German Paediatric Surveillance Unit Research Articles

Vitamin B12 Deficiency Newborn Screening.

Vitamin B12 deficiency (VitB12D) might cause neuro-developmental impairment in the first year of life. Newborn screening (NBS) for VitB12D was shown to be technically feasible and early treated infants developed favorably. This study aims to evaluate the impact of NBS in prevention of symptomatic infantile VitB12D. In a nationwide surveillance study in cooperation with the German Pediatric Surveillance Unit, incident cases with VitB12D (<12 months of age) were prospectively collected from 2021 to 2022. In total, 61 cases of VitB12D reported to German Pediatric Surveillance Unit were analyzed, either identified by NBS (N = 31) or diagnosed after the onset of suggestive symptoms (non-NBS; N = 30). Ninety percent of the infants identified by NBS were still asymptomatic, whereas the non-NBS cohort presented at median 4 month of age with muscular hypotonia (68%), anemia (58%), developmental delay (44%), microcephalia (30%), and seizures (12%). Noteworthy, symptomatically diagnosed VitB12D in the first year of life was reported 4 times more frequently in infants who did not receive NBS for neonatal VitB12D (14 in 584 800) compared with those screened for VitB12D as newborns (4 in 688 200; Fisher's Exact Test, odds ratio 4.12 [95% confidence interval: 1.29-17.18], P = .008). The estimated overall cumulative incidence was 1:9600 newborns per year for neonatal VitB12D and 1:17 500 for symptomatic infantile VitB12D. NBS for neonatal VitB12D may lead to a fourfold risk reduction of developing symptomatic VitB12D in the first year of life compared with infants without NBS.

Current practice of intracranial pressure monitoring in children with severe traumatic brain injury-a nationwide prospective surveillance study in Germany.

For management of severe traumatic brain injuries (sTBI) in children, the overall level of evidence to guide diagnostic and therapeutic procedures is low. Since 2016, international guidelines have subsequently suggested invasive intracranial pressure (ICP) monitoring in patients with initial Glasgow Coma Scale (GCS) ≤8. In Germany, ICP monitoring was an individual case decision from 2011 until the 2022 update of the German pediatric TBI guideline. The aim of this study was to evaluate current clinical practice of invasive ICP monitoring in Germany in children <10 years with respect to guideline recommendations. Anonymized clinical data on sTBI cases <10 years of age were collected in a nationwide prospective surveillance study via the German Pediatric Surveillance Unit ESPED from July 2019 until June 2022. Inclusion criteria for the surveillance study were sTBI (initial GCS ≤8) or neurosurgery following TBI. For this analysis, only cases with GCS ≤8 were subject to the present analysis. Descriptive analyses were performed to assess the proportion of ICP monitored patients and describe the cohort. Out of 217 reported cases, 102 cases met the inclusion criteria and thus qualified for ICP monitoring. Of these, 37 (36%) received ICP monitoring. Monitored patients were older, had lower median GCS values at presentation (4 vs. 5), higher mortality (32% vs. 22%), and were more frequently diagnosed with cerebral edema (68% vs. 37%). In children <10 years with sTBI, the present clinical management regarding ICP monitoring deviates from the current German national and international guidelines. The reasons remain unclear, with the low level of evidence in the field of ICP monitoring and the recency of changes in guideline recommendations as potential contributors. Prospective interventional studies should elucidate the benefit of ICP monitoring and ICP directed therapies to provide evidence-based recommendations on ICP monitoring.

Pediatric intensive care unit admissions network-rationale, framework and method of operation of a nationwide collaborative pediatric intensive care research network in Germany.

