Can German Health Insurance Claims Data Fill Information Gaps in Rare Chronic Diseases: Use Case of Haemophilia A.

Claims data are increasingly discussed to evaluate health care for rare diseases (resource consumption, outcomes and costs). Using haemophilia A (HA) as a use case, this analysis aimed to generate evidence for the aforementioned information using German Statutory Health Insurance (SHI) claims data. Claims data (2017-2019) from the German SHI 'AOK Bayern - Die Gesundheitskasse' were used. Patients with ICD-10-GM codes D66 and HA medication were included in descriptive analyses. Severity levels were categorized according to HA medication consumption. In total, 257 patients were identified: mild HA, 104 patients (mean age: 40.0 years; SD: 22.9); moderate HA, 17 patients, (51.2 years; SD: 24.5); severe HA, 128 patients, (34.2 years; SD: 18.5). There were eight patients categorized with inhibitors (37.8 years; SD: 29.6). Psychotherapy was reported among 28.8% (mild) to 32.8% (severe) of patients. Joint disease was documented for 46.2% (mild) to 61.7% (severe) of patients. Mean direct costs per patient per year were 1.34× for mild, 11× for moderate, 81× higher for severe HA patients and 223× higher for inhibitor patients than the mean annual expenditure per AOK Bayern insurant (2019). German SHI data provide comprehensive information. The patient burden in HA is significant with respect to joint disease and psychological stress regardless of the HA severity level. The cost of HA care for patients is high. Large cost ranges suggest that the individual situation of a patient must be considered when interpreting costs. The main limitation of SHI data analysis for HA was the lack of granularity of ICD codes.

Trends in Pediatric Mild Traumatic Brain Injury During COVID-19-Related Lockdown-A Single-Center Study.

BACKGROUND: A relevant number of visits to pediatric emergency departments (pED) are associated with mild traumatic brain injury (mTBI). On March 16, 2020, the Bavarian government declared a first full lockdown (LD) related to the coronavirus (COVID-19) pandemic. AIM: The aim of the study was to investigate the impact of LD on pediatric mTBI. METHODS: Retrospective chart review of presentations to a pED due to mTBI. Study periods covered LD (03/17/2020 through 05/05/2020) and the same time in 2017, 2018, and 2019 as reference period (RP). Comparative analyses were performed by Chi-square or Fisher's exact test. RESULTS: Numbers of mTBI cases decreased by half. Age distribution did not differ. A significantly higher proportion of mTBI were related to falls at home (p = 0.001). Further, a higher rate of hospital admissions (p = 0.03), a higher proportion of intensive care unit admissions (p = 0.001), a longer duration of hospital stay (p = 0.02), and a higher rate of intracranial pathologies on neuroimaging were observed during LD (p = 0.007). CONCLUSION: The decrease in mTBI presentations is likely due to an absolute decrease in numbers related to the LD measures, combined with a hesitation to present very minor mTBI to the hospital, because of fear of being infected or not to put additional strain on the healthcare system during this healthcare crisis. On the other hand, data of those that presented with mTBI tend to reflect the more severe spectrum of mTBI.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

Recanalization strategies in childhood stroke in Germany.

Childhood arterial ischemic stroke (CAIS) is a rare event. Diverse etiologies, risk factors, symptoms and stroke mimics hamper obtaining a fast diagnosis and implementing immediate recanalization strategies. Over a period of 3 years (2015-2017), the data of 164 pediatric patients (> 28 days of life-18 years) with a first episode of AIS were submitted to a hospital-based nationwide surveillance system for rare disorders (ESPED). We report a subgroup analysis of patients who have undergone recanalization therapy and compare these data with those of the whole group. Twenty-eight patients (17%) with a median age of 12.2 years (range 3.3-16.9) received recanalization therapy. Hemiparesis, facial weakness and speech disturbance were the main presenting symptoms. The time from onset of symptoms to confirmation of diagnosis was significantly shorter in the intervention group (4.1 h vs. 20.4 h, p ≤ 0.0001). Only in one patient occurred a minor bleed. Cardiac disease as predisposing risk factor was more common in the recanalization group. Recanalization therapies are feasible and increasingly applied in children with AIS. High awareness, timely diagnosis and a large amount of expertise may improve time to treatment and make hyperacute therapy an option for more patients.

Consensus Recommendations for Intramuscular COVID-19 Vaccination in Patients with Hemophilia.

