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Epidemiological data, especially population-based data, on respiratory syncytial virus (RSV)-related hospitalizations in Germany have been lacking to date. Since Palivizumab (Synagis, Abbott, USA) is already available and new vaccines for active immunization are under development, these data are urgently needed. From July 1996 to June 1999, nasopharyngeal aspirates of children hospitalized in Kiel with an acute respiratory tract infection were tested by multiplex reverse transcriptase polymerase chain reaction. Of 1,241 patients, 150 (12.1%) were RSV positive. RSV was the predominant pathogen detected through the end of the second year. In 37 (25%) children an underlying condition was present. For the city of Kiel and close surroundings, the cumulative incidence of RSV-positive hospitalizations in infants was 1,214/10(5) (725/10(5) in children less than 2 years). For those children less than 2 years old born with a gestational age of less than 32 weeks or 32-37 weeks, the cumulative incidence was 2,025/10(5) and 1,202/10(5), respectively (dose-effect response). For the group less than 32 weeks of age, bronchopulmonary dysplasia (BPD) as an underlying condition carried a relative risk of 17.8. The RSV season began between the end of September and January and ended between March and July. The population-based incidence of RSV-positive hospitalizations in Kiel is close to that reported from the UK and Scandinavia. Throughout Germany, approximately 10.000 RSV-related hospitalizations in infants can be expected annually. Prematurity is an effect modifier and BPD a strong risk factor for RSV-positive hospitalization in population-based studies. There is considerable variation in the start and end of the yearly epidemic. more...

To assess the reactogenicity and immunogenicity of the Biken acellular pertussis vaccine (Pa) following administration of a single vaccine dose to young adults with or without a history of prior pertussis immunization, 104 healthy, male and female adults without primary pertussis immunization were enrolled in Mainz (former West Germany; "not previously pertussis vaccinated", N-PPV-group); in parallel, 103 adults with a history of having received >/=four doses of a combined diphtheria-, tetanus-toxoid, whole-cell pertussis vaccine (DTwP) were enrolled in Magdeburg (former East Germany; "previously pertussis-vaccinated", PPV-group). Large areas of redness (>20 mm) were seen in 2.9%/1.0% of subjects in the N-PPV/PPV group, and a large swelling was seen in 6.8%/1.0%, respectively. As compared to baseline concentrations, antibody titers to PT and FHA were 77-(PT)/64-(FHA) (N-PPV group) and 94-(PT)/126-(FHA) fold (PPV group) higher. The study vaccine was safe and induced infrequent and mostly mild, local and general symptoms that all resolved spontaneously; it was highly immunogenic in adults, whether or not they had been previously vaccinated with DTwP. more...

Objective: The aim of this open, multicenter, randomized trial was to evaluate the immunogenicity and reactogenicity of a candidate combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio virus (DTaP-HBV-IPV) vaccine when given as either a mixed or as separate concomitant injections with Haemophilus influenzae type b (Hib) vaccine., Study Design: A total of 359 subjects were randomized to receive either DTaP-HBV-IPV/Hib (mixed administration - 180 subjects) or DTaP-HBV-IPV + Hib (separate administration in opposite limbs - 179 subjects) at 2, 3, and 4 months of age., Results: After vaccination, seroprotective antibody concentrations against diphtheria, tetanus, hepatitis B, and polio viruses and a high (> or = 97%) pertussis vaccine response were seen in almost all study participants. All subjects except one in the mixed administration group had postvaccination Hib anti-PRP antibody concentrations > or = 0.15 microg/mL. Of subjects in the mixed and separate group, 77.2% (geometric mean antibody concentration, 2. 62 microg/mL) and 88.6% (geometric mean antibody concentration, 4.45 microg/mL) had Hib anti-PRP concentrations > or = 1 microg/mL, respectively. The addition of the Hib component to the 5-component vaccine did not increase the incidence of local or general reactions., Conclusion: Both administrations of the candidate vaccine were found to be safe, immunogenic, and well tolerated. Although anti-PRP geometric mean antibody concentrations and the percent of subjects achieving the 1 microg/mL seroprotective level were lower after the mixed administration, they were in the range seen with monovalent Hib vaccines or with other DTaP-based/Hib combinations licensed in some European countries. Therefore both administrations have the potential to simplify childhood immunization. more...