The Pediatric Intensive Care Unit Admissions (PIA) network aims to establish a nationwide database in Germany to gather epidemiological, clinical, and outcome data on pediatric critical illness. The heterogeneity of pediatric patients in intensive care units (PICU) poses challenges in obtaining sufficient case numbers for reliable research. Multicentered approaches, such as patient registries, have proven effective in collecting large-scale data. However, Germany lacks a systematic registration system for pediatric intensive care admissions, hindering epidemiological and outcome assessments. The PIA network intends to address these gaps and provide a framework for clinical and epidemiological research in pediatric intensive care. The network will interconnect PICUs across Germany and collect structured data on diagnoses, treatment, clinical course, and short-term outcomes. It aims to identify areas for improvement in care, enable disease surveillance, and potentially serve as a quality control tool. The PIA network builds upon the existing infrastructure of the German Pediatric Surveillance Unit ESPED and utilizes digitalized data collection techniques. Participating units will complete surveys on their organizational structure and equipment. The study population includes patients aged ≥28 days admitted to participating PICUs, with a more detailed survey for cases meeting specific criteria. Data will be collected by local PIA investigators, anonymized, and entered into a central database. The data protection protocol complies with regulations and ensures patient privacy. Quarterly data checks and customized quality reports will be conducted to monitor data completeness and plausibility. The network will evaluate its performance, data collection feasibility, and data quality. Eligible investigators can submit proposals for data analyses, which will be reviewed and analyzed by trained statisticians or epidemiologists. The PIA network aims to improve pediatric intensive care medicine in Germany by providing a comprehensive understanding of critical illness, benchmarking treatment quality, and enabling disease surveillance.

Factors influencing the success and complications of intraosseous access in pediatric patients—a prospective nationwide surveillance study in Germany

BackgroundVascular access is essential for the efficient treatment of critically ill children, but it can be difficult to obtain. Our study was conducted to analyze the feasibility and short-term safety of intraosseous access (IO) use as well as factors influencing its success and the incidence of complications in pediatric emergencies and resuscitation. This dataset of systematically documented intraosseous access attempts constitutes one of the largest published in the literature.MethodsTwo-year nationwide prospective surveillance study in Germany from July 2017 to June 2019. Pediatric hospitals anonymously reported the case data of all children aged 28 days to 18 years who arrived with or were treated with an intraosseous access to the German Pediatric Surveillance Unit (GPSU). The main outcomes were the occurrence of complications, overall success and success at the first attempt. The influence of individual factors on outcomes was evaluated using multivariate regression models.ResultsA total of 417 patients underwent 549 intraosseous access attempts. The overall rates of success and success at the first attempt were 98.3% and 81.9%, respectively. Approximately 63.6% of patients were successfully punctured within 3 min from the time of indication. Approximately 47.7% of IO access attempts required patient resuscitation. Dislocation [OR 17.74 (5.32, 59.15)] and other complications [OR 9.29 (2.65, 32.55)] occurred more frequently in the prehospital environment. A total of 22.7% of patients experienced minor complications, while 2.5% of patients experienced potentially severe complications.ConclusionWe conclude that intraosseous access is a commonly used method for establishing emergency vascular access in children, being associated with a low (age-dependent) rate of severe complications and providing mostly reliable vascular access despite a relatively high rate of dislocation.

Microarray Analysis of Group B Streptococci Causing Invasive Neonatal Early- and Late-onset Infection.

Group B Streptococcus is the leading cause of meningitis and sepsis in newborns. Until now, there is no data of fast and simple typing of group B Streptococcus virulence factors using a genetic microarray and comparing these data to clinical manifestations. A prospective active surveillance study was conducted via 2 independent and nationwide reporting systems, the German Pediatric Surveillance Unit (ESPED) and the Laboratory Sentinel Group at Robert Koch-Institute. Surveillance was performed between 2001 and 2003 and between 2008 and 2010. Typing of virulence factors, serotypes, pilus islands and alpha-like proteins was done by means of a newly developed microarray method. We evaluated 475 isolates of invasive neonatal infections. Predominant virulence factors were serotype III (63%), pilus island 2b and pilus island 1 (50%) and alp rib (64%) (alp - alpha-like protein, rib -resistance to proteases, immunity, group B). There was no significant change over time or geographically within Germany. Serotype III, pilus island 2b + 1 and alp rib showed significant associations with late-onset disease and meningitis, whereas alp 5 had a significant association with early-onset disease. Based on serotypes, pilus islands and alpha-like proteins, it was possible to cluster 86% of all isolates into 5 genetic groups. The molecular epidemiology of a large collection of invasive neonatal infections showed similar distributions, as shown in smaller cohorts before. The microarray used proved to be a fast and reliable technique. Using this new tool, we were able to cluster the isolates according to their virulence factors. The clusters showed a better association with clinical data than single virulence factors.

