kaukasischen Bevölkerungsgruppe die häufigste genetisch bedingte hämolytische Anämie (1:5000). Sie wird in 4 Schweregrade eingeteilt, die wesentlich die Indikation zur Splenektomie bestimmen. Aufgrund der erhöhten Rate an Postsplenektomieinfektionen wird neuerdings die nahezu vollständige Splenektomie gegenüber der vollständigen Milzentfernung empfohlen.

Among the German population with migration background there are probably 150 000-200 000 carriers of thalassemia (α und β) and sickle cell disease, respectively, who have no or little symptoms. Compared to neighboring countries the number of sickle cell (1000-1500) and thalassemia patients (500-600) in Germany is rather low. This may explain the fact that hemoglobin diseases are not yet considered a public health problem in Germany. With optimal care 85-90 % of children with sickle cell disease and 100 % of children with thalassemia reach adulthood. In order to increase awareness for patients with hemoglobin diseases we discuss the most pertinent disease manifestations of adult patients and point out possibilities to obtain information. Specialists in regional centers should be addressed for acute management problems. Up to now it is difficult for many adult sickle cell and thalassemia patients to find a physician well enough informed and experienced to take over the care of their complex disease. Many adult patients are still taken care of by pediatricians. Urgently needed are reference centers with experience in management of hemoglobin diseases who are qualified for training hematologists and who can assure the transition of these patients from pediatrics to adult medical care.

ZusammenfassungGefürchtete Risiken des post-Splenektomiebzw. Hyposplenie-Status sind die der Immuninkompetenz bzw. des Auftretens schwerer Infektionen (Post-Splenektomie-Sepsis, PSS). Milz-erhaltende Operationstechniken werden deshalb gehäuft bei Notfall- und elektiven Splenektomien eingesetzt. Trotzdem ist die Morbidität und Mortalität bei Milzdysfunktion bzw. Asplenie noch immer hoch. Bei Erkrankungen, die mit einer gestörten Milzfunktion assoziiert sind, sollte deshalb die Milzfunktion getestet werden (Szintigraphie, pitted-Erythrozytenzählung bzw. Nachweis Howel-Jolly-Körperchen) und wenn die Milzfunktion nachweisbar gestört bzw. fehlend ist, Präventivmaßnahmen zur Verhinderung von PSS getroffen werden.Prophylaxen gegen kapselbildende Bakterien und Impfmaßnahmen sind bei Asplenie bzw. Hypo splenie unumgänglich. Zudem sollten sich Patienten und Ärzte des lebenslangen PSS-Risikos bewusst sein und dass die sofortige Antibiotikatherapie nicht nur bei Kindern und immunkompromittierten Patienten nötig ist, sondern auch bei Tierbissen und Auslandsreisen. Bei asplenischen oder hypo splenischen Patienten muss jede Fieberepisode sofort und sehr sorgfältig untersucht und prompt behandelt werden.

Overwhelming Post-Splenectomy Infection (OPSI or PSS), most frequently caused by encapsulated Gram-positive pathogens, is a complication after splenectomy. Reasons for splenectomy include trauma, or malignant and non-malignant hematologic diseases. OPSI-inducing bacteria are mainly Streptococcus pneumoniae and less frequently Haemophilus influenzae, Neisseria meningitides and Gram-negative bacilli. There exist very efficient--albeit often neglected--strategies, how to prevent infections in patients after splenectomy. These include vaccination, prophylactic antibiotics (always for 3 years during childhood and adolescence) and prompt antibiotic treatment, if an infection is suspected. Patients need to know the nature and likelihood of PSS and they should seek immediate medical attention if they become ill or febrile. Each patient should carry at all times a letter or card documenting the splenectomy. With these measures and precautions, the PSS-risk can be significantly reduced or at best be completely avoided.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Background: Splenectomy predisposes patients to invasive disease from pneumococci, meningococci, and Haemophilus influenzae; immunization is mandatory. However, data on the impact of the splenectomy on vaccine immunogenicity are scarce.Methods: A total of 41 children with hereditary spherocytosis (aged 5.8-14.4 years) had complete (16) or near-total (25) splenectomy. All received one dose of monovalent meningococcal C conjugate vaccine (MCV-C) and, 2 months later, a tetravalent meningococcal polysaccharide vaccine (MPV-ACWY). Serum bactericidal activity and antibodies against serogroups A and C were determined before and after they received MCV-C, and 4 weeks after they received MPV-ACWY.Results: Before vaccination, only four of the 16 children who had a complete splenectomy were protected against serogroup A, compared with 15 of the 25 who had near-total splenectomy (P < 0.050), with the latter responding to immunization with significantly higher serogroup A serum bactericidal activity: geometric mean (95 per cent confidence interval) 1625.5 (49.9 to 3201.1) versus 980.6 (2.00 to 6204.1) (P < 0.050). All patients achieved putative protective serum bactericidal activity titres (at least 8) against serogroup, C.Conclusion: Near-total splenectomy provides a favourable immunological basis for natural and vaccine-induced protection against meningococcal serogroup A and C infections. Sequential meningococcal vaccination is immunogenic in patients splenectomized for hereditary spherocytosis.

