SARS-CoV-2 variants and the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 among children in Germany.

PURPOSE: To investigate the relationship between the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in children and the predominance of different SARS-CoV-2 variants of concern (VOC) over time. METHODS: In relation to the Alpha, Delta, and Omicron VOC phases of the pandemic, the risk of developing PIMS-TS was calculated by analyzing data for rtPCR-confirmed SARS-CoV-2 infections reported to the German statutory notification system, along with data captured by a separate, national PIMS-TS registry. Both overall infection rates and age group-specific ratios of PIMS-TS during the different pandemic phases were calculated using the Alpha period as the baseline. RESULTS: The PIMS-TS rate changed significantly over time. When the Alpha VOC was dominant [calendar week (CW) 11 in March-CW 31 in August 2021], the PIMS-TS rate was 6.19 [95% confidence intervals (95% CI) 5.17, 7.20]. When Delta prevailed (CW 32 in August 2021-CW 4 in January 2022), the rate decreased to 1.68 (95% CI 1.49, 1.87). During the Omicron phase (CW 5 in January-CW 16 in April 2022), the rate fell further to 0.89 (95% CI 0.79, 1.00). These changes correspond to a decreased PIMS-TS rate of 73% (rate ratio 0.271, 95% CI 0.222; 0.332) and 86% (rate ratio 0.048, 95% CI 0.037; 0.062), respectively, in comparison to the Alpha period. Rate ratios were nearly identical for all age groups. CONCLUSION: The data strongly suggest an association between the risk for PIMS-TS and the prevailing VOC, with highest risk related to Alpha and the lowest to Omicron. Given the uniformity of the decreased risk across age groups, vaccination against SARS-CoV-2 does not appear to have a significant impact on the risk of children developing PIMS-TS.

[Measles surveillance in Germany. From sentinel to mandatory surveillance]. / Masern-Surveillance in Deutschland. Vom Sentinel zur Meldepflicht.

From September 1999 to March 2011, sentinel surveillance of measles was conducted by a self-selected sample of private physicians in Germany. From 2001, when mandatory surveillance for measles was established, two surveillance systems worked in parallel. The aim of this article is to summarize the strengths and limitations of sentinel versus mandatory surveillance. Active monthly reporting included case-based questionnaires on patients with (suspected) measles or zeroreporting. For confirmation of measles, the diagnostic patient specimens were sent to regional laboratories for serological tests or to the National Reference Laboratory (NRC). In the NRC in addition to serological tests measles-virus (MV) detection by PCR in urine, throat swabs, and oral fluid (since 2003) as well as MVgenotyping was offered. From January 2000 to December 2010, 934 out of 1,488 participating sentinel-practices did not see any measles case, while 554 reported 3,573 suspected cases. Measles was confirmed by laboratory testing in 801 cases, excluded in 473 cases, and the diagnosis remained uncertain in 215 cases. Of 3,100 analyzed cases, 2,712 (87 %) were unvaccinated, 217 (7 %) and 32 (1 %) were vaccinated with one or two doses, respectively, and for 139 (4 %) cases the vaccination status was unknown. The main reason for not being vaccinated against measles was refusal (n = 1,383). The confirmation rate was lower in the vaccinated than in the unvaccinated patients (19 % vs. 63 %). Since 2006, sentinel-cases have differed from notified cases by region and age. The proportion of sentinel cases from all NRC-investigated cases decreased from more than 50 % (2002) to less than 5 % (since 2007). Sentinel surveillance allowed for the detection of trends, delivered additional information for measles prevention, and played a major role in measles diagnostics. Since mandatory surveillance was established and sentinel surveillance no longer reflected the epidemiologic situation, the latter was abandoned in April 2011.

[Varicella vaccination in Germany. A provisional appraisal in the context of MMR vaccination]. / Die Varizellenimpfung in Deutschland. Eine Zwischenbilanz mit Blick auf die Masern-Mumps-Röteln- (MMR-)Impfung.