25 Years of ESPED as a Surveillance Tool for Rare Diseases in Children in Germany: A Critical Analysis

The German Paediatric Surveillance Unit (ESPED) was founded in 1992 to generate incidence data and detailed clinical descriptions of rare, childhood-onset diseases. Retrospective analysis of the ESPED epidemiological data collection from 1992-2017, and analysis of all published national and international publications originating from ESPED surveys. Center of Disease Control and Prevention (CDC) criteria for evaluating surveillance systems (simplicity, flexibility, timeliness, usefulness, data quality, representativeness, stability and acceptability) were adopted and applied to available ESPED data. Between 1992 and 2017 ESPED completed 96 prospective studies on rare diseases in children. The 3 most frequent clinical entities were: Infectious/communicable disease (n=30), neurological diseases (n = 14) and hematologic diseases (n=10). Studies resulted in 337 publications in national and international journals. The median impact factor of the 192 journal publications with (impact factor) was 2,587 (range 0,032-28,409). The highest impact factors were seen in the fields of endocrinology/metabolism (n=130; median IF=3,534), infectious diseases (n=83; median IF=3,131) and hematology (n=37; median IF=2,497). Our analysis indicates that ESPED surveys meet CDC quality standards. ESPED surveys are an important contributor in the field of clinical epidemiology in children with rare diseases. The high quality of ESPED surveys is reflected by high-impact publications in both national and international journals.

Cerebral Venous Thrombosis in Neonates, Children and Adolescents; Results from the German Pediatric Surveillance Unit for Rare Pediatric Diseases (ESPED)

INTRODUCTIONCerebral sinovenous thrombosis (CSVT) is a serious disease, that leads to longterm neurological sequaelae in the majority of survivors. There is uncertainty with regard to age specific individual risk factors, the impact of hereditary thrombophilia or underlying diseases on development of thrombosis or outcome. Previously published cohort studies have described epidemiology, treatment practices and outcomes, but those studies are limited due to small sample size or diversity of the populations included. Neonatal CSVT is seen as a disease entity different from cerebral thrombosis in older children with regard to etiology and outcome, evidence is lacking. OBJECTIVESTo evaluate the influence of transient risk factors and hereditary thrombophilia on clinical course, treatment practices and early outcome in a population based national cohort of children with CSVT. To study the influence of age (neonatal versus pediatric) on risk factors and outcome in CSVT. METHODSWe conducted a prospective nationwide surveillance study in pediatric patients <18 years through the hospital-based German Pediatric Surveillance Unit (ESPED). We included consecutive patients from 0-18 years of age admitted to hospitals in Germany with diagnosis of a first CSVT with an enrolment period between 2001-2010. Diagnosis was confirmed using MRI or CT imaging. Laboratory analysis of coagulation parameters have either been analyzed according to standardized thrombophilia screening protocols in the local hospitals or centrally in study center at the University of Muenster. We followed the course of disease over a period of 36 months. Follow up investigation included repetitive MRI or CT imaging and questionnaires on clinical outcome and recurrence. RESULTSA total of 599 patients, from birth to 18 years with a diagnosis of CSVT were enrolled in the study. We have observed a male predominance with 61%. 138 (23%) CSVT cases were diagnosed during the neonatal period, 461 (77%) patients were older than one month at time of diagnosis. In our cohort 40% of neonates and 20% of older infants/children developed thrombosis without identified underlying predisposing diseases. The majority of transient triggers associated with the development of thrombosis were local (mastoiditis, 18%) or systemic (sepsis, meningitis, 13%) infections or asparaginase administration during treatment for leukemia or lymphoma (12%). Outcome, dependent both on age at onset and existence of transient triggers was worse in children with spontaneous CSVT compared to triggered CSVT with regard to mortality rate (11 vs. 3%), patency of the veins and neurological impairment. Moreover, presenting symptoms as well as the clinical course differed between neonates and older infants/children. CONCLUSIONIn the pediatric population studied most of CSVT events were associated with infections as transient trigger. CSVT in neonates and children older than 1 months of age differed both with regard to underlying risk factors, treatment and outcome. Age specific, randomized controlled trials comparing treatment strategies are needed to optimize care in these patients. DisclosuresNo relevant conflicts of interest to declare.

