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Manas K Akmatov,* Jakob Holstiege,* Lotte Dammertz, Joachim Heuer, Claudia Kohring, Jörg Bätzing Department of Epidemiology and Health Care Atlas, Central Research Institute of Ambulatory Health Care, Berlin, Germany*These authors contributed equally to this workCorrespondence: Manas K Akmatov; Jakob Holstiege, Tel +49 3040052414 ; +49 3040052467, Fax +49 304005272414 ; +49304005272467, Email makmatov@zi.de; jholstiege@zi.dePurpose: We aimed to examine possible variations in diagnostic prevalence of hay fever between urban and rural regions as well as in age-specific temporal developments.Patients and Methods: We used nationwide outpatient claims data from the years 2010 to 2019. The data contain information for all individuals with statutory health insurance (SHI) in Germany who were treated at least once in respective years (n = 71,410,121 in 2019). Individuals with a confirmed diagnosis of hay fever were defined as prevalent cases. We examined the association between the degree of urbanization and age- and sex-standardized prevalence of hay fever. We used the age- and sex-structure of SHI insurees in the year 2010 as a reference population for direct standardization.Results: The standardized prevalence of hay fever increased from 6.2% in 2010 to 7.2% in 2019, corresponding to a relative increase of 16%. However, we observed a clear decrease in prevalence among children, with the strongest relative reduction in young children (0– 2 years: − 53%). The standardized prevalence in the total population in 2019 was lowest in rural areas with a low population density (6.6%) and highest in big urban municipalities (7.8%). In stark contrast, prevalence in 0– 14-year-olds was lowest in big urban municipalities (4.3%).Conclusion: We observed a decrease in the prevalence of hay fever in children and increase in the older age groups. A clear urban–rural association observed over years may be explained by environmental factors. Deviations from this general regional pattern in children of the age group 0– 14 years may be explained by differing age-specific risk factors of hay fever.Keywords: diagnostic prevalence, hay fever, urban–rural differences, statutory health insurance, temporal trends, Germany

Empirical data about contact frequencies of children is needed for estimating parameters in mathematical modelling studies that investigate the effect of targeting influenza intervention to children. A survey about the social contacts of school children was conducted in a primary school in Germany. The distribution of the daily numbers of contacts was stratified by age of the contacted person and by weekday. A negative binomial regression analysis was performed to investigate factors that influence contact behaviour. Using logistic regression analysis we examined the relationship between the numbers of private contacts and having been ill in the last 6 months. We computed effective contact numbers to take the heterogeneity in contact behaviour into account in assessing the contribution of children's contacts to the overall transmission of an infection. The possible effects of intervention measures such as school closure and vaccination on the transmission of respiratory-spread agents to other age groups are discussed. [ABSTRACT FROM AUTHOR]

Background: The epidemiological characterization of endometriosis, particularly with regard to its incidence, has been inadequate to date both in Germany and other countries. The goal of this study was to determine trends in the incidence of diagnosed endometriosis and changes in age structure at the time of first diagnosis over the period 2014-2022., Methods: Nationwide claims data from physicians in private practice, obtained according to relevant German law (§ 295 SGB V), were used to identify the population at risk for a first assured diagnosis of endometriosis (ICD-10-GM: N80) during each year of the study period, consisting of women and girls aged 10-52 who were insured by the statutory health insurance system and for whom at least two years of prior observation were possible. Patients were defined as incident if they were documented as having received a first confirmed diagnosis of endometriosis, according to the case definition, during the study year. The case definition comprised multiple options for validating the diagnosis., Results: The incidence of diagnosed endometriosis rose over the period of the study from 2.8 per 1000 persons at risk in 2014 to 4.1 per 1000 in 2022, corresponding to a 44% relative increase. There was also a marked shift in age-specific incidence toward higher values at younger ages: the median age at diagnosis fell from 37 years (2014) to 34 (2022)., Conclusion: This is the first study providing nationwide population-based data on the incidence of endometriosis in Germany. The observed rise in newly diagnosed cases is presumably mainly due to an increased awareness of endometriosis and to the growing recognition of the disease.

Introduction: Routine immunization programs have focused on increasing vaccination coverage, which is equally important for decreasing vaccine-preventable diseases (VPDs), particularly in low- and lower-middle-income countries (LMICs). We estimated the trends and projections of age-appropriate vaccination coverage at the regional and national levels, as well as place of residence and wealth index in LMICs., Methods: In total, 174 nationally representative household surveys from 2000 to 2020 from 41 LMICs were included in this study. Bayesian hierarchical regression models were used to estimate trends and projections of age-appropriate vaccination., Results: The trend in coverage of age-appropriate Bacillus Calmette-Guérin (BCG), third dose of diphtheria, tetanus, and pertussis (DTP3), third dose of polio (polio3), and measles-containing vaccine (MCV) increased rapidly from 2000 to 2020 in LMICs. Findings indicate substantial increases at the regional and national levels, and by area of residence and socioeconomic status between 2000 and 2030. The largest rise was observed in East Africa, followed by South and Southeast Asia. However, out of the 41 countries, only 10 countries are estimated to achieve 90% coverage of the BCG vaccine by 2030, five of DTP3, three of polio3, and none of MCV. Additionally, by 2030, wider pro-urban and -rich inequalities are expected in several African countries., Conclusion: Significant progress in age-appropriate vaccination coverage has been made in LMICs from 2000 to 2020. Despite this, projections show many countries will not meet the 2030 coverage goals, with persistent urban-rural and socioeconomic disparities. Therefore, LMICs must prioritize underperforming areas and reduce inequalities through stronger health systems and increased community engagement to ensure high coverage and equitable vaccine access., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Islam, Rahman, Rahman, Abe, Akmatov and Hashizume.)

Objective: We aimed to identify spatial clusters of high HIV prevalence in Germany., Methods: Using nationwide outpatient claims data comprising information of about 88% of the total German population (N = 72 041 683), we examined spatial variations and spatial clusters of high HIV prevalence at the district level (N = 401). People with HIV were identified using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10 codes) B20, B22, and B24 (HIV disease) documented as 'confirmed'., Results: Among 72 041 683 people with statutory health insurance in Germany in 2021, 72 636 had diagnosed HIV, which corresponds to a prevalence of 101 per 100 000 individuals (0.10%). Of these, 56 895 were males (78%). At a district level, the HIV prevalence varied by a factor of 32 between 13 in a rural district in Bavaria and 417 per 100 000 individuals in the German capital, Berlin. The spatial autocorrelation coefficient was 0.24 (p < 0.0001, Global Moran's I). Several high-prevalence spatial clusters of different sizes were identified, mostly located in western Germany. The largest cluster comprised eight districts in the southern part of Hesse, including the city of Frankfurt and the city of Mainz in Rhineland-Palatinate. The second cluster consisted of four districts in North Rhine-Westphalia, including the cities of Cologne and Düsseldorf. Two districts in southern Germany (Mannheim and Ludwigshafen) formed the third cluster. Only urban districts were observed in spatial clusters of high HIV prevalence., Conclusions: The current study identified for the first time spatial clusters with high HIV prevalence in Germany. This understanding is of particular importance when planning the general and specialized medical care of patients with HIV and to support preventive measures., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions., Methods: We applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell's palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison., Results: Of the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89-0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89-0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation., Conclusions: Changes in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation., (© 2023. The Author(s).)

Background and Purpose: Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder that is strongly associated with age. The aim of the present study was to describe current sex- and age-specific trends and regional differences in the incidence of IPD diagnosed in older people in Germany., Methods: This study was based on nationwide outpatient claims and drug prescription data from the German Statutory Health Insurance, covering approximately 87% of the general population. We conducted a cohort study in patients aged 50 years or older with observation time of at least 4 years. To assess the robustness of nationwide annual IPD incidence trends from 2013 to 2019, three case definitions with varying levels of stringency regarding coded outpatient diagnoses and drug prescriptions were applied., Results: In 2019, the population at risk comprised 30,575,726 persons. Using the primary and most specific case definition, annual age- and sex-standardized cumulative IPD incidence decreased stepwise from 137 (2013) to 106 (2019) new cases per 100,000 persons. The decline in incidence was seen in both sexes, in all age groups and in the majority of German regions. The relative decrease (2013-2019) in the annual age- and sex-standardized IPD incidence varied from 23% to 28% among case definitions., Conclusion: Our findings indicate a nationwide decline in the age- and sex-standardized incidence of IPD from 2013 to 2019 in Germany. This trend was consistent using different case definitions. Further research is needed to elucidate the factors underlying this trend., (© 2023 European Academy of Neurology.)