Plasminogen activator inhibitor 1 is known to be elevated in patients with hepatic VOD after intensive chemotherapy. To re-establish endogenous fibrinolysis and to inhibit thrombin formation, we used non-APC (zymogen) to normalize PAI-1 levels. As a consequence of thrombin formation inhibition and the consecutive inhibition of the coagulation cascade, this treatment is expected to reduce the elevated D-dimer level. Six pediatric stem cell recipients with moderate or severe VOD after busulfan or total body irradiation conditioning regimen are reported here who were therapy-refractory to defibrotide or rt-PA therapy. All patients had low levels of PC activity (16-39%). The administration of PC (60-240 IU/kg) led to a rapid and sustained rise in PC activity (target level >80%) with near normalization of prothrombin and partial thromboplastin time in all patients. Elevated PAI-1 levels declined. Five of the six patients showed a good clinical response with prompt resolution of clinical, sonographic, and laboratory signs of hepatic blood flow obstruction, while one patient with severe VOD, as well as concomitant liver GVHD and CMV disease, had a slow but detectable response to PC therapy. All patients survived.

Die chirurgische Standardtherapie der hereditären Sphärozytose ist die komplette Splenektomie. Die Asplenie führt aber zu einem lebenslang bestehenden Immundefizit. Bisher praktizierte Milzteilentfernungen, bei denen 10-40 % einer vergrößerten Milz erhalten wurden, induzierten oft ein überproportionales Wachstum des Milzrestes, Rezidivhämolysen und Folgeoperationen. Unsere Hypothese war, ob ein wesentlich kleinerer Milzrest überhaupt überleben und Rezidive effektiv verhindern kann. Dazu entwickelten wir das standardisierte Operationsverfahren der near-total Splenektomie, bei dem ein Milzrest von 10 cm³ erhalten wird, was einem durchschnittlichen Resektionsausmaß von 98 % entspricht. Innerhalb eines 7-Jahres-Zeitraums wurden 38 Patienten mit hereditärer Sphärozytose nach diesem Verfahren operiert. Wir berichten über die Operationsmethode und vergleichen diese mit anderen milzerhaltenden chirurgischen Verfahren.

Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator or other promoter cis elements and have high G+C content, functional Sp1 binding sites and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization and exhibited defective binding of TATA-binding protein (TBP) and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression and a disease phenotype in vivo.

OBJECTIVEThis study was undertaken to describe the radiographic and MRI appearances of arthropathy of the knees in 14 patients with beta-thalassemia major undergoing chelation therapy with deferiprone (L1).MATERIALS AND METHODSAll available radiographs and MRI studies of the knees in 14 beta-thalassemia major patients (mean age, 16.3 years; age range, 7-33 years) undergoing chelation therapy with L1 were retrospectively assessed for changes in the synovium, cartilage, and bone. Imaging findings and signs of knee arthropathy were correlated with chelation therapy and average serum ferritin concentration.RESULTSNine (64%) of the 14 patients developed arthralgia of the knees during treatment with L1. Abnormal imaging findings were present in all symptomatic and two asymptomatic patients (12/14, 86%) and included joint effusion, subchondral bone irregularity, and patellar beaks. Additional MRI findings were thickening and enhancement of the synovium; hypointense bands in the synovium; irregularly thickened epiphyseal and articular cartilage overlying subchondral bone defects; and, on T2-weighted sequences, hyperintense articular cartilage lesions. The degree of knee symptoms at the time of imaging did not reflect the severity of cartilage and subchondral bone changes.CONCLUSIONRadiologic changes can be seen in L1-related arthropathy and should be recognized. MRI of the knees should be considered in symptomatic children and young adults with thalassemia undergoing L1 chelation therapy for iron overload.

Objective: The authors used a new surgical technique of near total splenectomy (NTS) and report their experience. Background Data: Total splenectomy is indicated for the treatment of patients with hereditary spherocytosis (HS), but may be complicated by severe infections. Studies have shown that partial or subtotal parenchymal resections can lead to excessive regeneration of the residual parenchyma and hemolysis, requiring total splenectomy in a significant portion of patients. Our hypothesis was that a more radical approach to resection permanently decreases recurrent hemolysis. Methods: This cohort study included 31 patients with HS who underwent NTS according to a new surgical procedure developed by the authors. The end criterion was to conserve a remnant spleen of 10 cm3 in size. Results: Patient age ranged between 2-21 years. Mean remnant volume was 10 cm3 (6 - 12 cm3), i.e. 98% (94 - 99%) were resected. Six-month to 6-year follow-up data was available on 29 patients, 2 suffered remnant necrosis. The mean Hb-value increased from 9,7 to 13,4 g/dl postoperatively. No patients required transfusions, developed gallstones or symptomatic hemolysis. Conclusions: This new technique of NTS is safe, effective and minimizes the late sequelae of secondary splenectomy.

