The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.

The European sero-epidemiology network (ESEN2) aims to standardise serological surveillance of varicella zoster virus (VZV) in 11 participant countries. In each country, serum banks were collected between 1996 and 2003 and tested for VZV antibodies. Assay results were standardised so that international comparisons could be made. Age-specific forces of infection were calculated for three age groups (<5, 5-9 and >or=10 years of age) and used to estimate the base reproduction number (R(0)) and the herd immunity threshold (H). Most VZV infection occurred in childhood, but there was a wide variation in transmissibility, with R(0) ranging from 16.9 in the Netherlands to 3.3 in Italy. Herd immunity thresholds varied from 70% in Italy to 94% in the Netherlands. There are substantial differences in VZV sero-epidemiology within the European region, which will need to be taken into account in designing national policies regarding VZV vaccination.

Standardization of measles, mumps and rubella assays to enable comparisons of seroprevalence data across 21 European countries and Australia.

The aim of the European Sero-Epidemiology Network is to establish comparability of the serological surveillance of vaccine-preventable diseases in Europe. The designated reference laboratory (RL) for measles, mumps, rubella (MMR) prepared and tested a panel of 151 sera by the reference enzyme immunoassay (rEIA). Laboratories in 21 countries tested the panel for antibodies against MMR using their usual assay (a total of 16 different EIAs) and the results were plotted against the reference results in order to obtain equations for the standardization of national serum surveys. The RL also tested the panel by the plaque neutralization test (PNT). Large differences in qualitative results were found compared to the RL. Well-fitting standardization equations with R2> or =0.8 were obtained for almost all laboratories through regression of the quantitative results against those of the RL. When compared to PNT, the rEIA had a sensitivity of 95.3%, 92.8% and 100% and a specificity of 100%, 87.1% and 92.8% for measles, mumps and rubella, respectively. The need for standardization was highlighted by substantial inter-country differences. Standardization was successful and the selected standardization equations allowed the conversion of local serological results into common units and enabled direct comparison of seroprevalence data of the participating countries.

Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1.

Primary hyperoxaluria is characterized by severe urolithiasis, nephrocalcinosis, and early renal failure. As treatment options are scarce, we aimed for a new therapeutic tool using colonic degradation of endogenous oxalate by Oxalobactor formigenes. Oxalobacter was orally administered for 4 weeks as frozen paste (IxOC-2) or as enteric-coated capsules (IxOC-3). Nine patients (five with normal renal function, one after liver-kidney transplantation, and three with renal failure) completed the IxOC-2 study. Seven patients (six with normal renal function and one after liver-kidney transplantation) completed the IxOC-3 study. Urinary oxalate or plasma oxalate in renal failure was determined at baseline, weekly during treatment and for a 2-week follow-up. The patients who showed >20% reduction both at the end of weeks 3 and 4 were considered as responders. Under IxOC-2, three out of five patients with normal renal function showed a 22-48% reduction of urinary oxalate. In addition, two renal failure patients experienced a significant reduction in plasma oxalate and amelioration of clinical symptoms. Under IxOC-3 treatment, four out of six patients with normal renal function responded with a reduction of urinary oxalate ranging from 38.5 to 92%. Although all subjects under IxOC-2 and 4 patients under IxOC-3 showed detectable levels of O. formigenes in stool during treatment, fecal recovery dropped directly at follow up, indicating only transient gastrointestinal-tract colonization. The preliminary data indicate that O. formigenes is safe, leads to a significant reduction of either urinary or plasma oxalate, and is a potential new treatment option for primary hyperoxaluria.

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.

The seroepidemiology of Bordetella pertussis infection in Western Europe.