Historically, viral hepatitis has been a considerable public health problem in Central Asian countries, which may have worsened after the dissolution of the Soviet Union. However, up-to-date seroepidemiological studies are lacking. The aim of the present study was, therefore, to provide current estimates of the seroprevalence of viral hepatitis in Kyrgyzstan, one of the economically least developed countries in the region. We conducted a population-based cross-sectional study in 2018 in the capital of Kyrgyzstan, Bishkek ( n = 1075). Participants, children and adults, were recruited from an outpatient clinic. The data were collected during face-to-face interviews. A blood sample (6 mL) was collected from each participant and tested with ELISA for the presence of serological markers for five viral hepatitides (A, B, C, D, and E). Post-stratification weighing was performed to obtain nationally representative findings. The overwhelming majority of the study participants were positive for anti-HAV (estimated seroprevalence, 75.3%; 95% confidence interval, 72.5-77.9%). The weighted seroprevalence estimates of HBsAg, anti-HCV, and anti-HDV were 2.2% (1.5-3.3%), 3.8% (2.8-5.1%), and 0.40% (0.15-1.01%), respectively. Anti-HEV seropositivity was 3.3% (2.4-4.5%). Of the 33 HBsAg-positive participants, five (15%) were anti-HDV-positive. Our study confirms that Kyrgyzstan remains a highly endemic country for hepatitis virus A and C infections. However, seroprevalences of HBV and HDV were lower than previously reported, and based on these data, the country could potentially be reclassified from high to (lower) intermediate endemicity. The observed anti-HEV seroprevalence resembles the low endemicity pattern characteristic of high-income countries.

Background: This claims-based study aimed to assess recent nationwide trends in pediatric incidence of atopic diseases in Germany., Methods: Incidence of atopic dermatitis, asthma, and hay fever was assessed from 2013 to 2021 in annual cohorts of 0- to 17-year-old children and adolescents with statutory health insurance (N = 11,828,525 in 2021)., Results: Incidence of atopic dermatitis remained largely unchanged (15.2 cases per 1000 children in 2021) while hay fever incidence exhibited a fluctuating trend over the study period and amounted to 8.8 cases per 1000 in 2021. Asthma incidence decreased gradually between 2013 (12.4/1000) and 2019 (8.9/1000). This downward trend was followed by a further disproportionate reduction from 2019 to 2020 (6.3/1000) and a re-increase in 2021 (7.2/1000)., Conclusion: The findings complement nationwide prevalence surveys of atopic diseases in children and adolescents in Germany. Knowledge about temporal variations in risk of atopic diseases are crucial for future investigations of explanatory factors to enhance the development of preventive measures. While asthma incidence followed a declining trend throughout the study period, an unprecedentedly strong reduction in pediatric asthma risk was observed in 2020, the first year of the COVID-19-pandemic., Competing Interests: The authors reported no financial interests or potential conflicts of interest related to this study., (© 2023 The Author(s).)

Background: Venous thromboembolism (VTE) and arterial thromboembolism (ATE) are considered as two separate disease-entities. In recent years, studies have reported clear associations between VTE and atherosclerosis. We aimed to evaluate the long-term risk of ATE in VTE patients in comparison to controls without VTE., Methods: Nationwide outpatient claims data of all inhabitants with statutory health insurance in Germany were used for secondary data analysis between the years 2011 and 2020. Patients treated in 2013 were stratified by VTE event, and groups were 1:2-matched by age and sex. The hazard for an ATE event in a 5-year follow-up period between patients with and without VTE was calculated with multivariable Cox regression adjusted for age, sex, cardiovascular risk factors, and comorbidities., Results: Of 69,699,277 individuals treated in the year 2013 by German physicians in outpatient care, in total 686,382 individuals (age 59.8 ± 17.5 years, 65.4 % females) were included comprising 228,794 patients with VTE and 457,588 controls without VTE. VTE patients more often had cardiovascular risk factors (81.6 % vs. 62.2 %) and traditional VTE risk factors. The occurrence of ATE events during follow-up was 1.8 %-points higher in VTE patients in comparison to the controls (9.7 % vs. 7.9 %). VTE events were independently associated with increased occurrence of ATE events within follow-up (HR adjusted 1.19 [99%CI 1.16-1.23], p < 0.0001)., Conclusions: Patients with a VTE event have an increased long-term risk for subsequent arterial cardiovascular events. Large prospective cohorts are needed to identify patient subgroups with a very high ATE risk after VTE., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karsten Keller reports no conflict of interests. Claudia Kohring reports no conflict of interests. Ioannis T. Farmakis reports no conflict of interests. Luca Valerio reports no conflict of interests. Stefano Barco received lecture/consultant fees from Bayer HealthCare, Concept Medical, BTG Pharmaceuticals, INARI, Boston Scientific, and LeoPharma; institutional grants from Boston Scientific, Bentley, Bayer HealthCare, INARI, Medtronic, Concept Medical, Bard, and Sanofi; and economical support for travel/congress costs from Daiichi Sankyo, BTG Pharmaceuticals, and Bayer HealthCare, outside the submitted work. Jörg Bätzing reports no conflict of interests. Manas K. Akmatov reports no conflict of interests. Stavros Konstantinides reports institutional grants and personal lecture/advisory fees from Bayer AG, Daiichi Sankyo, and Boston Scientific; institutional grants from Inari Medical; and personal lecture/advisory fees from MSD and Bristol Myers Squibb/Pfizer. Thomas Münzel reports no conflict of interests. TM is PI of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. Lukas Hobohm received lecture/consultant fees from MSD and Actelion, outside the submitted work. Jakob Holstiege reports no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: The prodromal phase of Parkinson disease (PD) may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk., Objective: To identify the association of a subsequent diagnosis of PD with a range of risk factors and prodromal features, including lifestyle factors, comorbidities, and potential extracerebral manifestations of PD., Design, Setting, and Participants: This was a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2011, and December 31, 2020. Included were patients with incident diagnosis of PD without a previous diagnosis of parkinsonism or dementia and controls matched 1:2 for age, sex, region, and earliest year of outpatient encounter., Exposures: Exposures were selected based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD., Main Outcomes and Measures: Previously postulated risk factors and prodromal features of PD, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding., Results: A total of 138 345 patients with incident PD (mean [SD] age, 75.1 [9.8] years; 73 720 male [53.3%]) and 276 690 matched controls (mean [SD] age, 75.1 (9.8) years; 147 440 male [53.3%]) were identified. Study participants were followed up for a mean (SD) of 6.0 (2.0) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, odds ratio (OR), 1.62; 95% CI, 1.36-1.92; alcohol misuse, OR, 1.32; 95% CI, 1.21-1.44; hypertension, OR, 1.29; 95% CI, 1.26-1.31; anosmia, OR, 2.16; 95% CI, 1.59-2.93; and parasomnias (including RBD), OR, 1.62; 95% CI, 1.42-1.84. In addition, there were associations with restless legs syndrome (OR, 4.19; 95% CI, 3.91-4.50), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), epilepsy (OR, 2.26; 95% CI, 2.07-2.46), migraine (OR, 1.21; 95% CI, 1.12-1.29), bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67), and schizophrenia (OR, 4.48; 95% CI, 3.82-5.25). The following diagnoses were also found to be associated with PD: sensory impairments beyond anosmia, such as hearing loss (OR, 1.14; 95% CI, 1.09-1.20) and changes of skin sensation (OR, 1.31; 95% CI, 1.21-1.43). There were also positive associations with skin disorders (eg, seborrheic dermatitis, OR, 1.30; 95% CI, 1.15-1.46; psoriasis, OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders (eg, gastroesophageal reflux, OR, 1.29; 95% CI, 1.25-1.33; gastritis, OR, 1.28; 95% CI, 1.24-1.33), conditions with a potential inflammatory component (eg, seronegative osteoarthritis, OR, 1.21; 95% CI, 1.03-1.43), and diabetes types 1 (OR, 1.32; 95% CI, 1.21-1.43) and 2 (OR, 1.24; 95% CI, 1.20-1.27). Associations even 5 to 10 years before diagnosis included tremor (odds ratio [OR], 4.49; 95% CI, 3.98-5.06), restless legs syndrome (OR, 3.73; 95% CI, 3.39-4.09), bipolar disorder (OR, 3.80; 95% CI, 2.82-5.14), and schizophrenia (OR, 4.00; 95% CI, 3.31-4.85)., Conclusions and Relevance: Results of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.