In 2004, a general varicella immunization was introduced in Germany for infants from the age of 11 months, followed by the subsequent recommendation in 2009 of a second vaccine dose. The vaccination is carried out at the same time as the immunization against measles, mumps, and rubella (MMR). Results of the nationwide sentinel surveillance of varicella and herpes zoster implemented by the Varicella Working Group (Arbeitsgemeinschaft Varizellen, AGV) show that the defined goals for varicella immunization (reduction of varicella-related morbidity, complications and hospitalizations) have been reached within a few years owing to the advances in vaccine coverage. Although coverage rates for varicella have not yet reached the same levels as for MMR, varicella immunization seems to have benefited from the established MMR immunization schedule. Moreover, there is no evidence for an adverse effect on the use and acceptance of the MMR vaccine. Lessons learnt in measles epidemiology (such as trends in the incidence of the disease in adolescents and infants), as well as in the history of MMR recommendations, may be useful for the evaluation of future epidemiological changes with respect to varicella and herpes zoster. In view of a rapidly waning immunity against the varicella zoster virus after vaccination with one dose and the lifelong persistence of the virus, achieving a robust and sustainable immunity in the general population seems to be an ambitious goal. However, this accomplishment will be indispensable in preventing breakthrough infections and a shift of varicella to older ages and in avoiding an increase in herpes zoster incidence.

Measles outbreak in an asylum-seekers' shelter in Germany: comparison of the implemented with a hypothetical containment strategy.

In order to contain a measles outbreak in a German asylum-seekers' shelter, serological testing of all residents was performed, followed by selective vaccination of those with negative test results/not tested. In this paper we describe the outbreak epidemiologically and then compare the implemented strategy with a hypothetical mass vaccination of all individuals unvaccinated or with unknown vaccination status born after 1970 as recommended by the German Standing Committee on Vaccination in terms of potentially avoided cases, logistics, and costs. Three hundred (70%) residents participated in the serological testing, of which 39 (13%) were seronegative. In total, 144 individuals were eligible for vaccination, while a mass vaccination would have targeted 359 persons. However, serological testing was time- and personnel consuming and revealed several logistical problems. Its costs amounted to €90 000, double that of mass vaccination that additionally might have avoided three of the eight cases. Mass vaccination seems the preferred measure for measles outbreak control in such settings.

Estimating vaccination coverage in the absence of immunisation registers--the German experience.

Immunisation registers are regarded as an appropriate solution to measure vaccination coverage on a population level. In Germany, a decentralised healthcare system and data protection regulations constrain such an approach. Moreover, shared responsibilities in the process of immunisation and multiple providers form the framework for public health interventions on vaccination issues. On the national level, those interventions consist mainly of conceptualising immunisation strategies, establishing vaccination programmes, and issuing recommendations. This paper provides an overview on sources and methods for collecting appropriate coverage data at national level and their public health relevance in Germany. Methods of data collection and available information on immunisations are described for three approaches: school entrance health examination, population surveys and insurance refund claim data. School entrance health examinations allow regional comparisons and estimation of trends for a specific cohort of children and for all recommended childhood vaccinations. Surveys deliver population based data on completeness and timeliness of selected vaccinations in populations defined by age or socio-demographic parameters and on knowledge and attitudes towards vaccination. Insurance refund claim data inform continuously on immunisation status (e.g. of children aged two years) or on vaccination incidence promptly after new or modified recommendations. In a complex healthcare system, the German National Public Health Institute (Robert Koch Institute, RKI) successfully compiles coverage data from different sources, which complement and validate one another. With the German approach of combining different data sources in the absence of immunisation registers, it is possible to gain solid and reliable data on the acceptance of vaccination programmes and target groups for immunisation. This approach might be of value for other countries with decentralised healthcare systems.

Assessment of varicella vaccine effectiveness in Germany: a time-series approach.

A multivariate time-series regression model was developed in order to describe the 2005-2008 age-specific time-course of varicella sentinel surveillance data following the introduction of a varicella childhood vaccination programme in Germany. This ecological approach allows the assessment of vaccine effectiveness under field conditions by relating vaccine coverage in cohorts of 24-month-old children to the mean number of cases per reporting unit in the sentinel network. For the 1-2 years age group, which is directly affected by the vaccination programme, a one-dose vaccine effectiveness of 83·2% (95% CI 80·2-85·7) was estimated which corresponds to previous approaches assessing varicella vaccine effectiveness in the field in the USA.

Potential benefits from currently available three pneumococcal vaccines for children--population-based evaluation.