BACKGROUND: Currently available coronavirus disease 2019 (COVID-19) vaccines are approved for intramuscular injection and efficacy may not be ensured when given subcutaneously. For years, subcutaneous vaccination was recommended in patients with hemophilia to avoid intramuscular bleeds. Therefore, recommendations for the application of COVID-19 vaccines are needed. METHODS: The Delphi methodology was used to develop consensus recommendations. An initial list of recommendations was prepared by a steering committee and evaluated by 39 hemophilia experts. Consensus was defined as ≥75% agreement and strong consensus as ≥95% agreement, and agreement as a score ≥7 on a scale of 1 to 9. After four rounds, a final list of statements was compiled. RECOMMENDATIONS: Consensus was achieved that COVID-19 vaccines licensed only for intramuscular injection should be administered intramuscularly in hemophilia patients. Prophylactic factor replacement, given on the day of vaccination with a maximum interval between prophylaxis and vaccination of 24 hours (factor VIII and conventional factor IX concentrates) or 48 hours (half-life extended factor IX), should be provided in patients with moderate or severe hemophilia. Strong consensus was achieved that patients with mild hemophilia and residual factor activity greater than 10% with mild bleeding phenotype or patients on emicizumab usually do not need factor replacement before vaccination. Swelling, erythema, and hyperthermia after vaccination are not always signs of bleeding but should prompt consultation of a hemophilia care center. In case of injection-site hematoma, patients should receive replacement therapy until symptoms disappear. CONCLUSIONS: Consensus was achieved on recommendations for intramuscular COVID-19 vaccination after replacement therapy for hemophilia patients depending on disease severity.

Emergency care provided to refugee children in Europe: RefuNET: a cross-sectional survey study.

BACKGROUND: Refugee children and young people have complex healthcare needs. However, issues related to acute healthcare provision for refugee children across Europe remain unexplored. This study aimed to describe the urgent and emergency healthcare needs of refugee children in Europe, and to identify obstacles to providing this care. METHODS: An online cross-sectional survey was distributed to European healthcare professionals via research networks between 1 February and 1 October 2017 addressing health issues of children and young people aged <18 years fulfilling international criteria of refugee status, presenting to emergency departments. Survey domains explored (1) respondent's institution, (2) local healthcare system, (3) available guidance and educational tools, (4) perceived obstacles and improvements required, (5) countries of origin of refugee children being seen and (6) presenting signs and symptoms of refugee children. RESULTS: One hundred and forty-eight respondents from 23 European countries completed the survey, and most worked in academic institutions (n=118, 80%). Guidance on immunisations was available for 30% of respondents, and on safeguarding issues (31%), screening for infection (32%) or mental health (14%). Thirteen per cent reported regular teaching sessions related to refugee child health. Language barriers (60%), unknown medical history (54%), post-traumatic stress disorder (52%) and mental health issues (50%) were perceived obstacles to providing care; severity of presenting illness, rare or drug-resistant pathogens and funding were not. CONCLUSIONS: Many hospitals are not adequately prepared for providing urgent and emergency care to refugee children and young people. Although clinicians are generally well equipped to deal with most types and severity of presenting illnesses, we identified specific obstacles such as language barriers, mental health issues, safeguarding issues and lack of information on previous medical history. There was a clear need for more guidelines and targeted education on refugee child health.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.

Childhood Arterial Ischaemic Stroke: Clinical Presentation, Risk Factors and Management.

Childhood arterial ischaemic stroke (AIS) is a rare, but potentially life-threatening event which requires early diagnosis and adequate treatment. The reported significant time delay to childhood AIS diagnosis may be associated with low awareness, the more nonspecific clinical presentation as well as difficult clinical differentiation to more common "stroke mimics" and a less established "acute care structure" with delayed access to proper neuroimaging. Compared with adult stroke care, experiences with acute reperfusion therapies like thrombolysis and mechanical thrombectomy are promising but limited and not based on clinical trials. The etiological work-up is absolutely essential, as the child's individual risk profile determines acute management, secondary prevention, risk of recurrence and outcome. Follow-up care should be organized in a multidisciplinary setting covering all bio-psycho-social aspects to achieve the best integration of the child into its educational, later professional and social environments.

Health Care Transition of Adolescents and Young Adults with Haemophilia: the Situation in Germany and the Munich experience.

Patients suffering from haemophilia encounter various phases in life, in which individual needs, life situations, and self- and disease perception change rapidly. One of these phases spans from the beginning of puberty until early adulthood, in which individuals gain self-responsibility and reach independence and autonomy. In this challenging time that determines future health, adolescents and young adults need sustainable familiar and professional support. A change in health care team and treatment centre may expose adolescent patients to threats but also provides the possible opportunity to be well prepared. While there is emerging evidence that the so-called health care transition programmes are effective in maintaining quality of care in other disease areas, transition programmes for patients with haemophilia are still rare in Germany, and the evidence is limited. We describe the situation in Germany, discuss our experience in Munich and review some of the available guidance; we conclude that transition programmes should become a standard of care in haemophilia.

How Do I Counsel Parents of a Newly Diagnosed Boy with Haemophilia A?