High titres of pertussis toxin (PT) antibody have been shown to be predictive of recent infection with Bordetella pertussis. The seroprevalence of standardized anti-PT antibody was determined in six Western European countries between 1994 and 1998 and related to historical surveillance and vaccine programme data. Standardized anti-PT titres were calculated for a series of whole-cell and acellular pertussis vaccine trials. For the serological surveys, high-titre sera (> 125 units/ml) were distributed throughout all age groups in both high- (> 90%) and low-coverage (< 90%) countries. High-titre sera were more likely in infants in countries using high-titre-producing vaccines in their primary programme (Italy, 11.5%; Western Germany, 13.3%; France, 4.3%; Eastern Germany, 4.0%) compared to other countries (The Netherlands, 0.5%; Finland, 0%). Recent infection was significantly more likely in adolescents (10-19 years old) and adults in high-coverage countries (Finland, The Netherlands, France, East Germany), whereas infection was more likely in children (3-9 years old) than adolescents in low-coverage (< 90%; Italy, West Germany, United Kingdom) countries. The impact and role of programmatic changes introduced after these surveys aimed at protecting infants from severe disease by accelerating the primary schedule or vaccinating older children and adolescents with booster doses can be evaluated with this approach.

European Sero-Epidemiology Network: standardisation of the assay results for pertussis.

A standardisation process was developed in order to compare and harmonize serological results of pertussis toxin (PT) antibody measurements performed by laboratories using different technical procedures for detection. This involved the development of a common panel, of sera by a designed reference centre, the distribution of the panel to each participating laboratory for testing with their routine methods, the comparison of the obtained results to those of the reference centre, and the calculation of standardisation equations by regressing the quantitative results against those of the reference centre. As a cut-off indicative of protection against pertussis has not yet been defined, a particular emphasis was laid upon achieving standardisation of high titre results that would allow epidemiological evaluations based on the estimation of the incidence of recent infections rather than on the traditional approach of determining the population immunity profile. A generally good agreement was achieved between the participating laboratories, all using ELISA procedures very similar in many crucial aspects, and standardisation equations were produced useful to enable inter-country comparison during the next stages of the European Sero-Epidemiology Network (ESEN) project concerning the serological surveillance of immunity to pertussis in Europe.

Sero-epidemiology of mumps in western Europe.

Six countries (Denmark, England and Wales, France, Germany, Italy and The Netherlands) conducted large serological surveys for mumps, in the mid-1990s, as part of the European Sero-Epidemiology Network (ESEN). The assay results were standardized and related to the schedules and coverage of the immunization programmes and the reported incidence of mumps. Low incidence of disease and few susceptibles amongst adolescents and young adults was observed in countries with high mumps vaccine coverage (e.g. The Netherlands). High disease incidence and large proportions of mumps virus antibody negative samples in adolescent and young adult age groups was noted in countries with poor vaccine coverage (e.g. Italy). The build-up of susceptibles in older children and adolescents in England and Wales, France, the former West Germany and Italy indicate the possibility of further mumps outbreaks in secondary school environments. To control mumps in western Europe, current MMR immunization programmes will need to be strengthened in a number of countries. Sero-surveillance of mumps is an important component of disease control and its usefulness will be enhanced by the development of an international mumps standard.

[Laboratory tests in The Child and Adolescent Health Survey]. / Laboruntersuchungen im Kinder- und Jugendgesundheitssurvey.

Laboratory tests will be performed as part of the National Health Survey for Children and Adolescents to identify health risks and to determine the seroprevalence of disease markers. The parameters were selected from haematology, clinical chemistry, allergology, endocrinology and serology of infectious diseases as indicators of individual health risks, to validate information collected by means of the questionnaires and to identify age specific immunity gaps of vaccine-preventable diseases.

[The Child and Adolescent Health Survey as a source of data for assessment of the essential aspects of health care in childhood and adolescence]. / Der Kinder- und Jugendgesundheitssurvey als Datenquelle zur Beschreibung wesentlicher Aspekte der gesundheitlichen Versorgung im Kindes- und Jugendalter.

The German National Health Survey for Children and Adolescents aims at collecting representative data on the health status of the population in the 0 to 18 years age bracket. Examination of about 18.000 participants is planned. In this cross-sectional study relevant data concerning health services will be gathered. These include parameters of health care demands, health insurance, vaccination status and drug utilisation. The data collection will start in the first quarter of 2003 and will probably be terminated in the last quarter of 2005. The study design has been tested in a pilot study for one year and was adapted to the demands of this specific health survey. The instruments used for data collection are a self-administered questionnaire as well as a standardised, computer-based medical interview.