Kawasaki Disease in Germany: A Prospective, Population-based Study Adjusted for Underreporting.

National estimates of Kawasaki disease (KD) incidence often do not include incomplete cases (diagnosed based on only laboratory or echocardiographic criteria), and/or they rely on retrospective case reports and data registries where underreporting is known to be a problem. We conducted a prospective nationwide KD surveillance study in children younger than 5 years through the hospital-based German Pediatric Surveillance Unit (ESPED). We accounted for underreporting through applying capture-recapture methodology in 2 federal states using hospital discharge records with KD International Statistical Classification of Diseases and Related Health Problems 10th revision code (ie, M30.3). KD diagnosis (complete and incomplete) was established according to the American Heart Association criteria, 2004. Incidence of KD, corrected for underreporting, was 7.2 of 100,000 in children younger than 5 years in Germany. Underreporting to ESPED was estimated at 37%-44%. Overall, 315 validated KD cases were reported. Of the 64 (20%) incomplete cases, 58% (37/64) were detected through echocardiographic findings and 42% (27/64) through laboratory criteria alone. Incomplete cases were younger than complete cases (1.2 vs. 2.0 years, P = 0.0001) and had more coronary aneurysms (43% vs. 11%, P = 0.0001). A substantial number of incomplete KD cases were diagnosed based on the laboratory and echocardiographic criteria only. This was particularly the case in relation to infants younger than 1 year-an age group known to have an increased risk of developing coronary aneurysms. In addition, we found a high rate of underreporting to national Pediatric Surveillance Units. We suggest that improved surveillance and development of better diagnostic tests remain a high priority.

Pseudotumor Cerebri in Childhood and Adolescence - Results of a Germany-wide ESPED-survey

No valid epidemiological data on Pseudotumor cerebri (PTC) in childhood and adolescence are available. This national survey aims to raise awareness of the PTC in paediatrics and contribute to a better understanding of age-related characteristics. Over 1 year (January-December 2008) new cases of PTC in childhood and adolescence from all paediatric hospitals in Germany were collected by the German Paediatric Surveillance Unit for rare diseases (ESPED). With a total of 61 cases, an annual incidence of 0.5 per 100 000 children <18 years was found. Children of all age groups were affected. A female preponderance and obesity was only found in adolescents. Clinical presentation was variable. Headaches represent the most common symptom affecting prepubertal children less frequently. A wide range of vision problems could be documented (papilledema, visual loss, double vision, visual field defects, disturbed colour and stereo vision). In 10 patients no papilledema was found. Comorbidities were reported in 23% of patients. 14 children gained remission after lumbar puncture without medication. Acetazolamide was the drug of choice, with relatively low dosages used. Escalation strategies were variable. 2 patients were treated invasively (sinus venous stent, LP shunt). PTC in childhood and adolescence appears to be as frequent as in the general population. Unspecific clinical characteristics and the broad spectrum of ophthalmologic findings emphasize the importance of a skilful neuroophthalmological investigation. Inconsistent therapeutic approaches are most likely due to a lack of diagnostic and therapeutic standards. Present diagnostic criteria and guidelines for the management of paediatric PTC do not sufficiently consider paediatric aspects.