BACKGROUND: Currently there are 3 pneumococcal vaccines available in Germany. The aim of this study is to evaluate the potential of the three currently available pneumococcal vaccines to reduce the burden of invasive pneumococcal disease in children. SUBJECTS: Children younger than 16 years who have been hospitalized because of IPD between July 2007 and June 2009 in a German pediatric hospitals. METHOD: Surveillance of IPD in German pediatric hospitals and laboratories serving these hospitals. The case definition is isolation of Streptococcus pneumoniae from any normally sterile body site. The actual number of IPD cases is based on the capture recapture method combining information from both reporting systems. RESULTS: In the study period an estimated yearly number of 164 IPD cases occurred among children younger than 2 years compared to 144 and 116 cases among children aged 2-4 years and 5-15 years. Among children under 2 years of age, 69 cases were caused by serotypes covered by PCV10 compared to 103 cases potentially preventable by PCV13. Among children aged 2-4 years 94 IPD cases were caused by serotypes covered by PCV13 compared to 108 cases covered by PPV23. CONCLUSION: The newly available pneumococcal conjugate vaccines with better serotype coverage have the potential to further reduce IPD burden in Germany. The additional benefit of vaccination of children aged 2-4 years at high risk for pneumococcal infections with PPV23 is questionable.

Impact of the routine varicella vaccination programme on varicella epidemiology in Germany.

Routine varicella vaccination with one dose for children of 11 to 14 months was recommended in Germany in 2004 to reduce disease incidence and severe complications. A country-wide varicella sentinel surveillance system was initiated in 2005 to detect trends of disease frequency and vaccine uptake and to evaluate the vaccination programme. A convenient sample of about 1,000 paediatricians and general practitioners was recruited to report on a monthly basis on varicella cases by age groups seen in their practice, and on varicella vaccine doses administered. Sentinel data from April 2005 to March 2009 show a reduction of 55% of varicella cases in all ages; 63% in the age group 0-4 years and 38% in 5-9-year-olds. The number of vaccine doses per reporting unit in all regions and physician groups increased during the same period. The number of reported cases as well as administered vaccines differed between physician groups and regions with different reimbursement policies. Where reimbursement was settled early and vaccine doses were increasing varicella cases started to decrease early as well. Besides reimbursement policies the availability and vaccination schedules influenced vaccine uptake. Sentinel surveillance provided valid data on trends for varicella associated morbidity, vaccine uptake and the age distribution of cases. The results confirm that following the introduction of routine varicella vaccination, varicella morbidity started to decline in Germany.

Spotlight on measles 2010: preliminary report of an ongoing measles outbreak in a subpopulation with low vaccination coverage in Berlin, Germany, January-March 2010.

Since early January 2010, Berlin has been experiencing a measles outbreak with 62 cases as of 31 March. The index case acquired the infection in India. In recent years, measles incidence in Berlin has been lower than the German average and vaccination coverage in school children has increased since 2001. However, this outbreak involves schools and kindergartens with low vaccination coverage and parents with critical attitudes towards vaccination, which makes the implementation of public health interventions challenging.

[Surveillance programmes to evaluate the effectiveness of vaccination programmes using vaccination against Haemophilus influenzae type b and varicella as examples]. / Durchführung von Surveillanceprogrammen zur Uberprüfung der Wirksamkeit von Impfprogrammen am Beispiel von Haemophilus influenzae Typ b und Varizellen.

To evaluate the effectiveness of vaccination programmes, it is not only important to know the effectiveness of the specific vaccine itself but also to have knowledge about the epidemiology of the corresponding vaccine-preventable disease. Only a high acceptance of a vaccination programme by the population will show an effect at the population level (herd immunity). At the moment, data routinely collected in Germany are not sufficient to evaluate the effectiveness of vaccination programmes. Hence, additional surveillance programmes have to be initialised. The frequency of the vaccine-preventable disease in the population under surveillance determines mainly the design of the surveillance. In this article we describe the different requirements for surveillance programmes for common as well as for rare vaccine-preventable diseases. An example for the latter will be the ESPED study on the effectiveness of hexavalent vaccines against Haemophilus influenzae type b, an example for the first will be the varicella sentinel of the Working Group on Measles and Varicella. Both surveillance programmes for evaluation of the effectiveness of the respective vaccination programme are financed only partly by the public funds. We discuss the possible limitations of a funding from other sources.