With the recent approval of improved therapeutic options for patients suffering from haemophilia A such as the extended half-life, recombinant factor concentrates, non-factor VIII replacement therapies like Emicizumab and after consideration of the currently running clinical trials investigating even more advanced approaches, counselling of parents of a newly diagnosed boy with haemophilia A has not become less demanding. Parents need to be informed about the pathophysiology, the chronic nature and the potential risks that are commonly associated with this disease and its treatment, depending on disease severity. Above all, the safety and efficacy of the medicinal drug(s) to be used are of utmost importance, given the impact of non-virus-inactivated plasma-derived factor concentrates in the 1980s. As a consequence, the subsequent development and registration of recombinant clotting factors from mammalian, and recently, even human, cell cultures are seen by many as a breakthrough, although, regarding the product-type-dependent development of inhibitors in previously untreated patients, the discussion is still open. Clinical data for the humanised bispecific antibody Emicizumab in paediatric patients below 2 years of age without inhibitors who suffer from severe haemophilia A are currently limited.

Prevalence of Obesity in Young Patients with Severe Haemophilia and Its Potential Impact on Factor VIII Consumption in Germany.

Similar to the general population, overweight and obesity have increasingly become a medical and economic burden also in patients with haemophilia in industrialized nations. In this study in seven German haemophilia centres, we identified a prevalence of overweight and obesity of 25.2% among 254 young patients <30 years (median: 13 years; range: 0-30 years) with severe haemophilia A and without a history of inhibitors. The median FVIII dosage based on bodyweight was significantly higher in normal weight compared with overweight or obese patients (96.9 vs. 72.9 IU/kg/week, respectively; p < 0.0001). This suggests that an individualized dosing regime which might be based on FVIII pharmacokinetics, physical activity and pre-existing haemophilic arthropathy is applied rather than dosing by bodyweight only. The bleeding rates observed in obese (median: 1; range: 0-17) versus normal weight patients (median: 2; range: 0-28) did not differ significantly (p = 0.057). Lower bleeding rates might be due to reduced activity or expected higher FVIII plasma levels in overweight patients. Due to the increasing prevalence of overweight/obesity in patients with haemophilia an interdisciplinary approach for individualized haemophilia treatment and weight loss programmes might be helpful for optimal and economical treatment for this group of patients.

Perioperative management of hemostasis in children and adolescents.

Invasive procedures in children are in most cases elective and are carried out in otherwise healthy children. While many surgeries are still performed in a hospital, more and more procedures are defined as "outpatient procedures," leading to increased discussion about safety and risks. This review will examine common practices, review the sparse literature and provide recommendations regarding the identification of children with increased bleeding risk, planning for children with known bleeding disorders and strategies for perioperative management. In conclusion, after careful planning, surgeries can be performed safely even in children with known bleeding disorders.

[The remains of the day: A working day in a university children's hospital]. / Was vom Tage übrig bleibt ­ Arbeitsalltag einer Universitätsmedizin für Kinder und Jugendliche.

BACKGROUND: Limited time available for direct patient contact and a lot of time required for administrative duties have been reported by physicians working in adult medicine. OBJECTIVE: To characterize the typical daily work routine in a major pediatric university hospital. MATERIALS AND METHODS: A self-administered questionnaire was completed by physicians in the University Children's Hospital, Munich. The questionnaire captured the time spent on direct patient contact and on administrative tasks as well as the physicians' clinical experience and the location where the respective work was actually carried out (inpatient ward, outpatient emergency department, specialized outpatient clinic or department for developmental medicine). RESULTS: Most physicians (91.7 %) reported daily working hours beyond the regular schedule of 8.5hours. The proportion of time dedicated to direct patient contact was 31.2 % (95 % confidence interval: 25.2-37.1). Considering the number of patients in the work units, the average amount of time available for each individual patient varied between 14 minutes in the pediatric ward and 52 minutes in the department for developmental medicine. The reported times spent on patient contact did not significantly differ between physicians with > 5 years and those with ≤ 5 years of clinical experience. CONCLUSION: Although physicians in a university pediatric hospital work long daily hours, only restricted time is available for direct patient contact defined as physical examination of the child and face-to-face communication with patients and families.

Ultrasound Assisted Endovascular Thrombolysis in Adolescents: 2 Case Reports.