[Surveillance of measles in Germany]. / Masernüberwachung in Deutschland.

In Germany, as in the entire WHO Region Europe, the goal has been set to eliminate measles by the year 2007. In order to achieve this, high vaccination rates of >/= 95 % are necessary as well as an intensive surveillance consisting of a continuous record of the age and region-specific incidence, vaccination rates and the seroprevalence. Data on the vaccination status, recorded in the districts at the time of school entry, are collected centrally and evaluated at the RKI since 1998. The vaccination rate for the 1(st) dose against measles is on the average 84.6 % and for the 2(nd) dose 14.3 %. A nationwide sentinel established in 1999 with over 1200 medical practitioners permits an estimate of the country-wide measles incidence on the basis of the registered measles cases. Results from the year 2000 showed a very big difference between the old Federal States (mean incidence of 46.8 illness per 100 000) and the new Federal States (0.9 per 100 000). Most of those falling sick were unvaccinated (85.4 %), where 35 % refused the vaccination. Thirty-nine percent of the cases were examined in the laboratory and from these 58 % were clinically confirmed; 10 % of the cases occurred in those receiving one dose of vaccine and none in those receiving 2 doses. The age peak of the sick children was between 1 to 4 years of age. Measles notification is obligatory in Germany since January 2001. From these data, the incidence of the 1(st) quarter has been calculated. It varies widely depending on the State (e. g. Bavaria 5.7 / 100.000 vs < 0.5 % in new Federal States). The seroprevalance studies conducted in 1993 and in 1995/96 show large gaps in immunity of small children and suggests that the MMR vaccination may have been carried out too late. The elimination of measles in Germany can only be achieved if the vaccination rates are increased and the 1(st) MMR vaccination is performed as early as possible. In particular, the vaccination rates for the 2(nd) dose are inadequate to be able to reach those with vaccine failures in a greater proportion and to close the gaps of vaccination.

Seroprevalence of varicella-zoster virus in the German population.

The present study was conducted to generate data on the epidemiology of varicella-zoster virus (VZV) infections in Germany as a basis for health economic evaluations of varicella vaccination strategies. The survey was designed as a cross-sectional, age-stratified study of the VZV seroprevalence in the German population. The status of immunity of 4602 individuals a aged 0 to >70 years was investigated by means of an indirect enzyme immunoassay and the fluorescent antibody to membrane assay. After waning of maternal antibodies over the period of 6-9 months seropositivity rates remained low by the end of the 1st year of life. By the age of 4-5 years 62.5% (95% CI; 56.0-68.5) of the pre-school children had already been infected with VZV and at the age of 10-11 years 94.2% (95% CI; 91.0-96.0) of children were positive for anti-VZV antibodies. Among the age-group of >40 years old, only few individuals were susceptible for VZV. The median antibody levels to VZV did not significantly decline with increasing age. In comparison with figures of previous studies the age-specific seroprevalence data presented here do not provide evidence for an upward shift in the age distribution of varicella in Germany. Since the majority of VZV infections occurs during the early childhood, the best option to reduce the circulation of wild-type VZV in the population would be the immunization of young children.

The seroepidemiology of rubella in western Europe.

Most of the countries in western Europe have now implemented mass infant rubella immunization programmes, instead of or in addition to selective vaccination in order to achieve the elimination of congenital rubella syndrome. The European countries Denmark, England and Wales, Finland, France, Germany, Italy and the Netherlands undertook large, national serological surveys collecting several thousand serum specimens during 1994-8. Antibodies against rubella virus were detected by a variety of enzyme immuno-assays. Comparability of the assay results was achieved by a standardized methodology. The age- and sex-stratified serological results were related to the schedules, coverage of rubella vaccination and the incidence in these countries. The results show widely differing levels of immunity to rubella both in the general population and in the specific age groups of males and females. A low rate (< 5%) of susceptibles in childhood and adolescents of both sexes was obtained only in Finland and the Netherlands. Countries such as Italy with only moderate coverage for the infant immunization programme currently have both high susceptibility levels in the general population and in the at-risk population. The likelihood is of continued epidemics of rubella with cases of congenital rubella syndrome. The continued implementation of selective vaccination will help to offset the impact of this ongoing transmission and to protect women on reaching childbearing age.