Rotavirus Disease in Germany—A Prospective Survey of Very Severe Cases

Rotavirus (RV) gastroenteritis is a notifiable disease in Germany. The reports to the authorities contain few data concerning the severity of disease. The aims of this study were to determine incidence and outcome of very severe cases of RV disease. Cases of very severe RV disease were collected by the German Paediatric Surveillance Unit for rare diseases (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland) using anonymous questionnaires based on hospitalized patients between April 2009 and March 2011. Inclusion criteria were detection of RV antigen in feces, patient aged 0-16 years and 1 or more of the following criteria: intensive care treatment, hypernatremia or hyponatremia (>155 mmol/L or <125 mmol/L), clinical signs of encephalopathy (somnolence, seizures, apnea) and RV-associated death. During 2 years, 130 cases of very severe RV disease were reported, 101 of 130 were verified. Seventeen patients had nosocomial infection, of whom 14 were neonates in intensive care. Among those, 12 infants had verified or suspected necrotizing enterocolitis. Eighty-four community-acquired cases were reported, median age was 10.5 months (0-108 months). The median hospital stay was 6 days, and 48 patients needed intensive care treatment. Among children less than 5 years of age, the yearly incidence of community-acquired very severe RV disease was 1.2 of 100,000 (95% confidence interval: 0.9-1.4/100,000). A total of 26 of 84 and 10 of 84 patients had severe hypernatremia or hyponatremia, respectively, and 58 of 84 patients had signs of encephalopathy. Three deaths were reported (1 nosocomial and 2 community acquired). RV infection in Germany can have a life-threatening course. A substantial number are nosocomial infections.

Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population

Familial Mediterranean fever (FMF) is an autoinflammatory disease and belongs to the heterogeneous group of hereditary recurrent fever syndromes (HRFs). The aims of the study were to determine the incidence of FMF in Germany and to describe the spectrum of pyrin mutations and the clinical characteristics in children. A prospective surveillance of children with HRF including FMF was conducted in Germany during a time period of 3 years by the German paediatric surveillance unit for rare paediatric diseases (ESPED). Monthly inquiries were sent to 370 children's hospitals (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated pyrin mutations, and more than three self-limiting episodes of fever >38.5 °C with increased inflammation markers. In n1, 122 patients with FMF and 225 pyrin mutations were identified. Ninety-two of 122 (75 %) children were of Turkish origin. The minimum incidence of FMF was estimated to be 3 (95 % CI: 2.48-3.54) per 10(6) person-years in the whole children population and 55 (95 % CI: 46-66) per 10(6) person-years in Turkish children living in Germany. N1 U n2 amounted to 593 asymptomatic and symptomatic carriers of 895 mutations (overlap of 73 cases with 134 mutations). p.Met694Val (45 %), p.Met680Ile (14 %), p.Val726Ala (12 %), and p.Glu148Gln (11.5 %) were the most common pyrin mutations. Despite FMF being the most frequent of the HRFs, its incidence in Germany is low. Twenty-five to 50 FMF patients ≤ 16 years are newly diagnosed per year. The disease is most commonly observed in individuals of Turkish ancestry.

Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children

Autoinflammatory diseases (AIDs) are characterized by recurrent, self-limiting systemic inflammation. Disorders include hereditary recurrent fever (HRF) syndromes such as hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). To determine the incidence of HIDS and report clinical and genetic characteristics together with the underlying MVK genotypes in German children, a prospective active surveillance was conducted in Germany during a period of 3 years. Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to two laboratories (Laboratory-ESPED, n2) performing genetic analyses. Inclusion criteria were a MVK mutation-positive patient ≤16 years of age with more than three self-limiting episodes of fever >38.5°C associated with increased inflammation markers. Clinical, epidemiological, and genetic data were assessed via questionnaires. Eight out of 16 patients were identified in Clinic-ESPED (n1) and 15 of 16 in Laboratory-ESPED (n2). Clinical and laboratory surveys overlapped in 7 of 16 cases. Incidence of HIDS was estimated to be 0.39 (95% CI: 0.22, 0.64) per 10(6) person-years. HIDS symptoms generally started in infancy with recurrent fever episodes lasting 3-12 (median, 4.5) days and recurring every 1-12 weeks. Fever was accompanied by abdominal pain, vomiting, diarrhea, cervical lymphadenopathy, and sometimes by headache, skin and joint symptoms. The patients carried 11 different MVK mutations mostly in compound heterozygosity (75%, 12 out of 16). The most frequent mutation was p.Val377Ile (81%, 13 out of 16). In Germany, the incidence of HIDS is very low with 0.39 per 10(6) person-years.