The incidence and serotype distribution of Streptococcus pneumoniae as a cause of invasive diseases are unknown with regard to most European countries. From January 1997 through December 1998, population-based nationwide prospective surveillance was undertaken for invasive pneumococcal disease (IPD) in children in Germany, based on monthly independent reports from all pediatric hospitals and from clinical microbiology laboratories. On the basis of 896 reported IPD cases (including 404 with meningitis), the incidences per 10(5) children in different age groups were as follows: children aged <1 year, 18.9 (9.7 for meningitis); children aged <2 years, 16. 0 (7.2 for meningitis); for children aged <5 years, 8.9 (3.9 for meningitis); and for children aged <16 years, 3.2 (1.4 for meningitis). The proportions of cases involving strains (304 serotyped) included in conjugate vaccines were as follows: for the 7-valent vaccine, 52%; for the 9-valent, 62%; and for the 11-valent, 71%. None of the isolates were resistant to penicillin or cefotaxime. Although the rate for meningitis is similar, other manifestations of IPD are less commonly diagnosed in Germany than in other countries. The serotype distribution only partially matched that used in the recent development of pneumococcal conjugate vaccines. more...

The aim of this study was to generate urgently needed data on respiratory pathogens in German children using an economical and efficient tool. Nasopharyngeal aspirates of hospitalized children 0-16 years of age with an acute respiratory tract infection were tested by a nine-valent multiplex reverse-transcriptase polymerase chain reaction. Of 1281 children, 449 (35%) had an acute respiratory tract infection caused by at least one of the organisms studied; there were 29 cases of dual infection. At least 34-42% of severe acute respiratory tract infections in children under 5 years of age were caused by viruses. In children over 5 years of age, this proportion was 23% (P<0.001). Infection during the first 2 years of life was most frequently due to respiratory syncytial virus (n = 162 cases). Parainfluenza virus type 3 (n = 22) and type 1 (n = 14) were detected almost exclusively in children under 5 years of age. Influenza A (n = 90) and adenoviruses (n = 98) were prevalent in all age groups. The frequency of influenza B virus isolation (n = 17) rose significantly after the age of 5 years. Mycoplasma pneumoniae infection (n = 24 cases, 5.2%) was most frequent in 5- to 16-year-old patients. Only one case of Chlamydia pneumoniae infection was found. Since the distribution of pathogens within the different types of lower respiratory tract infections is very similar, it seems that host factors determine which form of lower respiratory tract infection develops in an individual patient. The multiplex reverse-transcriptase polymerase chain reaction may, in the future, become an important tool for epidemiological studies as well as for individual diagnosis. more...