Nonsense/stop mutations in the ankyrin-1 gene (ANK1) are a major cause of dominant HS (dHS) (frequency of 23% in German dHS patients). To date, no common mutation has been found and therefore a simple mutation screening is not feasible. The reduced expression of one cDNA allele in the (AC)n microsatellite polymorphism of the ankyrin-1 gene, as seen in about 20% of Czech patients with dHS, may identify candidates with a possible frameshift/nonsense mutation. In order to verify the efficiency of this screening we screened the ankyrin-1 gene of 22 Czech dHS patients for both the reduced cDNA allele expression in the frequent (AC)n and the common exonic 26/39 polymorphisms, as well as for polymerase chain reaction (PCR) single-stranded conformation polymorphisms in any one of the 42 exons of ANK1. Anomalous PCR products were sequenced. We found seven new ANK1 frameshift/nonsense mutations in nine patients with, but in none of six patients without, a reduced cDNA allele expression (efficiency of 78%). We conclude that screening of dHS patients for such a reduced allele expression in common ANK1 polymorphisms is an efficient procedure for the identification of candidates for frameshift/nonsense mutations in the ankyrin-1 gene.

Red cell (RBC) deformability and membrane-bound immunoglobulin G (IgG) were studied to better understand premature clearance of erythrocytes in hereditary spherocytosis. Averaged deformability profiles from cells having comparable cell age revealed that splenectomy was more beneficial for spectrin/ankyrin-deficient than for band 3-deficient RBCs. Splenectomy prevented an early loss of young cells in both types of deficiencies. It had an additional beneficial effect on spectrin/ankyrin-deficient but not band 3-deficient RBCs. It prolonged the survival of mature spectrin/ankyrin-deficient RBCs such that they lost their deformability more slowly than RBCs from patients who had not undergone splenectomy. Band 3-deficient RBCs lost their deformability at the same rate before and after splenectomy. In HS patients with band 3 deficiency who underwent splenectomy, RBC deformability inversely correlated with the number of RBC-bound IgG (up to 140 molecules per cell). In spectrin/ankyrin deficiency, RBC-bound IgG remained at control levels (60 IgG or less per cell). It appears that spectrin/ankyrin-deficient RBCs escaped opsonization by releasing band 3-containing vesicles because their band 3 content and deformability dropped in parallel with increasing cell age. Band 3-deficient RBCs did not lose band 3 with increasing cell age. Hence, it is possible that band 3 clusters required for bivalent binding of low-affinity-IgG, naturally occurring antibodies were retained in band 3-deficient RBCs with a relative excess of skeletal proteins but were released from spectrin/ankyrin-deficient RBCs, in which vesicle budding was facilitated by an impaired skeleton.

Asplenia in childhood may be congenital (e.g. Ivemark-syndrome) or acquired (functional hyposplenism in sickle cell disease; after splenectomy or bone marrow transplantation). Hereditary spherocytosis is the most common indication for splenectomy in childhood. Virtually every patient without spleen has a significantly increased risk of severe postsplenectomy infection (mostly caused by Streptococcus pneumoniae). Therefore, vaccinations against pneumococci, haemophilus influenzae and, under certain circumstances, meningococci are recommended. In addition a continuous prophylaxis with antibiotics should be performed for at least three years (or even longer depending on the disease) after splenectomy followed by lifelong interventional application of broad spectrum antibiotics in case of any unclear infection or high fever. This prophylaxis must be started as early as four months of age in sickle cell disease. In future the use of penicillin may be hampered by the growing resistance of pneumococci. Due to this fact the indication for splenectomy in childhood should be restricted to patients with hematologic disease (spherocytosis and other hemolytic anemias, chronic ITP etc.) and moderate to severe symptoms. It is unclear whether partial splenectomy for spherocytosis (and other hemolytic anemias) is an alternative regarding both longlasting reduction of hemolysis and prevention of severe infection. After trauma every effort should be undertaken to preserve a splenic remnant.

After splenectomy, the risk of patients with hereditary spherocytosis for sepsis and meningitis is increased for life (frequency 1.8% in our sample), in order to preserve the immunologic function of the spleen, we performed subtotal splenectomies in 18 children and juveniles with spherocytosis (length of observation: 6 months to 4 years). The residual spleen measured between 10 ml (intrasegmental resection) and 34-70 ml (segmental resection; 30% of age-matched normal size). Hemoglobin concentrations normalized after surgery in all cases. However, reticulocyte counts and bilirubin content, which were normal after surgery, showed a moderate increase during the postoperative observation period. In parallel, the residual spleen grew up to normal values. Phagocytic function of the remnant was nearly comparable to that of normal-sized spleen. In conclusion, subtotal splenectomy leads to a near-normalization of increased hemolysis during the current observation period. Our results indicate that patients with hereditary spherocytosis may show lasting improvement of anemia after subtotal splenectomy with conserved phagocytic splenic function; further follow-up observation must clarify whether the spleen distinctly regrows over normal limits and hemolysis reoccurs.