Incidence of Intussusception in Early Infancy: A Capture-Recapture Estimate for Germany

Rotavirus (RV) vaccination with the first generation vaccine (Rotashield) has been associated with intussusception (IS). Reliable age specific baseline incidence data for children ≤6 months of age in particular is fundamental for further post marketing monitoring of potential effects of recently introduced new RV vaccines. IS incidence was estimated by a 2-source capture-recapture calculation (CRC) based on ESPED (German Paediatric Surveillance Unit) reports and on hospital discharge records for 2006 and 2007. ESPED as well as hospital records were validated according to the Brighton Collaboration's Group definition for definite IS. Children that have been treated for IS in a hospital in one of two states of Germany (North-Rhine Westphalia and Bavaria). The annual IS incidence for infants <1 year in Germany calculated with the CRC estimate in Germany was 61.7/100 000 (95% CI: 54.5-70.1). However, the incidence appeared to vary by month of age over a range of 19.2/100 000 cases (95% CI: 12.5-30.4) in the first 3 months of life to 98.5/100 000 cases (95% CI: 80.9-120.6) during the 6 (th) to 8 (th) month. The male to female ratio for infants was 1.7:1 (95%CI: 1.6-1.8). The average incidence estimate for IS in infants (< 1 year) confirms previous estimates in Germany and Switzerland. However, age specific baseline incidence estimates for IS substantially vary during the first year of life. This has to be taken into account when analysing episodes of IS potentially associated with RV vaccination.

Analysis of Cryopyrin-Associated Periodic Syndromes (CAPS) in German Children: Epidemiological, Clinical and Genetic Characteristics

Cryopyrin-associated periodic syndromes (CAPS) are rare disorders belonging to the group of hereditary periodic fever (HPF)syndromes. These auto-inflammatory diseases(AID) are characterized by recurrent episodes of inflammation with attacks of fever variably associated with serosal, synovial and / or cutaneous inflammation, usually in a self-limiting manner, and with a mostly monogenic origin. The aims were to determine the incidence of CAPS and the spectrum of mutations in the NLRP3 (formerly= CIAS1) gene and to describe the clinical manifestations. A prospective surveillance of children with CAPS was conducted in Germany during a time period of 3 years(2003-2006). Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to 2 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated NLRP3 mutation, more than 3 self-limiting episodes of fever > 38.5 ° C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires. 6 out of 14 patients were identified in Clinic-ESPED (n1) and 13 / 14 in Laboratory-ESPED(n2). Clinical and laboratory surveys overlapped in 5 of 14 cases. The incidence of CAPS in German children was estimated to be 3.43 per 10⁷ person-years. The patients carried 11 different NLRP3 mutations and were classified as MWS(n = 6), CINCA (n = 4), FCAS (n = 1) and undefined CAPS (n = 3). The incidence of CAPS in Germany is very low and corresponds to 2-7 newly diagnosed patients ≤ 16 years per year.

Evaluation der Prozess- und Ergebnisqualität der Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED)

The German paediatric surveillance unit (ESPED) was founded in 1992 with the objective to generate incidence data and to describe symptoms, diagnostic procedures, therapy and prevention for rare paediatric diseases requiring in hospital treatment. Every month the ESPED office sends a mailing card to the heads of all paediatric departments asking for the incident diagnosis of up to 12 conditions. In 2007 about 96% of the cards are returned. Each condition is represented by a principal investigator. Up till now surveillance of 52 conditions has been performed. Reports on the mailing card prompt immediate mailing of the full questionnaire. For 43 conditions the return rates were in the range of 70-100% and for 7 conditions <70% (unknown 2). The highest return rates were achieved if the principal investigator was supported by staff comprising at least two persons or if the mailing of the questionnaire was handled by the ESPED office. The scientific impact of the ESPED System was assessed by the impact factors of the journals, in which the respective ESPED studies were published. By August 31 (st) 2008 the investigators of 38 studies reported up to 7 publications per conditions surveyed. A total of 104 publications was reported: 27 of these appeared in journals without an impact factor. Among the 77 other publications 10 appeared in journals with an impact factor >10. Surveillance in ESPED has contributed significantly to high quality research on rare conditions in children.