The sero-epidemiology of diphtheria in Western Europe. ESEN Project. European Sero-Epidemiology Network.

Seven countries in Western Europe collected large, representative serum banks across the entire age range and tested them for diphtheria anti-toxin (sample size ranged from 2991 to 7715). Although a variety of assays were used, the results were all standardized to those of a reference laboratory and expressed in international units. The standardization process, and the availability of similar, large data sets allowed comparative analyses to be performed in which a high degree of confidence could be ascribed to observed epidemiological differences. The results showed that there were large differences in the proportion of adults with insufficient levels of protection amongst different countries. For instance, roughly 35% of 50- to 60-year-olds were found to be seronegative (titre < or = 0.01 IU/ml) in Finland compared with 70-75% in the United Kingdom. Furthermore, the proportion of seronegative adults would be expected to increase in some countries, notably Italy and the western part of Germany. In those countries with vaccination of military recruits there was a marked sex-related difference in the proportion of seropositive individuals. All countries have high levels of infant vaccine coverage (> 90%) but the accelerated schedule in the United Kingdom appears to result in lower anti-toxin titres than elsewhere. In Sweden, booster doses are not offered until 10 years of age which results in large numbers of children with inadequate levels of protection. Although the United Kingdom and Sweden both have higher proportions of seronegative children than elsewhere the likelihood of a resurgence of diphtheria in these countries seems remote.

The European Sero-Epidemiology Network: standardizing the enzyme immunoassay results for measles, mumps and rubella.

The ESEN (European Sero-Epidemiology Network) project was established to harmonize the seroepidemiology of five vaccine preventable infections including measles, mumps and rubella in eight European countries. This involved achieving comparability both in the assay results from testing in different centres and also sampling methodology. Standardization of enzyme immunoassay results was achieved through the development of common panels of sera by designated reference centres. The panels were tested at the reference laboratory and then distributed to each participating laboratory for testing using their routine methods. Standardization equations were calculated by regressing the quantitative results against those of the reference laboratory. Our study found large differences in unitage between participants, despite all using an EIA method standardized against an international or local standard. Moreover, our methodology adjusted for this difference. These standardization equations will be used to convert the results of main serosurvey testing into the reference country unitage to ensure inter-country comparability.

European sero-epidemiology network: standardisation of the results of diphtheria antitoxin assays.

A European Sero-Epidemiological Network (ESEN) was established with the aim to co-ordinate and harmonise serological surveillance of immunity to communicable diseases in Europe. In this study the inter-laboratory standardisation of diphtheria toxin antibody measurements is reported. A standard panel of 162 sera was tested by the participating laboratories using an in vitro assay of their choice: VERO cell toxin neutralisation assay (NT), double-antigen delayed time-resolved fluorescence immuno-assay (DA-DELFIA), double-antigen enzyme-linked immunosorbent assay (DAE), toxin binding inhibition test (ToBI) and an indirect enzyme-linked immunosorbent assay (ELISA). The results were standardised using regression against the NT. The variations due to inter-laboratory and inter-assay variation, which would otherwise make it difficult directly to compare the main serum bank results by the different laboratories and the various assays were successfully minimised by the standardisation. The regression equations obtained will be used to transform the respective local results of testing the main serum bank into the reference test unitages. This study also gave the opportunity to compare the various assays within and between laboratories. This demonstrated a very high correlation between DA-DELFIA, DAE, ToBI and the NT. The ELISA showed a good correlation, too, however sera below some 0.1 IU/ml were overestimated.

Immune response after primary and re-vaccination with different combined vaccines against measles, mumps, rubella.