Seasonal influenza outbreaks, especially in high-risk groups such as the elderly, represent an important public health problem. Prevailing inadequate efficacy of seasonal vaccines is a crucial bottleneck. Understanding the immunological and molecular mechanisms underpinning differential influenza vaccine responsiveness is essential to improve vaccination strategies. Here we show comprehensive characterization of the immune response of randomly selected elderly participants (≥ 65 years), immunized with the adjuvanted influenza vaccine Fluad. In-depth analyses by serology, multi-parametric flow cytometry, multiplex and transcriptome analysis, coupled to bioinformatics and mathematical modelling, reveal distinguishing immunological and molecular features between responders and non-responders defined by vaccine-induced seroconversion. Non-responders are specifically characterized by multiple suppressive immune mechanisms. The generated comprehensive high dimensional dataset enables the identification of putative mechanisms and nodes responsible for vaccine non-responsiveness independently of confounding age-related effects, with the potential to facilitate development of tailored vaccination strategies for the elderly., (© 2022. The Author(s).)

The aim of the study was to examine whether the COVID-19 pandemic had any effect on antibiotic prescription rates in children in Germany. Using the nationwide outpatient prescription data from the Statutory Health Insurance from 2010 to 2021, changes in the monthly prescriptions of systemic antibiotics dispensed to children aged 0-14 years were examined ( n = 9,688,483 in 2021). Interrupted time series analysis was used to assess the effect of mitigation measures against SARS-COV-2, introduced in March and November 2020, on antibiotic prescription rates. In the pre-pandemic period, the antibiotic prescription rates displayed a linear decrease from 2010 to 2019 (mean annual decrease, -6%). In 2020, an immediate effect of mitigation measures on prescription rates was observed; in particular, the rate decreased steeply in April (RR 0.24, 95% CI: 0.14-0.41) and November 2020 (0.44, 0.27-0.73). The decrease was observed in all ages and for all antibiotic subgroups. However, this effect was temporary. Regionally, prescription rates were highly correlated between 2019 and 2020/2021. Substantial reductions in antibiotic prescription rates following the mitigation measures may indicate limited access to medical care, changes in care-seeking behavior and/or a decrease of respiratory infections. Despite an all-time low of antibiotic use, regional variations remained high and strongly correlated with pre-pandemic levels., Competing Interests: The authors declare no conflicts of interest.

IntroductionEvidence of nationwide and regional morbidity of Lyme borreliosis (LB) in Germany is lacking.AimsWe calculated the total number of incident LB cases in Germany in 2019, compared regional variations, investigated the extent of possible under-reporting in notification data and examined the association between high incidence areas and land cover composition.MethodsWe used outpatient claims data comprising information for people with statutory health insurance who visited a physician at least once between 2010 and 2019 in Germany (n = 71,411,504). The ICD-10 code A69.2 was used to identify incident LB patients. Spatial variations of LB were assessed by means of Global and Local Moran's Index at district level. Notification data were obtained for nine federal states with mandatory notification from the Robert Koch Institute (RKI).ResultsOf all insured, 128,177 were diagnosed with LB in 2019, corresponding to an incidence of 179 per 100,000 insured. The incidence varied across districts by a factor of 16 (range: 40-646 per 100,000). We identified four spatial clusters with high incidences. These clusters were associated with a significantly larger proportion of forests and agricultural areas than low incidence clusters. In 2019, 12,264 LB cases were reported to the RKI from nine federal states, while 69,623 patients with LB were found in claims data for those states. This difference varied considerably across districts.ConclusionsThese findings serve as a solid basis for regionally tailored population-based intervention programmes and can support modelling studies assessing the development of LB epidemiology under various climate change scenarios.

Background: This study aimed to describe recent developments of multiple sclerosis (MS) prevalence in Germany and to assess utilization patterns of disease-modifying drugs (DMDs)., Methods: We used nationwide outpatient claims data of the statutory health insurance (SHI) from the years 2012 to 2019, covering 87% of the total German population. In annual cross-sectional analyses, MS prevalence was measured as the percentage of the SHI population affected by MS. Annual agent-specific prescription prevalence of DMDs was calculated by the number of patients receiving the DMD per 1.000 MS patients., Results: From 2012 to 2019, the prevalence of MS increased gradually from 0.27% to 0.34%. The overall DMD prescription prevalence in MS patients rose from 436 per 1,000 MS patients (2012) to 483 (2019). From 2012 to 2019 the prescription prevalence of interferon-beta 1a and interferon-beta 1b decreased sharply from 180.2 to 70.8 (-61%) and 80.2 to 34.1 (-57%), respectively. In contrast, the prescription prevalence of teriflunomide (2012: 8.5; 2019: 54.5) and fingolimod (2012: 28.5; 2019: 63.8) exhibited a pronounced increase by factors of 5.4 and 2.2, respectively., Conclusion: MS prevalence in Germany steadily increased in recent years. MS treatment patterns changed markedly indicating a shifting predominance of DMD injectable drugs to oral medications., (Copyright © 2022. Published by Elsevier B.V.)

Background: The manifestation of multiple sclerosis (MS) in childhood and adolescence occurs in 3%-5% of all MS cases. However, the immunomodulatory and symptomatic treatment options in this population group are still limited., Objective: We aimed to elucidate the prescription frequency of medications used in pediatric patients with multiple sclerosis (PwMS) compared with the general population, considering the entire spectrum of medications prescribed., Methods: Based on nationwide outpatient drug prescription data and statutory health insurance (SHI) physicians' claims data from 2018, we conducted a population-based cross-sectional study in Germany. Children and adolescents aged ⩽17 years ( n  = 11,381,939) diagnosed with MS ( n  = 613), and a matched (age, sex, and health insurance sector) control group ( n  = 6130) were included. The prescription prevalence was measured as the proportion of MS patients with ⩾1 prescription., Results: Of the 613 pediatric PwMS with a median age of 16 years, 403 (65.7%) were female. For 15 out of the 18 different active agents analyzed, PwMS had a significantly higher prescription prevalence than the control group (Fisher's exact test: p  ⩽ 0.037). The most frequently prescribed drugs in PwMS were ibuprofen (28.4%; anti-inflammatory drug), cholecalciferol (23.0%; vitamin D3), and interferon beta-1a (21.5%; disease-modifying drug, DMD). The proportions of DMD prescriptions and antibiotic prescriptions were higher among PwMS aged 15-17 years than among those ⩽14 years (DMD: 43.4% vs 34.2%, p  = 0.05; antibiotic: 34.1% vs 24.8%, p  = 0.031). In contrast, younger PwMS were more likely to receive a prescription for anti-inflammatory/anti-rheumatic drugs (36.6% vs 26.5%, p  = 0.02)., Conclusion: Our study analyzing real-world medication data showed that interferon beta, anti-inflammatory drugs, and vitamins play an essential role in the treatment of pediatric PwMS. Future research should evaluate longitudinal treatment patterns of pediatric PwMS, paying particular attention to the time of diagnosis, time of first DMD initiation, and therapy switches., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.B., Ja.Ho., Ju.Ha., and M.K.A. declare no competing interests. D.E., M.P. had no personal financial interests to disclose other than being employees of the German MS Registry funded by many public and corporate sponsors. N.F. is an employee of the MSFP. Moreover, NF is an employee of the University Medical Center Rostock and received travel funds for research meetings from Novartis. None resulted in a conflict of interest. P.S.R. has received speaking fees, honoraria from advisory boards, and financial support for research activities from AbbVie, Alexion, Almirall, Amicus, Biogen, Celgene, Daiichi-Sankyo, Merck Serono, Novartis, Roche, Sandoz, Sanofi Genzyme, and Teva. None resulted in a conflict of interest. AS has no personal financial interests to disclose, other than being the leader of the German MS Registry, which receives funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German MS Trust, German MS Society, Biogen, Celgene (Bristol Myers Squibb), Merck, Novartis, Roche, and Sanofi. None resulted in a conflict of interest. U.K.Z. has received speaking fees, travel support, and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Janssen, Merck Serono, Novartis, Octapharm, Roche, Sanofi Genzyme, Teva, as well as EU, BMBF, BMWi, and DFG. None resulted in a conflict of interest., (© The Author(s), 2021.)