Neurologic Varicella Complications Before Routine Immunization in Germany

Varicella is an acute febrile, highly infectious disease. We describe the incidence and types of neurologic complications in children up to 16 years old. Hospitalized varicella cases were prospectively captured by active nationwide surveillance through the German Pediatric Surveillance Unit for Rare Diseases from January 2003 to December 2004. Neurologic complications occurred in 232 (25.4%) of 918 hospitalized children with varicella, and were the most frequent reason for hospitalization. The median age was 4.2 years (interquartile range 2.5-5.9). The median duration of hospital stay was 6 days (interquartile range 3-11). Neurologic complications were more frequent (P=0.054) in immunocompetent (32%) than immunocompromised (4%) children. The most frequent diagnoses comprised acute cerebellar ataxia in 72 (31.0%), febrile convulsion in 69 (29.7%), meningoencephalitis in 52 (22.4%), cerebral convulsions in 21 (9.1%), syncope in 9 (3.9%), and cerebral vasculitis/infarction in 6 (2.6%) of all children with neurologic complications. Twenty-eight (12%) demonstrated sequelae (18 with ataxia, four with epilepsy, two with hemiparesis, three with cerebral nerve palsy, and one with dysesthesia). Three patients died. The yearly incidence of neurologic varicella-associated hospitalizations was estimated at 2.4 neurologic complications per 100,000 children, corresponding to about one neurologic complication in 2000 varicella cases.

Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics

TNF receptor 1-associated periodic syndrome (TRAPS) is a rare disease belonging to the heterogeneous group of hereditary periodic fever (HPF) syndromes. By their monogenic origins, the HPF syndromes are clearly differentiated from other periodic inflammatory episodes occurring in autoimmune, neoplastic and infectious diseases. We aim to determine the incidence of TRAPS and the spectrum of mutations in the TNFRSF1A gene, and to give a brief survey of clinical signs. A prospective surveillance of children with TRAPS was conducted in Germany during a time period of 3 years (2003-06). Monthly inquiries were sent to 370 children's hospitals by the German Pediatric Surveillance Unit (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were TNFRSF1A mutation-positive patients < or =16 years of age, more than three self-limiting episodes of fever >38.5 degrees C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires. Of the 23 cases included, 19 were identical in 20 clinical and 22 laboratory reports. The incidence of TRAPS in German children was estimated to be approximately 5.6 per 10(7) person-years. In 20 TRAPS patients of the Clinic-ESPED, median age of onset and duration of fever periods were 6 (range 1-16) years and 6.3 (range 2-24) days, respectively. Main symptoms were arthralgia, abdominal pain, lymphadenopathy, headache and skin involvement. The R92Q substitution was found in 19 (83%) of 23 cases. The incidence of TRAPS is low and corresponds to 6-10 newly diagnosed patients < or =16 years per year in Germany.

The Burden of Varicella Complications Before the Introduction of Routine Varicella Vaccination in Germany

The true burden of varicella complications in Germany is not known. We investigated the incidence and pattern of varicella complications in children and adolescents using 3 independent surveillance sources. Prospective nationwide surveillance in all pediatric hospitals through the German Pediatric Surveillance Unit [Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (ESPED)] was used to ascertain hospitalized varicella cases in children <or=16 years of age between January 2003 and December 2004. In the federal state, North-Rhine Westphalia (NRW), a practice sentinel network [European Diabetes Study Group (EURODIAB)] and pediatric hospital based International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) surveillance were additionally used to refine incidence estimates via capture-recapture methodology. A total of 918 hospitalized varicella patients (male-to-female: 55%/45%) with a median age of 3.3 years (interquartile range, 1.4-5.2) and a median hospital stay of 5 days (interquartile range, 3-8) were reported. Varicella associated complications occurred in 80% of the hospitalizations, most frequently being neurologic (25.4%), skin infectious (23.2%), and gastrointestinal tract complications (15.0%). Most hospitalizations (77%) occurred in previously healthy children. A predisposing condition existed in 207 children (23%): immunosuppression 7%, atopic dermatitis 7%, and other underlying chronic conditions 9%. Severity of varicella complications was related to increasing age and immunosuppression. Permanent or possible sequelae were reported in 15 (1.7%) and 78 (8.7%) of all children, respectively; 10 children died. Capture-recapture analyses yielded an incidence of 14.1 (95% confidence interval, 9.7-18.6) varicella hospitalizations/100,000 children, corresponding to 1996 (95% confidence interval, 1363-2629) varicella-related hospitalizations per year in Germany. These data show that the severity of varicella complications in healthy children has been previously underestimated.