[Overview and assessment of available data sources to determine incidence of vaccine preventable diseases, vaccination coverage, and immune status in Germany]. / Uberblick und Bewertung der verfügbaren Datenquellen zur Inzidenz impfpräventabler Krankheiten, zum Durchimpfungsgrad und zum Immunstatus in Deutschland.

The surveillance of vaccine preventable diseases and vaccination coverage is necessary in order to deliver epidemiological data with respect to national vaccination recommendations and control targets. The data available on the incidence of vaccine preventable diseases, vaccination coverage, and immune status of the population are fragmentary and do not allow the epidemiological situation to be fully assessed. Although the majority of vaccine preventable diseases are under surveillance nationwide (by statutory reporting or sentinel surveillance), data are not available for some diseases. In addition, data on vaccination coverage are not collected centrally. Nationwide data on vaccination coverage are only available for children at school entry. Use of secondary data such as data from health insurance companies or associations of statutory health insurance physicians provides an opportunity to close gaps in knowledge and to improve the surveillance of vaccine preventable diseases.

Molecular epidemiology of penicillin-non-susceptible Streptococcus pneumoniae isolates from children with invasive pneumococcal disease in Germany.

A population-based nationwide surveillance of antibiotic resistance associated with invasive pneumococcal disease (IPD) in children and adolescents (aged<16 years) was performed in Germany between 1997 and 2004. In total, 1517 isolates were collected, of which 5.1% and 1.1% were intermediately- or fully-resistant, respectively, to penicillin G. During the 8-year study period, an increase in resistance to both penicillin G and erythromycin A was observed, and the frequency of isolates exhibiting reduced susceptibility to penicillin G or erythromycin A increased from 1.4% and 11.1%, respectively, in 1997, to 8.7% and 29.0%, respectively, in 2004. Among the penicillin non-susceptible pneumococcal isolates, serotypes 14 (24.5% of isolates), 23F (16.0%) and 6B (16.0%) were found most frequently. Multilocus sequence typing of 58 (62%) penicillin G non-susceptible isolates revealed that sequence type (ST) 156 (Spain9V-3 clone) and its single-locus variant ST 557 were widespread in Germany. Moreover, 17 new penicillin G non-susceptible STs were defined for the first time. The study illustrated the genetic heterogeneity of antibiotic-resistant pneumococcal isolates in Germany.

An outbreak of measles in Lower Bavaria, Germany, January-June 2007.

Between January and June 2007, a total of 90 cases of measles were notified in Passau and Rottal-Inn, two districts of Lower Bavaria in south-east Germany sharing a border with Austria.

Two outbreaks of measles in Germany 2005.

Measles re-emerged in some counties in Germany in 2005, despite increasing vaccination coverage rates in children at school entry in recent years, which had led to decreasing incidence (with the lowest incidence ever recorded, 0.2 cases per 100,000 inhabitants in 2004). Regional outbreaks have been detected by the mandatory reporting system in the states of Hesse and Bavaria. Although both outbreaks led to similar incidences in the affected areas (14 and 12 cases respectively per 100,000 inhabitants) they differed in age distribution, transmission patterns and measles virus genotype. In Hesse, 223 cases were submitted, from which 160 belonged to 41 clusters mainly defined by ,000). Results of measles virus diagnosis showed genotype D4 and identical nucleotide sequences for all analysed cases from Hesse. In Bavaria, 279 cases were submitted, most of which had occurred in schools and preschool facilities. Age-specific attack rate was highest in children aged between 5-9 years (129 per 100,000). Laboratory diagnosed viruses were identified as genotype D6 and were identical at the nucleotide level. In both outbreaks the vast majority of cases (95% in Hesse and 98% in Bavaria) were in unvaccinated children, but vaccination coverage differed in the affected areas and was slightly lower in Bavaria than in Hesse. Local accumulation of unvaccinated children and their concentration in schools and kindergarten preceded the outbreak in Bavaria. Despite high average vaccination coverage levels, local variations may lead to regionally limited outbreaks.

1(((5-Nitrofuranyl)methylene)amino)-4 and/or-5-substituted 2-imidazolidinones.