Background: Research has shown that the risk for a severe course of COVID-19 is increased in the elderly population and among patients with chronic conditions. The aim of this study was to provide estimates of the size of vulnerable populations at high risk for a severe COVID-19 course in Germany based on the currently available risk factor data., Methods: We used nationwide outpatient claims data from the years 2010 to 2019 collected according to § 295 of the Code of Social Law V, covering data for all statutory health insurees (SHI) which is nearly 87% of the entire German population. We considered 15 chronic disorders based on the current state of knowledge about clinically relevant risk factors. Three risk groups for a severe COVID-19 course were defined: 1. individuals in the age group 15 to 59 years with at least two comorbid disorders; 2. individuals aged 60 to 79 years with at least one disorder and 3. all individuals 80 years and older irrespective of the presence of chronic conditions. Regional analysis was conducted at the level of administrative districts (n = 401)., Results: Overall, 26% of individuals over 15 years were at high risk for a severe COVID-19 course in 2019 amounting to a total number of nearly 18.5 million individuals in Germany. This included 3.8 million individuals in risk group 1, 9.2 million in risk group 2, and 5.4 million in risk group 3, corresponding to 8, 50 and 100% of German inhabitants in the respective age groups. On the level of the 17 administrative regions formed by the Association of SHI Physicians (ASHIP regions), the proportion of individuals at high risk ranged between 21% in Hamburg and 35% in Saxony-Anhalt. Small-area estimates varied between 18% in Freiburg (Baden-Württemberg) and 39% in the district Elbe-Elster (Brandenburg)., Conclusions: The present study provides small-area estimates of populations at high risk for a severe COVID-19 course. These data are of particular importance for planning of preventive measures such as vaccination., Trial Registration: not applicable., (© 2021. The Author(s).)

Background and Purpose: Prevalence data are needed to reveal trends regarding the pediatric multiple sclerosis (MS) situation worldwide. The aim was to identify changes in MS diagnosis prevalence in pediatric patients over a 10-year period in Germany., Methods: This analysis is based on nationwide outpatient claims data of children aged <18 years covered by the German statutory health insurance (n = 11,381,939 in 2018). People with MS (PwMS) had ≥1 documented MS diagnosis (International Classification of Diseases, 10th Revision, German modification code G35.x). The annual pediatric MS diagnosis prevalence was analyzed regarding age, sex, and place of residence during 2009-2018., Results: The prevalence of pediatric MS developed from 5.3 (2009) to 5.4 (2018)/100,000 insured population aged <18 years. The MS prevalence in patients aged 15-17 years showed a moderate increase over 10 years (19.6-22.7/100,000), whereas patients ≤14 years old showed a slight decrease (1.9-1.7/100,000). The sex ratio (female:male) in 2018 was relatively balanced in PwMS aged ≤14 years (1.32) but female-dominated in those aged 15-17 years (2.47). The formerly different prevalence of pediatric MS between East and West Germany has converged since 2012., Conclusions: So far, this is the largest study of pediatric MS prevalence in terms of source population size (87% of German children <18 years of age, n = 11,381,939 in 2018) and study period (2009-2018) worldwide. The analyses revealed an increase in MS prevalence and a female-dominated sex ratio in "older" adolescents compared to younger patients., (© 2021 European Academy of Neurology.)

Background: The study aim was to examine the secular trends and regional variations in pharmacotherapy of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Germany., Methods: We used nationwide drug prescription data of outpatient care (2009 to 2016). The study population comprised patients aged between 5 and 14 years with the diagnoses "hyperkinetic disorders" (ICD-10 code F90) (e.g. n = 262,766 in 2016). The examined drugs were methylphenidate, amphetamines, atomoxetine and guanfacine., Results: Overall, the proportion of patients received any prescription showed a decreasing trend over years (2010, 51%; 2016, 44%). The proportion of methylphenidate prescription was higher in Western than Eastern federal states. However, atomoxetine was more often prescribed in Eastern than Western federal states. The proportion of methylphenidate prescriptions issued by pediatric psychiatrists increased from 28% (2009) to 41% (2016)., Conclusion: A decreasing trend in use of pharmacotherapy may be explained by prescription restrictions issued by the Federal Joint Committee in recent years., (© 2021. The Author(s).)

Background: We previously reported that deaerated breath condensate pH (dEBC pH) can identify preschool children with recurrent wheezing at high asthma risk., Objective: To assess the ability of preschool dEBC pH to predict asthma risk at school age., Methods: Children of the baseline cohort were recontacted for follow-up. Asthma diagnosis at school age was evaluated according to Global Initiative for Asthma recommendations in 135 children who at baseline had been classified into the following groups: (asymptomatic) atopic wheezers (n = 30), (asymptomatic) nonatopic wheezers (n = 57), allergic rhinitis only (n = 14), and healthy controls (n = 34)., Results: All (100%) former atopic wheezers, 12 (21%) of nonatopic wheezers, 2 (14%) of allergic rhinitis group, and 1 (3%) of healthy controls had developed asthma at follow-up. Among all children with baseline wheezing, baseline dEBC pH predicted asthma at follow-up with an area under the receiver operating characteristic curve (AUC) of 0.72 (sensitivity, 0.67; specificity, 0.76; at pH 7.83). Combining pH and Capacity class (CAP) led to substantial gain in sensitivity (0.96) and negative predictive value (NPV, 0.94). Additional clinical information (Asthma Predictive Index, family atopy, family asthma, and inhaled corticosteroids) further increased the potential to predict asthma (AUC, 0.94) and raised sensitivity (0.98) and NPV (0.97) to nearly perfect values., Conclusion: Our findings suggest (1) that dEBC pH combined with CAP class may serve as highly sensitive, noninvasive marker for the early detection of young asymptomatic preschool children with increased asthma risk, and (2) the need for additional biomarkers with high specificity to optimize early risk stratification in this clinically challenging scenario., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined the full spectrum of comorbid disorders in all statutory-health-insured children aged 5 to 14 years with ADHD in 2017 by using nationwide claims data in Germany. Method: Children with ADHD ( n = 258,662) were compared for the presence of 864 comorbid diseases with a control group matched by gender, age, and region of residence ( n = 2,327,958). Results: Among others, metabolic disorders (odds ratio [OR] = 9.18; 95% confidence interval [CI] = [8.43, 9.99]), viral pneumonia (OR = 4.95; 95% CI = [2.37, 10.33]), disorders of white blood cells (OR = 4.55; 95% CI = [3.83, 5.40]), kidney failure (OR = 3.33; 95% CI = [2.65, 4.18]), hypertension (OR = 3.26; 95% CI = [3.00, 3.55]), obesity (OR = 2.85; 95% CI = [2.80, 2.91]), type 2 diabetes (OR = 2.61; 95% CI = [2.11, 3.23]), migraine (OR = 2.49; 95% CI = [2.37, 2.61]), asthma (OR = 2.19; 95% CI = [2.16, 2.22]), atopic dermatitis (OR = 2.10; 95% CI = [2.16, 2.23]), juvenile arthritis (OR = 1.56; 95% CI = [1.39, 1.76]), glaucoma (OR = 1.51; 95% CI = [1.30, 1.75]), and type 1 diabetes (OR = 1.30; 95% CI = [1.20, 1.40]) were more likely to be diagnosed in ADHD children. Conclusion: Along with psychiatric diseases, various somatic diseases were more common in ADHD children. The results have direct implications for patient care, including fine-grained diagnostics and personalized therapy.