Objective: This study was designed to investigate the differences between TIVA with propofol/remifentanil (P/R) and balanced anaesthesia with sevoflurane/fentanyl (S/F) in gynaecological laparoscopic surgery. Emphasis was put on haemodynamic reaction, recovery profile, postoperative side effects and patient satisfaction., Methods: Sixty patients were randomly assigned to receive either total intravenous anaesthesia with propofol/remifentanil or anaesthesia with sevoflurane/fentanyl. After premedication (midazolam) and induction of anesthesia (propofol, atracurium) in both groups, either 1 microgram/kg fentanyl (S/F) or 1 microgram/kg remifentanil (P/R) was injected. Anaesthesia was maintained with 0.5 microgram/kg/min remifentanil (reduced to 50% after 5 min) and 0.06 microgram/kg/min propofol (P/R) or 1.7 vol % sevoflurane (S/F). Both groups were mechanically ventilated with 30% oxygen in air. The administration of sevoflurane and the infusion of the anaesthetics were adjusted to maintain a surgical depth of anaesthesia. For postoperative analgesia 1 g paracetamol was administered rectally prior to surgery. After recovery 20 mg/kg metamizol was given intravenously. At the end of surgery the anaesthetics were discontinued and haemodynamics, early emergence from anaesthesia, pain level, frequency of analgesic demand, incidence of PONV, shivering and patient satisfaction were assessed. Parameters were recorded for 24 h postoperatively., Results: Recovery time after propofol-remifentanil anaesthesia was significantly shorter than after administration of sevoflurane and fentanyl (spontaneous ventilation 4.1 vs. 6.3 min, extubation 4.3 vs. 9.3 min, eye opening 4.4 vs 8.2 min, stating name 5.3 vs. 13.2 min, stating date of birth 5.4 vs. 13.3 min). There were no significant differences between the groups in shivering, pain score, analgesic demand and PONV. The S/F group responded to tracheal intubation with significantly higher blood pressure than the P/R group. During maintenance of anaesthesia heart rate in patients with S/F was significantly higher (P/R:HR max +16/-10; S/F:HR max +24/-0.). Measured on a scale (S/F 62%)., Conclusion: Compared with patients given balanced anaesthesia with sevoflurane and fentanyl, TIVA with propofol and remifentanil proved to be particularly suited for gynaecological laparoscopic surgery. Its major advantages are haemodynamic stability, significantly shorter times of emergence, and the exceptional acceptance by the patients. more...

This study was performed to evaluate the sensitivity of immunoglobulin (Ig)G and IgA antibodies to pertussis toxin and filamentous hemagglutinin in diagnosing pertussis from a single serum sample. The pertussis group was defined according to the World Health Organization pertussis case definition. The control group coughed for 21 days or more but had no microbiological or serological evidence of Bordetella infection. Both cohorts were divided into infants (< 12 months of age), toddlers (1-4 years) and school children (5-10 years). There were 525 subjects in the pertussis group and 321 in the control group, with an even distribution of genders. IgG and IgA antibodies to pertussis toxin and filamentous hemagglutinin were measured in a standardized enzyme immunoassay. Antibody levels beyond the 95 percentile of the control cohort were regarded as indicative of recent contact, setting the specificity level at 0.95. Acute serum samples drawn between 1 week and 3 weeks after the onset of coughing showed a low sensitivity (2-19%) for diagnosing pertussis. In convalescent samples taken 5-10 weeks after the onset of symptoms, detection of IgG anti-pertussis toxin was the best single test, with a sensitivity of 61%, 65%, and 74% in infants, toddlers and school children, respectively. A combination of IgG anti-pertussis toxin and IgA anti-filamentous hemagglutinin using age-specific reference values had a sensitivity of 81-89% in diagnosing pertussis from a single serum sample taken 5-10 weeks after the beginning of symptoms. more...

Background: Chickenpox and zoster are an important cause of morbidity among children and adults. The ability of a new, thermostable vaccine to induce varicella-zoster-virus (VZV)-specific humoral and cell mediated immunity when given simultaneously with diphtheria-tetanus-acellular pertussis vaccine (DTaP) as a booster dose in the second year of life was investigated., Methods: A new, temperature stable varicella vaccine (OKA-strain, SB-Biologicals, Rixensart, Belgium) was given simultaneously with a booster dose of DTaP vaccine. VZV-specific humoral and cell-mediated immunity was studied in the first 27 out of 232 vaccinated children at 16-28 months of age, from blood samples drawn just before and six weeks after vaccination. VZV-specific antibody response, T-cell proliferation, cytokine production and expression of activation markers (CD25, HLADR) on T-cells were analyzed., Results: Vaccination resulted in a significant rise of VZV-specific serum IgG titers and in a strong VZV-specific T-cell response in all vaccinated infants. Analysis of the expression of activation marker revealed activation of both CD4+-T-helper- and CD8+-T-cells., Conclusions: The varicella vaccine given simultaneously with DTaP produced strong B- and T-cell responses alike. This is the first report to show that CMI to VZV is conferred to young children by vaccination with a temperature stable VZV vaccine. more...