The humoral immune response after primary and re-vaccination confirmed the high immunogenicity of the combined vaccines used: "MMR-Vax(R)", "Pluserix(R)" and "Triviraten(R)". The investigation of paired serum samples of prevaccinal seronegative infants (n90-100% for all three components with the exception of the mumps component of "Triviraten(R)" (38%). However, by additional methods (plaque neutralisation test, immunofluorescence test) mumps antibodies could be detected in 93.4% of infants having received vaccine "Triviraten(R)". The mean values of antibody activities against the three components did not differ significantly after vaccination with "MMR-Vax(R)" and "Pluserix(R)". However, after vaccination with "Triviraten(R)" the mean antibody values were significantly lower (P<0.01) against the measles strain "Edmonston-Zagreb" and especially lower (2-20 times) against the mumps virus strain "Rubini". Revaccination of pre-vaccinal seropositive schoolchildren and adolescents (n=676) with "MMR-Vax(R)" and "Pluserix(R)" produced no different results. The rate of vaccinees responding with a booster reaction reached 68.4% for measles and mumps, but only 8.6% for rubella. A booster reaction could be observed in 100% of those vaccinees who had antibodies at a low level, also in the case of naturally acquired immunity. The low-level range for antibodies against measles was defined as 0.15<0. 40 IU/ml, mumps 1:230

Safety and characterization of the immune response engendered by two combined measles, mumps and rubella vaccines.

We performed a randomized trial to compare the safety and immunogenicity of two combined measles, mumps and rubella vaccines in healthy children 14-24 months of age. Triviraten Berna Vaccine (Swiss Serum and Vaccine Institute), contains the Edmonston Zagreb 19 strain of measles virus, the Rubini mumps virus strain and the Wistar RA 27/3 rubella strain while MMR-Vax (Merck, Sharp & Dohme, West Point, PA) contains the Enders attenuated Edmonston measles strain, the Jeryl Lynn mumps strain and the Wistar RA 27/3 rubella strain. Immunization with Triviraten Berna was associated with a significantly lower incidence of swelling and redness at the injection site in addition to a reduced rate of fever compared with MMR-Vax. Seroconversion rates for the measles and rubella vaccine components were comparable in all tests used. However, seroconversion for the mumps vaccine component was test-dependent. Using an ELISA, the seroconversion rate following immunization with MMR-Vax was significantly (P < 0.01) higher than for Triviraten Berna. In contrast, nearly identical rates were obtained using an indirect immunofluorescence test. Both vaccines were equally effective at engendering antibodies capable of neutralizing wild type mumps virus. Geometric mean ELISA antibody titers against measles and mumps virus were higher following immunization with MMR-Vax while that for rubella was higher after immunization with Triviraten Berna. A small number (N = 13) of adolescents immunized either with MMR-Vax or Triviraten Berna were reimmunized with Triviraten Berna and various humoral and cellular response parameters to the measles and mumps vaccine components analyzed. While few subjects mounted a humoral antibody response to measles, most likely due to elevated baseline titers, there was a marked lymphoproliferative response. Anti-mumps virus ELISA antibody titers were higher both at baseline and after reimmunization in subjects who received MMR-Vax for primary immunization. However, there was no difference in either neutralizing titer or proliferative response in subjects primed with MMR-Vax or Triviraten Berna either before or after reimmunization.

A method for the bony and dental reconstruction of the maxilla in dentate patients.

Reconstruction was carried out on eleven patients using a vascularized full thickness calvarial bone flap following partial maxillectomy. The donor site was covered with a split calvarial bone graft. Intraorally a mucosal transposition flap was used to cover the graft. Six months later implants were inserted and were allowed to heal for three months before dental rehabilitation began. No serious complications were encountered.

[Improving the facial profile by implant supported dentures]. / Untersuchung zur Profilverbesserung durch implantatgetragenen Zahnersatz.

Forty toothless patients were examined over a period of 3 years for the purpose of improving the face profile after integration of implant-supported, removable full dentures. The data before the treatment were related to the corresponding normal values. The same parameters were measured 3 months after the prosthetic treatment was finished and were compared to the preoperative data. In all parameters we saw an significant increase in the normal value rate.