Background: Individuals with chronic diseases have a higher risk of serious complications or even death in case of influenza infection. The European Union (EU) set a goal to reach a vaccination coverage of 75% in seniors and chronically ill individuals. The aim of this study was to assess influenza vaccination uptake among individuals with a wide spectrum of chronic diseases and examine its regional variations and temporal trends over a period of the last ten years., Methods: We used nationwide SHI-physician outpatient claims data from the years 2009 to 2018 covering 87% of the total German population to assess influenza vaccination uptake among individuals over 1 year of age with at least one of the following chronic diseases: pulmonary, cardiovascular, liver, kidney, metabolic, neurological and musculoskeletal diseases, as well as immune deficiency disorders, including HIV infection., Results: Influenza vaccination coverage varied across patient populations between 19% (multiple sclerosis) and 44% (chronic kidney disease) in the influenza season 2017/18. Vaccination coverage was slightly higher among females than males, except for HIV/AIDS patients. Among HIV-patients vaccination coverage was higher by 7 percent points among males (43%) than females (37%). The coverage was higher nearly for all patient groups in the eastern than western federal states. Over the observation period vaccination uptake showed decreasing trends in most of the target groups. Among patients with HIV/AIDS and immune deficiency disorders a stagnating trend was observed., Conclusions: Vaccination uptake among chronically ill individuals is suboptimal and far from the EU-defined target of 75%. There were substantial variations in coverage by disease groups, individual factors and regions. The disease-specific evaluation of the current study allows identification of populations at higher risk with considerable vaccination gaps. Further efforts are needed to improve vaccination uptake in these vulnerable population groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In countries with low endemic Methicillin-resistant Staphylococcus aureus (MRSA) prevalence, identification of risk groups at hospital admission is considered more cost-effective than universal MRSA screening. Predictive statistical models support the selection of suitable stratification factors for effective screening programs. Currently, there are no universal guidelines in Germany for MRSA screening. Instead, a list of criteria is available from the Commission for Hospital Hygiene and Infection Prevention (KRINKO) based on which local strategies should be adopted. We developed and externally validated a model for individual prediction of MRSA carriage at hospital admission in the region of Southeast Lower Saxony based on two prospective studies with universal screening in Braunschweig (n = 2065) and Wolfsburg (n = 461). Logistic regression was used for model development. The final model (simplified to an unweighted score) included history of MRSA carriage, care dependency and cancer treatment. In the external validation dataset, the score showed a sensitivity of 78.4% (95% CI: 64.7-88.7%), and a specificity of 70.3% (95% CI: 65.0-75.2%). Of all admitted patients, 25.4% had to be screened if the score was applied. A model based on KRINKO criteria showed similar sensitivity but lower specificity, leading to a considerably higher proportion of patients to be screened (49.5%).

The aim of this study was to estimate the prevalence of concurrent diagnoses of asthma/COPD and examine its full spectrum of comorbid disorders in Germany. We used nationwide outpatient claims data comprising diagnoses of all statutory health insurees (40+ years) in 2017 (N = 40,477,745). The ICD-10 codes J44 (COPD) and J45 (asthma) were used to identify patients. The odds of 1,060 comorbid disorders were examined in a case-control study design. Of all insurees, 4,632,295 (11%) were diagnosed with either asthma or COPD. Of them, 43% had asthma only, 44% COPD only and 13% both diseases. The prevalence of concurrent asthma/COPD was 1.5% with a slightly higher estimate among females than males (1.6% vs. 1.4%) and constant increase by age in both sexes. Comorbid disorders were very common among these patients. 31 disorders were associated with a strong effect size (odds ratio > 10), including other respiratory diseases, but also bacterial (e.g., mycobacteria, including tuberculosis) and fungal infections (e.g., sporotrichosis and aspergillosis). Patients with concurrent asthma/COPD suffer from comorbid disorders involving various body systems, which points to the need of a multidisciplinary care approach. Regular screening for common comorbid disorders may result in better clinical course and prognosis as well as improvement of patients' quality of life.

Background: A central component of the German antibiotic resistance strategy is to monitor the outpatient prescribing of systemic antibiotics nationwide, across all of the statutory health-insurance providers, in order to provide a basis for targeted quality-assurance measures., Methods: All outpatient drug prescription data from patients covered by the statutory health-insurance carriers in Germany in the age groups 0-14, 15-64, and ≥ 65 years were assessed. The chosen primary outcome measure under study was the prescription rate (number of antibiotic prescriptions per 1000 insurees per year) for the years 2010 to 2018., Results: Over the period of the study, a 21% decline was seen in the use of systemic antibiotics in outpatients, from 562 to 446 prescriptions per 1000 insurees per year in 2010 and 2018, respectively. The most marked reduction in the prescription rate-by 41%-was seen among child and adolescent insurees (in other age groups: -17% among those aged 15-64, -12% among those aged 65 and older). A downward trend was seen in all regions of Germany, and for most of the active substance groups for which data were obtained. In 2018, the prescription rate varied by a factor of 1.8 among regions, with the highest rate in the Saarland (572 per 1000 insurees per year) and the lowest in Brandenburg (318 per 1000 insurees per year)., Conclusion: The observed nationwide decline in the prescription of antibiotics to outpatients in all age groups may be a result of the numerous initiatives that have been put into action to reinforce the appropriate use of antibiotics in Germany. A change in pediatric prescribing practices is demonstrated by the marked reduction in this age group. The remaining major differences across German regions underscore the importance of regionally tailored programs for the promotion of rational antibiotic use.

BackgroundPrescribing of systemic antibiotics in general and of cephalosporins in particular in German paediatric outpatients has previously been reported to be higher than in other European countries.AimOur objective was to assess recent trends in antibiotic prescribing in German children.MethodsThis study was conducted as consecutive annual cross-sectional analyses and included all children aged 0-14 years (n = 9,389,183 in 2018) covered by statutory health insurance in Germany. Annual antibiotic prescription rates from 2010 to 2018 were calculated for the age groups 0-1, 2-5, 6-9 and 10-14 years. Poisson regression was used to estimate trends of prescription rates by age group and antibiotic subgroup.ResultsOverall, the age-standardised antibiotic prescription rate decreased significantly by 43% from 746 prescriptions per 1,000 persons in 2010 to 428 per 1,000 in 2018 (p < 0.001). Reductions were most pronounced in the age groups 0-1 year (-50%) and 2-5 years (-44%). The age group 2-5 years exhibited the highest prescription rate with 683 per 1,000 in 2018 (0-1 year: 320/1,000; 6-9 years: 417/1,000; 10-14 years: 273/1,000). Cephalosporins (second and third generation) accounted for 32% of prescribed antibiotics.ConclusionsMarked reductions in antibiotic prescribing during the last decade indicate a change towards more judicious paediatric prescribing habits. Compared with other European countries, however, prescribing of second- and third-generation cephalosporins remains high in Germany, suggesting frequent first-line use of these substances for common respiratory infections. Considerable regional variations underline the need for regionally targeted interventions.

Objective: To investigate asthma morbidity in Germany by calculating current prevalence, examining its temporal and spatial trends and estimating the total number of asthmatics in Germany and calculating age-, sex- and residence-specific risk., Methods: We used claims data reported by physicians during 2009-2016, including outpatient diagnoses of all statutory health insured individuals, comprising 85.3% (70 416 019/82 521 653) of the total population in Germany in 2016. We performed a spatial analysis of asthma prevalence according to administrative district by calculating Global and Local Moran's  I . We assessed the risk of asthma by sex, age, type of residence (rural versus urban) and federal state (East versus West) using a multilevel parametric survival regression., Findings: We estimated that 4.7 million individuals were affected by asthma in 2016, including 0.8 million children and 3.9 million adults. We observed a slightly higher prevalence (with an increasing trend) among adults (5.85%; 3 408 622/58 246 299) compared to children (5.13%; 624 899/12 169 720), and calculated an age-standardized prevalence of 5.76% (95% confidence interval, CI: 5.76-5.77). We found evidence of a strong spatial autocorrelation (Global Moran's  I : 0.50, P  < 0.0001), and identified local spatial clusters with higher levels of prevalence. Living in the western (versus eastern) federal states and living in densely populated large urban municipalities (versus rural area) were independently associated with an increased risk of asthma, with hazard ratios of 1.33 (95% CI: 1.32-1.34) and 1.32 (95% CI: 1.31-1.32), respectively., Conclusion: Our insights into the spatial distribution of asthma morbidity may inform public health interventions, including region-specific prevention programmes and control., ((c) 2020 The authors; licensee World Health Organization.)