A series of 1-[[(5-nitrofuranyl)methylene]amino]-4- and/or -5-substituted 2-imidazolidinones was prepared utilizing three different reaction sequences. The structure of 4, the product derived from 4-methyl-2-imidazolidinone (2a), was verified by synthesis using an alternate, unequivocal route. The levo isomer l-4 was prepared by a series of reactions starting with L(+)-2-amino-1-propanol (l-10). All of the nitrofurans were examined for potential use as chemotherapeutic agents for urinary tract infections. Based on the high level of activity in the urine and the in vitro antibacterial activity (MIC) 4, l-4, and 16 are considered to be the most active as urinary tract agents.

Haemophilus influenzae type b disease: impact and effectiveness of diphtheria-tetanus toxoids-acellular pertussis (-inactivated poliovirus)/H. influenzae type b combination vaccines.

BACKGROUND: Since 1996 in Germany primary infant immunization against Haemophilus influenzae has been most commonly given in the form of diphtheria-tetanus toxoids-acellular pertussis/H. influenzae type b (DTaP/Hib) or diphtheria-tetanus toxoids-acellular pertussis (-inactivated poliovirus)/H. influenzae type b (DTaP-IPV/Hib) combination vaccines. These combination vaccines elicit lower anti-Hib antibody concentrations than the equivalent Hib conjugate administered as a separate injection, but the clinical relevance of this phenomenon is unknown. METHODS AND FINDINGS: To assess the impact of DTaP/Hib combination vaccines on the incidence of invasive Hib disease in Germany, two independent surveillance systems, one hospital- and one laboratory-based, were used during 1998 and 1999 for detection of cases. Vaccination histories of all cases detected were obtained by telephone contact with parents or health care providers. During the 2-year study period invasive H. influenzae disease in the <5-year age group continued to fall, with a mean annual incidence of 1.01/100 000 children. National vaccination coverage rates revealed that only 70% of children given DTaP/Hib or DTaP-IPV/Hib received the recommended three doses in their first year of life, but the overall effectiveness of these vaccines was high at 97.5% (95% confidence interval, 96.3 to 98.4) for those who had received at least one dose. In subjects who received the full 3-dose schedule, effectiveness was 98.8% (95% confidence interval, 98.2 to 99.3). CONCLUSION: Although it is well-documented that DTaP/Hib vaccines elicit lower anti-Hib titers than separate vaccines, such combinations are effective in reducing the incidence of invasive H. influenzae type b disease.

Anonymous unlinked testing as a sentinel approach: experience in Germany.

STUDY OBJECTIVE: To establish a laboratory sentinel as a supplementary instrument for monitoring the seroprevalence of HIV among childbearing women as a proxy to the heterosexually active population. DESIGN/SETTING: Anonymous unlinked testing of neonatal dried blood spots has been performed in central laboratories of three federal states since 1993. The survey uses residual dried blood spots collected on Guthrie cards for screening of infants for metabolic disorders. These are eluted and tested for HIV antibodies. Data retained with the specimen are only district of residence along with year and month of birth. PARTICIPANTS: Because maternal IgG crosses the placenta before birth, the presence of antibodies in newborns reflects the infection status of the mother. Childbearing women are fairly representative for the heterosexually active general population. MAIN RESULTS: The observed HIV prevalence in childbearing women of less than 1 per thousand confirms the assumption of a low rate of HIV infection in the general population. Significant time trends could not be detected, but HIV prevalence was higher in metropolitan compared with rural areas. CONCLUSIONS: Laboratory sentinels in general and the anonymous unlinked testing of neonatal dried blood spots in particular can supply additional information on HIV seroprevalence. This surveillance system could be expanded to utilise residual samples of other sources as well as to monitor the immunity against specific vaccine preventable diseases and other infectious diseases of public health relevance.

Epidemiology of pneumococcal disease in children in Germany.

UNLABELLED: Recently published and as yet unpublished data allow a reasonable estimate of the annual burden of pneumococcal disease in Germany. At least 277,000 episodes of otitis media and at least 2,000 episodes of sinusitis occur in children under the age of 5 y. Pneumococcal meningitis was found in 200 children under the age of 16 y; the estimate for all age groups ranges from 450 to 1100 cases. Of approximately 150,000 cases of ambulatory pneumococcal pneumonia, at least 63,000-105,000 patients are hospitalized each year. CONCLUSION: Further studies of pneumococcal epidemiology in Germany are needed, and continued surveillance will be necessary for a better understanding of the overall burden of pneumococcal disease in children as well as adults.