Incidence and Clinical Presentation of Invasive Neonatal Group B Streptococcal Infections in Germany

Streptococcus agalactiae (group B Streptococcus) is an important cause of morbidity and mortality in newborn infants. So far, there have been no published data on the incidence, morbidity, and mortality of invasive neonatal group B Streptococcus infections in Germany. A prospective active surveillance study involving all of the pediatric hospitals, which reported their cases to the German Pediatric Surveillance Unit, and all of the microbiological laboratories serving pediatric hospitals, which reported their cases to the Laboratory Sentinel Group at Robert Koch Institute Berlin, was conducted between 2001 and 2003. Capture-recapture analysis was used to evaluate the completeness of reported neonatal invasive group B Streptococcus infections. We collected and analyzed data from 347 and 360 infants with invasive group B Streptococcus infection during the first 3 months of life, as reported by pediatricians to the German Pediatric Surveillance Unit and microbiologists to the Robert Koch Institute Berlin, respectively. Using capture-recapture analysis, we calculated an incidence of 0.47 per 1000 live births. Nearly 60% of the infants suffered from early-onset disease, and 16% of these presented with meningitis. In contrast, 61.8% of infants with late-onset disease presented with meningitis. Prematurity was present in 22.4% of early-onset disease and 39.7% of late-onset disease cases, respectively. A high proportion of infants suffered from sequelae because of group B Streptococcus infection at the time of discharge from the hospital. Most common sequelae were hydrocephalus and cerebral seizure. Case fatality rate was 4.3%. This study, which is the first to provide information on the current national incidence and morbidity of invasive group B Streptococcus infection in Germany, demonstrates remarkable country-specific variation in comparison with other European countries, which gather data in a similar fashion. Therefore, the importance of country-specific prevention guidelines has to be stressed.

Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany.

The lack of epidemiological data on the frequency and/or burden of organic acidurias (OA) and mitochondrial fatty acid transport and oxidation disorders (mtFATOD) is one reason for hesitation to expand newborn screening (NBS) by tandem mass spectrometry (MS-MS). From 1999 to 2000, the frequency of ten potentially treatable OA and mtFATOD was assessed by active nation-wide surveillance on cases presenting with clinical symptoms using the German Paediatric Surveillance Unit (ESPED) system. Case ascertainment was complemented by a second independent source: 3-monthly inquiries in the metabolic laboratories performing secondary selected screening for OA and mtFATOD. Frequency estimates for clinically symptomatic cases older than 7 days in a birth cohort of 844,575 conventionally screened children was compared to the frequency found in a cohort of 382,247 screened by MS-MS in Bavaria and Baden-Württemberg. The overall frequency of the ten conditions considered was 1:8,000 (95% CI 1:11,000-1:6,000) by MS-MS as compared to 1:23,000 (95% CI 1:36,000-1:17,000) in symptomatic cases presenting mainly with metabolic crisis. The contributions of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), other mtFATOD and OA were 29, 4 and 13 among the 46 cases identified by MS-MS, and 19, 1 and 13 among the 33 clinically symptomatic cases, respectively. Acute metabolic crisis, with a lethal outcome in four patients, was reported for 22/33 clinically symptomatic cases. No clinically symptomatic cases were reported from cohorts with screened by MS-MS. ten potentially treatable organic acidurias and mitochondrial fatty acid transport and oxidations disorders were more common than phenylketonuria with organic acidurias accounting for 28% of the cases detected by newborn screening and 39% of the cases identified on high risk screening. These conditions were related to considerable morbidity and mortality. Considerations for their inclusion in expanded newborn screening programmes might be warranted.