Background: There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage., Methods: We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls., Results: Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution., Conclusions: The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.

Background: So far the extent of regional variation of heart failure (HF) prevalence in Germany is unknown., Methods: Using a full sample of nationwide claims data covering ambulatory care of approximately 87% of the German population, this study aimed to (i) examine regional differences of HF prevalence on the level of 402 German administrative districts and (ii) investigate factors associated with HF prevalence. This study included all statutory health-insured patients aged ≥ 40 years in 2017, comprising about 40 million individuals. Age- and sex-standardized HF prevalence was estimated on the district level. Two-level logistic regression analysis was employed to study the influence of the district-related factors degree of urbanisation and regional socio-economic status on HF diagnosis, adjusted for the individual's age and sex., Results: HF prevalence in 2017 was 6.0%. Standardized prevalence on the district level varied by a factor of 4.3 (range 2.8-11.9%). Regional socio-economic status and degree of urbanisation were independently associated with HF prevalence. The prevalence increased with decreasing degree of urbanisation. The adjusted risk of suffering from HF was 40% higher in 'rural areas with a low population density' as compared to 'big urban municipalities' (odds ratio 1.40, 99% CI 1.24-1.59)., Conclusion: Strong regional variations in HF prevalence may inform future public health policies regarding targeted resource planning and prevention strategies. High prevalence in areas with low population density adds to the challenge of ensuring universal access to health services in rural German regions.

Background: The immune response to seasonal influenza vaccines decreases with advancing age. Therefore, an adjuvanted inactivated trivalent influenza vaccine (Fluad®) exists for elderly individuals. Fluad® is more immunogenic and efficacious than conventional influenza vaccines. However, the immune response varies and may still result in high frequencies of poor responders. Therefore, we aimed to a) examine the prevalence of a weak response to Fluad® and b) identify potential risk factors., Methods: A prospective population-based study among individuals 65-80 years old was conducted in 2015/2016 in Hannover, Germany (n = 200). Hemagglutination-inhibition titers 21 days after vaccination with Fluad® served as indicator of vaccine responsiveness., Results: The percentage of vaccinees with an inadequate vaccine response varied depending on the influenza strain: it was lowest for H3N2 (13.5%; 95% CI, 9.4-18.9%), intermediate for B strain (37.0%; 30.6-43.9%), and highest for H1N1 (49.0%; 42.2-55.9%). The risk of a weak response to the influenza A H1N1 strain was independently associated with self-reported diabetes (AOR, 4.64; 95% CI, 1.16-18.54), a history of herpes zoster (2.27; 1.01-5.10) and, to a much lesser extent, increasing age (change per year, 1.08; 0.99-1.16). In addition, herpes zoster was the only risk factor for a weak response to the H3N2 antigen (AOR, 3.12; 1.18-8.23). We found no significant association between sex, Body Mass Index, cancer, hypertension, heart attack and CMV seropositivity and a weak response to these two influenza A antigens. Despite its occurence in over one third of vaccinees, none of the variables examined proved to be risk factors for a weak response to the B antigen., Conclusions: A considerable proportion of elderly individuals displayed a weak vaccine response to this adjuvanted seasonal influenza vaccine and further efforts are thus needed to improve immune responses to influenza vaccination among the elderly. Diabetes and herpes zoster were identified as potentially modifiable risk factors for a poor vaccine response against influenza A antigens, but the results also reveal the need for broader investigations to identify risk factors for inadequate responses to influenza B antigens., Trial Registration: No. NCT02362919 (ClinicalTrials.gov, date of registration: 09.02.2015).

Introduction: Helicobacter pylori ( H. pylori ) is a common infection and known risk factor for gastric cancer. We assessed cross-sectional and longitudinal associations to study the impact of H. pylori seropositivity on metabolic diseases. Methods: Helicobacter pylori seropositivity in serum samples of the KORA study was analyzed by multiplex serology. We calculated sex-specific prevalence of H. pylori seropositivity for the year 2007 based on the first follow-up survey (termed F4) of the KORA study S4. We identified factors associated with H. pylori seropositivity in the F4 survey. Further, we assessed relative risks of incident metabolic diseases/risk factors at the time of the second follow-up survey of S4 (termed FF4) and H. pylori seropositivity at the F4 survey as a determinant. Models were adjusted for age, sex, overweight status, physical activity, smoking status, education level, alcohol intake, and other metabolic diseases. Results: Based on 3,037 persons aged 32 to 82 years, the H. pylori prevalence for 2007 was 30.2% in men ( n = 1,465) and 28.1% in women ( n = 1,572). Increasing age, current smoking, low education and no alcohol intake were significantly associated with H. pylori seropositivity in the F4 survey. However, no association between H. pylori seropositivity and BMI, metabolic diseases (type 2 diabetes, hypertension and dyslipidemia, gout or increased uric acid) and gastrointestinal diseases (gastritis, inflammatory bowel disease, and gastric or duodenal ulcer) was observed. No significant associations between H. pylori seropositivity and one of the five investigated incident metabolic diseases/risk factors were detected in the longitudinal analysis. Conclusion: We identified associations between age, smoking, education and alcohol intake and H. pylori seropositivity but no impact of H. pylori seropositivity on incident metabolic diseases/risk factors.

Background: Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data., Methods: Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered., Results: Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data., Conclusion: As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.

There is a controversy regarding temporal trends in prevalence of attention-deficit/hyperactivity disorder (ADHD). Using nationwide claims data containing data for approximately six million statutory health insured children we aimed to examine a) trends of ADHD administrative prevalence during 2009-2016; b) regional variations in prevalence, and c) factors associated with an increased chance of ADHD diagnosis. The ICD-10 code 'F90-hyperkinetic disorder' was used to define an ADHD case. Global and Local Moran's I tests were used to examine the spatial autocorrelation and k-means-cluster analysis to examine the course of ADHD prevalence in administrative districts over years. Two-level logistic regression was applied to examine individual- and district-level factors associated with ADHD diagnosis. The administrative prevalence of ADHD was 4.33% (95% CI: 4.31-4.34%). We observed pronounced small-area differences on the district level with prevalences ranging between 1.6% and 9.7%. There was evidence of strong spatial autocorrelation (Global Moran's I: 0.46, p < 0.0001). The k-means-method identified six clusters of different size; all with a stagnating trend in the prevalence over the observation period of eight years. On the district level, a lower proportion of foreign citizens, and a higher density of paediatric psychiatrists and paediatricians were positively associated with ADHD with a more pronounced effect in urban districts.

This study aimed at providing a current and nearly complete picture of the patterns of the initiation of disease-modifying antirheumatic drugs (DMARDs) in patients with newly diagnosed RA. Based on ambulatory drug prescription data and physician billing claims data covering 87% of the German population, we assembled a cohort of incident RA patients aged 15-79 years (n = 54,896) and assessed the prescription frequency of total DMARDs, conventional synthetic (csDMARDs) and biologic DMARDs (bDMARDs) within the first year of disease. Using multiple logistic regression, we estimated the chance of early DMARD receipt based on age, sex, serotype and specialty of prescribing physician while controlling for region of residence. In total, 44% of incident RA patients received a DMARD prescription within the first year of disease. In multiple regression, younger patients (< 35 years) had 1.7-fold higher chances of receiving a csDMARD than patients aged ≥ 65 years [odds ratio (OR): 1.65 with 95% confidence interval (CI) 1.51-1.80] and almost tenfold higher chances to receive a bDMARD [OR (95% CI) 9.5 (8.0-11.3)]. Seropositivity and a visit to a rheumatologist were positively associated with DMARD initiation [OR (95% CI) 2.8 (2.6-2.9) and 5.9 (5.6-6.2) for csDMARDs, respectively]. Based on data covering 87% of the German population, the present study revealed that less than half of incident RA patients receive DMARDs within the first year of disease and that marked differences exist according to age. The study highlights the importance of involving a rheumatologist early in the management of RA.