Descending iliofemoral thrombosis in children is a rare event. Anticoagulation therapy with low-molecular-weight-heparin is standard of care. However, patency cannot be achieved in all cases, increasing the risk for rethrombosis and postthrombotic syndrome. To reduce the risk of venous valve failure in adults, local catheter-directed thrombolysis is used to reopen vessels. Two adolescent girls (17 and 15 years old) presented with acute descending iliofemoral thrombosis of the left common iliac, external, and common femoral veins. Anticoagulation with enoxaparin was started until insertion of an EkoSonic Mach 4e catheter for ultrasound-assisted local thrombolysis with recombinant tissue plasminogen activator and administration of unfractionated heparin. Success was monitored by increases in D-dimer levels and ultrasound findings. After 24 hours respectively 48 hours, complete recanalization was obtained. No complication occurred except minimal local bleeding. Screening for hereditary thrombophilia revealed a heterozygous antithrombin mutation in 1 girl (ie, the 15-year-old). May-Thurner syndrome was identified in both girls, necessitating stenting of the left common iliac veins and continuation of anticoagulation therapy with enoxaparin and acetylsalicylic acid. No rethrombosis or complications occurred during the follow-up period. Ultrasound-assisted catheter-directed local thrombolysis with the EkoSonic Mach 4e system was effective in achieving immediate recanalization of the occluded veins and should be considered in children experiencing descending iliofemoral thrombosis. The fast recanalization might reduce the incidence of postthrombotic syndrome. May-Thurner syndrome is regularly found in these patients, and if present, requires stenting of the common iliac vein to avoid early reocclusion. However, long-term patency of iliac vein stenting in children remains to be examined.

[Haemostatic disorders in children]. / Hämostaseologie in der Pädiatrie.

Haemorrhagic and thrombotic events occur in both children and adults. The underlying causes are congenital or acquired disorders. In contrast to haemorrhagic disorders, inherited thrombotic disorders nearly exclusively in association with additional external risk factors lead to thrombotic events predominantly during the newborn period and adolescence. It is necessary to be aware of age-specific properties of coagulation in order to correctly interpret clinical and laboratory findings and to provide optimal care for children with haemorrhagic and thrombotic complications.

Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A. A patient-level meta-analysis.

The impact of treatment-related factors on inhibitor development in previously untreated patients (PUPs) with haemophilia A is still debated. We present the results of a collaborative, individual patient data meta-analytic project. Eligible data sources were published cohorts of PUPs for which patient-level data were available. The exposures of interest were factor (F)VIII type (recombinant [rFVIII] vs plasma-derived [pdFVIII]) and treatment intensity (≥ vs < 150 IU/kg/week) at first treatment. Family history of inhibitors, F8 mutations, age, treatment regimen (on-demand vs prophylaxis), secular trend and surgery were analysed as putative confounders using different statistical approaches (multivariable Cox regression, propensity score analyses, CART). Analyses accounted for the multi-centre origin of the data. We included 761 consecutive, unselected PUPs with moderate to severe haemophilia A from 10 centres in Egypt, Germany, Israel and Italy. A total of 27 % of patients developed inhibitors; 40 % and 22 % of patients treated with rFVIII and pdFVIII (unadjusted HR 2.2, 95 % CI 1.6-2.9), respectively; 51 % and 24 % of patients receiving high- and low-intensity treatment (unadjusted HR 2.9, 95 % CI 2.0-4.2), respectively. In adjusted analyses, only treatment intensity remained an independent predictor; the effect of FVIII type was largely due to confounding, but with a significant interaction between FVIII type and treatment intensity. This patient-level meta-analysis confirms, across different statistical approaches, that high-intensity treatment is a strong risk factor for inhibitor development. The possible role of FVIII type in subgroups is suggested by the test for interactions but could not be proven because of the limited subgroups sample sizes.

Influence of factor 5 rs6025 and factor 2 rs1799963 mutation on inhibitor development in patients with hemophilia A--an Israeli-German multicenter database study.

OBJECTIVE: The present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA]. PATIENTS AND METHODS: 216 patients with F8<2% born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. The first HA patient per family who presented for diagnosis was included in the present study. RESULTS: 32 of 216 children [14.8%] tested for F5/F2 carried either the F5 or the F2 variant. HRI occurred in 14 out of 32F5/F2-carriers compared with 40 of 184 without F5/F2. Multivariate analysis adjusted for F8 genotype, treatment intensity, first-line use of plasma derived FVIII versus recombinant FVIII concentrates revealed that the presence of F5/F2 independently increases the risk of HRI development to odds [OR] of 3.4. Large deletions in the F8 gene [OR: 5.10], patients from Israel [OR: 4.0], the increase of FVIII per one IU/kgbw [OR: 1.05] and birth year [OR: 1.12] were significantly associated with the risk to develop HRI. CONCLUSION: Data presented here suggest that HRI development is of multifactorial origin and that F5 and F2 mutations may contribute to this risk.

Risk factors for high-titer inhibitor development in children with hemophilia A: results of a cohort study.

Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, "intensive treatment moments" and "year of birth" (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for "year of birth", underlying risk gene mutations (HR/CI: 2.37/1.40-3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04-1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.