Objectives: The aims of this study were to (a) assess knowledge of official vaccination recommendations and attitudes towards vaccinations among adults and (b) examine their association with vaccination uptake among adults., Methods: This study was part of the HaBIDS study (Hygiene and Behaviour Infectious Diseases Survey), which is an online panel established in March 2014 in Lower Saxony, Germany with males and females aged between 15 and 69 years (n = 2379). Every few months, participants completed questionnaires on different aspects of infectious diseases. In September 2014, knowledge of vaccination recommendations, attitudes towards vaccinations and information on uptake of vaccinations in the last 10 years (practice) were collected using a knowledge-attitude-practice (KAP) questionnaire. Multiple correspondence analysis was applied to identify underlying structures in each KAP domain and fractional polynomial regression analysis to examine the associations of knowledge and attitudes with vaccination uptake., Results: Of the 2379 panel members, 1698 (71%) completed the KAP questionnaire on vaccinations. The majority of participants (80%) knew that the vaccine against diphtheria and tetanus should be administered every 10 years. Regarding other recommendations, the proportion of correct answers varied between 35% and 60%. 82% of participants agreed that adult vaccinations should be mandatory for selected groups such as health care workers and 40% stated that vaccinations should be mandatory for all adults. For the different vaccines, the odds of being unvaccinated were 1.5- to 5-times higher among participants with poor knowledge of vaccination recommendations compared to participants with good knowledge. Participants with negative attitudes towards vaccinations were also more likely to be unvaccinated., Conclusions: Efforts should be undertaken to improve knowledge of official vaccination recommendations in the general population and reduce common misconceptions about vaccinations. This information can be provided during general practitioner visits or through media campaigns., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Group A streptococci may induce lymphopenia, but the value of lymphocyte loss as early biomarkers for systemic spread and severe infection has not been examined systematically. Methods: We evaluated peripheral blood cell indices as biomarkers for severity and spread of infection in a mouse model of Streptococcus pyogenes skin infection, using two isolates of greatly differing virulence. Internal organs were examined histologically. Results: After subcutaneous inoculation, strain AP1 disseminated rapidly to peripheral blood and internal organs, causing frank sepsis. In contrast, seeding of internal organs by 5448 was mild, this strain could not be isolated from blood, and infection remained mostly localized to skin. Histopathologic examination of liver revealed microvesicular fatty change (steatosis) in AP1 infection, and examination of spleen showed elevated apoptosis and blurring of the white pulp/red pulp border late (40 h post infection) in AP1 infection. Both strains caused profound lymphopenia, but lymphocyte loss was more rapid early in AP1 infection, and lymphocyte count at 6 h post infection was the most accurate early marker for AP1 infection (area under the receiver operator curve [AUC] = 0.93), followed by the granulocyte/lymphocyte ratio (AUC = 0.89). Conclusions: The results suggest that virulence of S. pyogenes correlates with the degree of early lymphopenia and underscore the value of peripheral blood indices to predict severity of bacterial infections in mice. Early lymphopenia and elevated granulocyte/lymphocyte ratio merit further investigation as biomarkers for systemic spread of S. pyogenes skin infections in humans and, possibly, related pyogenic streptococci in humans and animals.

Background: Varicella zoster virus (VZV) reactivation spans the spectrum from uncomplicated segmental herpes zoster to life-threatening disseminated CNS infection. Moreover, in the absence of a small animal model for this human pathogen, studies of pathogenesis at the organismal level depend on analysis of human biosamples. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuroinfection and neuroinflammation. We therefore applied a targeted metabolomics screen of CSF to three clinically distinct forms of VZV reactivation and infectious and non-infectious disease controls in order to identify biomarkers for CNS involvement in VZV reactivation., Methods: Metabolite profiles were determined by targeted liquid chromatography-mass spectrometry in CSF from patients with segmental zoster (shingles, n = 14), facial nerve zoster (n = 16), VZV meningitis/encephalitis (n = 15), enteroviral meningitis (n = 10), idiopathic Bell's palsy (n = 11), and normal pressure hydrocephalus (n = 15)., Results: Concentrations of 88 metabolites passing quality assessment clearly separated the three VZV reactivation forms from each other and from the non-infected samples. Internal cross-validation identified four metabolites (SM C16:1, glycine, lysoPC a C26:1, PC ae C34:0) that were particularly associated with VZV meningoencephalitis. SM(OH) C14:1 accurately distinguished facial nerve zoster from Bell's palsy. Random forest construction revealed even more accurate classifiers (signatures comprising 2-4 metabolites) for most comparisons. Some of the most accurate biomarkers correlated only weakly with CSF leukocyte count, indicating that they do not merely reflect recruitment of inflammatory cells but, rather, specific pathophysiological mechanisms. Across all samples, only the sum of hexoses and the amino acids arginine, serine, and tryptophan correlated negatively with leukocyte count. Increased expression of the metabolites associated with VZV meningoencephalitis could be linked to processes relating to neuroinflammation/immune activation, neuronal signaling, and cell stress, turnover, and death (e.g., autophagy and apoptosis), suggesting that these metabolites might sense processes relating to end-organ damage., Conclusions: The results provide proof-of-concept for the value of CSF metabolites as (1) disease-associated signatures suggesting pathophysiological mechanisms, (2) degree and nature of neuroinflammation, and (3) biomarkers for diagnosis and risk stratification of VZV reactivation and, likely, neuroinfections due to other pathogens., Trial Registration: Not applicable (non-interventional study).

The spread of infectious diseases and vaccination history are common subjects of epidemiological and immunological research studies. Multiplexed serological assays are useful tools for assessing both current and previous infections as well as vaccination efficacy. We developed a serological multi-pathogen assay for hepatitis A, B and C virus, cytomegalovirus (CMV), Toxoplasma gondii , and Helicobacter pylori using a bead-based multiplex assay format. The multi-pathogen assay consisting of 15 antigens was utilized for the analysis of the serological response in elderly individuals of an influenza vaccination study ( n = 34). The technical assay validation revealed a mean intra-assay precision of coefficient of variation (CV) = 3.2 ± 1.5% and a mean inter-assay precision of CV = 8.2 ± 5.3% across all 15 antigens and all tested samples, indicating a robust test system. Furthermore, the assay shows high sensitivities (ranging between 94% and 100%) and specificities (ranging between 93% and 100%) for the different pathogens. The highest seroprevalence rates in our cohort were observed for hepatitis A virus (HAV; 73.5%), followed by CMV (70.6%), T. gondii (67.6%) and H. pylori (32.4%). Seroprevalences for hepatitis B virus (HBV, 8.8%) and hepatitis C virus (HCV, 0%) were low. The seroprevalences observed in our study were similar to those from other population-based studies in Germany. In summary, we conclude that our multiplex serological assay represents a suitable tool for epidemiological studies., Competing Interests: B.G. had presentations at DiaSorin and Roche. The other authors declare no conflict of interest.

Background: Knowing about predictors of attrition in a panel is important to initiate early measures against loss of participants. We investigated attrition in both early and late phase of an online panel with special focus on preferences regarding mode of participation., Methods: We used data from the HaBIDS panel that was designed to investigate knowledge, attitudes, and practice regarding infections in the German general population. HaBIDS was divided into two phases: an initial phase when some participants could choose their preferred mode of participation (paper-and-pencil or online) and an extended phase when participants were asked to become members of an online panel that was not limited regarding its duration (i.e. participants initially preferring paper questionnaires switched to online participation). Using competing risks regression, we investigated two types of attrition (formal withdrawal and discontinuation without withdrawal) among online participants, separately for both phases. As potential predictors of attrition, we considered sociodemographic characteristics, physical and mental health as well as auxiliary information describing the survey process, and, in the extended phase, initial mode preference., Results: In the initial phase, higher age and less frequent Internet usage predicted withdrawal, while younger age, higher stress levels, delay in returning the consent form, and need for receiving reminder emails predicted discontinuation. In the extended phase, only need for receiving reminder emails predicted discontinuation. Numbers of withdrawal in the extended phase were too small for analysis. Initial mode preference did not predict attrition in the extended phase. Besides age, there was no evidence of differential attrition by sociodemographic factors in any phase., Conclusions: Predictors of attrition were similar in both phases of the panel, but they differed by type of attrition (withdrawal vs. discontinuation). Sociodemographic characteristics only played a minor role for both types of attrition. Need for receiving a reminder was the strongest predictor of discontinuation in any phase, but no predictor of withdrawal. We found predictors of attrition, which can be identified already in the early phase of a panel so that countermeasures (e.g. special incentives) can be taken.

Elderly individuals have the highest burden of disease from influenza infection but also the lowest immune response to influenza vaccination. A better understanding of the host response to influenza vaccination in the elderly is therefore urgently needed. We conducted a biphasic prospective, population-based study from Dec. 2014 to May 2015 (pilot study) and Sept. 2015 to May 2016 (main study). Individuals 65-80 y of age were randomly selected from the residents' registration office in Hannover, Germany, for the pilot (n = 34) and main study (n = 200). The pilot study tested recruitment for study arms featuring 2, 4, or 5 visits/blood draws. The 5-visit (day 0, 1/3, 7, 21, 70 with respect to vaccination) study arm was selected for the main study. Both studies featured vaccination with Fluad™ (Novartis, Italy), a detailed medical history, a physical exam, recording of adverse events, completion of a questionnaire on common infections and an end-of-study questionnaire, and blood samples. Response rates in the pilot and main studies were 3.7% and 4.0%, respectively. Willingness to participate did not differ among the study arms (Fisher's exact test, p = 0.44). In both studies, there were no losses to follow-up. Compliance with study visits, blood sampling and completion of the questionnaires was very high (100%, >97%, 100%, respectively), as were participants' acceptance of and satisfaction with both phases of the study. The low response rates indicate the need for optimized recruitment strategies if the study population is to be representative of the general population. Nonetheless, the complex prospective study design proved to be highly feasible.

Background: We determined the prevalence of anti-nuclear autoantibodies (ANAs) in the German adult population and examined the association between ANAs and cardiovascular and metabolic disorders., Methods: We used data and blood samples from the pretest phases of the German National Cohort, obtained from six of the 18 study centers (n = 1199). All centers applied standardized instruments including face-to-face interviews, anthropometric measurements and collection of blood samples. Self-reported histories of diabetes mellitus, heart attack and elevated blood cholesterol and/or lipids were recorded. Height, weight and blood pressure were measured. ANAs were detected using a semi-automated system (AKLIDES®; Medipan GmbH, Dahlewitz, Germany). A positive ANA was defined as a titer ≥ 1:80. ANA were classified as weakly (1:80 or 1:160), moderately (1:320 or 1:640) or strongly (≥1:1280) positive. Specific autoantibodies against nuclear antigens were detected with second-step assays according to the ANA staining pattern. Associations between the assessed disorders and ANA positivity and pattern were examined using sex and age-adjusted mixed-effects logistic regression models., Results: Thirty-three percent (95% confidence interval; 31-36%) of the 1196 participants (measurements could not be obtained from three samples) were ANA positive (titer ≥ 1:80). The proportions of weakly, moderately and strongly positive ANA were 29%, 3.3% and 1.3%, respectively. ANA positivity was more common among women than men across all titers (χ 2 , p = 0.03). ANA positivity, even when stratified according to height of titer or immunofluorescent pattern, was not associated with diabetes, elevated blood cholesterol and/or lipids, obesity or hypertension. Second-step autoantibody assays were positive in 41 of the 83 samples (49%) tested, with anti-DFS70 (n = 13) and anti-dsDNA (n = 7) being most frequent. These subgroups were too small to test for associations with the disorders assessed., Conclusions: The prevalence of ANA positivity in the German general population was similar to values reported from other countries. Contrary to other studies, there was no association with selected self-reported and objectively measured cardiovascular and metabolic variables.

We examined acceptability, preference and feasibility of collecting nasal and oropharyngeal swabs, followed by microbiome analysis, in a population-based study with 524 participants. Anterior nasal and oropharyngeal swabs were collected by certified personnel. In addition, participants self-collected nasal swabs at home four weeks later. Four swab types were compared regarding (1) participants' satisfaction and acceptance and (2) detection of microbial community structures based on deep sequencing of the 16 S rRNA gene V1-V2 variable regions. All swabbing methods were highly accepted. Microbial community structure analysis revealed 846 phylotypes, 46 of which were unique to oropharynx and 164 unique to nares. The calcium alginate tipped swab was found unsuitable for microbiome determinations. Among the remaining three swab types, there were no differences in oropharyngeal microbiomes detected and only marginal differences in nasal microbiomes. Microbial community structures did not differ between staff-collected and self-collected nasal swabs. These results suggest (1) that nasal and oropharyngeal swabbing are highly feasible methods for human population-based studies that include the characterization of microbial community structures in these important ecological niches, and (2) that self-collection of nasal swabs at home can be used to reduce cost and resources needed, particularly when serial measurements are to be taken.

Background: Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice)., Methods: We used data from a longitudinal panel, the Hygiene and Behaviour Infectious Diseases Study (HaBIDS), conducted in 2014/2015 in four regions in Lower Saxony, Germany. Individuals were recruited using address-based probability sampling. In two regions, individuals could choose between paper-and-pencil and online questionnaires. In the other two regions, individuals were offered online-only participation. We compared sociodemographic characteristics of respondents who filled in all panel questionnaires between the mixed-mode group (n = 1110) and the online-only group (n = 482). Using 134 items, we performed multinomial logistic regression to compare responses between survey designs in terms of type (missing, "do not know" or valid response) and ordinal regression to compare responses in terms of content. We applied the false discovery rates (FDR) to control for multiple testing and investigated effects of adjusting for sociodemographic characteristic. For validation of the differential response patterns between mixed-mode and online-only, we compared the response patterns between paper and online mode among the respondents in the mixed-mode group in one region (n = 786)., Results: Respondents in the online-only group were older than those in the mixed-mode group, but both groups did not differ regarding sex or education. Type of response did not differ between the online-only and the mixed-mode group. Survey design was associated with different content of response in 18 of the 134 investigated items; which decreased to 11 after adjusting for sociodemographic variables. In the validation within the mixed-mode, only two of those were among the 11 significantly different items. The probability of observing by chance the same two or more significant differences in this setting was 22%., Conclusions: We found similar response patterns in both survey designs with only few items being answered differently, likely attributable to chance. Our study supports the equivalence of the compared survey designs and suggests that, in the studied setting, using online-only design does not cause strong distortion of the results.

Objective: To examine the impact of hepatitis B vaccination schedules and types of vaccines on hepatitis B vaccination timing., Methods: We used data for 211 643 children from demographic and health surveys in 47 low- and middle-income countries (median study year 2012). Data were from vaccination cards and maternal interviews. We grouped countries according to the vaccination schedule and type of vaccine used (monovalent or combination). For each country, we calculated hepatitis B vaccination coverage and timely receipt of vaccine doses. We used multivariable logistic regression models to study the effect of vaccination schedules and types on vaccination delay., Findings: Substantial delays in vaccination were observed even in countries with fairly high coverage of all doses. Median delay was 1.0 week (interquartile range, IQR: 0.3 to 3.6) for the first dose ( n  = 108 626 children) and 3.7 weeks (IQR: 1.4 to 9.3) for the third dose ( n  = 101  542). We observed a tendency of lower odds of delays in vaccination schedules starting at 6 and at 9 weeks of age. For the first vaccine dose, we recorded lower odds of delays for combination vaccines than for monovalent vaccines (adjusted odds ratio, aOR: 0.76, 95% confidence interval, CI: 0.71 to 0.81)., Conclusion: Wide variations in hepatitis B vaccination coverage and adherence to vaccination schedules across countries underscore the continued need to strengthen national immunization systems. Timely initiation of the vaccination process might lead to timely receipt of successive doses and improved overall coverage. We suggest incorporating vaccination timing as a performance indicator of vaccination programmes to complement coverage metrics.