Acute respiratory tract infections (ARIs) are leading causes of morbidity and, in developing countries, mortality in children. A multiplex reverse transcription-PCR (RT-PCR) assay was developed to allow in one test the detection of nine different microorganisms (enterovirus, influenza A and B viruses, respiratory syncytial virus [RSV], parainfluenzaviruses type 1 and type 3, adenovirus, Mycoplasma pneumoniae, and Chlamydia pneumoniae) that do not usually colonize the respiratory tracts of humans but, if present, must be assumed to be the cause of respiratory disease. Clinical samples from 1,118 children admitted to the Department of Pediatrics because of an ARI between November 1995 and April 1998 were used for a first clinical evaluation. Detection of one of the microorganisms included in the assay was achieved for 395 of 1,118 (35%) clinical samples, of which 37.5% were RSV, 20% were influenza A virus, 12.9% were adenovirus, 10.6% were enterovirus, 8.1% were M. pneumoniae, 4.3% were parainfluenzavirus type 3, 3.5% were parainfluenzavirus type 1, 2.8% were influenza B virus, and 0.2% were C. pneumoniae. Seasonal variations in the rates of detection of the different organisms were observed, as was expected from the literature. The levels of concordance with the data obtained by commercially available enzyme immunoassays were 95% for RSV and 98% for influenza A. The results show that the multiplex RT-PCR-enzyme-linked immunosorbent assay is a useful and rapid diagnostic tool for the management of children with ARI. Studies of the overall benefit of this method with regard to the use of antibiotics, the use of diagnostic procedures including additional microbiological tests, and hospitalization rate and duration are warranted. more...

Objective: To assess the frequency of serologic evidence for an infection with microorganisms other than Bordetella pertussis in children with pertussis-like coughs., Methods: The study was performed within a protective efficacy trial of an acellular pertussis vaccine. Children who coughed for >7 days and had no laboratory evidence of recent infection with B. pertussis were eligible for the present study. Antibodies to Mycoplasma, Chlamydia, respiratory syncytial virus and influenza viruses A and B were measured by complement fixation, and antibodies to adenovirus and parainfluenza viruses 1, 2 and 3 were measured by enzyme-linked immunosorbent assay (ELISA) in acute and convalescent serum samples. Significant titer rises (4-fold titer rise in complement fixation, 100% increase of units in ELISA) and concentrations of antibodies beyond age-specific reference values were regarded as indicative of recent infection. In some children IgM antibodies to Epstein-Barr virus and to cytomegalovirus were also measured by ELISA., Results: A total of 149 of 1179 (12.6%) children had no laboratory evidence of B. pertussis infection. Serologic evidence for other infections were found in 56% (83 of 149). Adenovirus (33), parainfluenza viruses 1, 2 and 3 (18), Mycoplasma pneumoniae (15) and respiratory syncytial virus (14) were most common. Of this group 48% had been vaccinated against pertussis., Conclusion: We present data that a proportion of pertussis-like coughs in children may be caused by adenovirus, parainfluenza viruses, respiratory syncytial virus and Mycoplasma. The differential diagnosis of pertussis-like coughs by laboratory methods should include these infections, especially in vaccinated children. more...

A new noninvasive technique that reveals cross sectional images of scattering media is presented. It is based on a continuous wave frequency modulated radar, but uses a tunable laser in the near infrared. As the full width at half maximum resolution of 16 μm is demonstrated with an external cavity laser, the chirp optical coherence tomography becomes an alternative to conventional short coherence tomography with the advantage of a simplified optical setup. The analysis of two-layer solid phantoms shows that the backscattered light gets stronger with decreasing anisotropic factor and increasing scattering coefficient, as predicted by Monte Carlo simulations. By introducing a two-phase chirp sequence, the combination of lateral resolved perfusion and depth resolved structure is shown. © 1998 Society of Photo-Optical Instrumentation Engineers. more...

Unlabelled: Acellular pertussis vaccines are less reactogenic than whole cell pertussis vaccines, but they are also more expensive. Based on simulation models, we compared the costs and effects of three alternative pertussis vaccination strategies in German children to "no prevention": (1) vaccination with whole-cell vaccine at 45% coverage (vaccine efficacy 90%), (2) vaccination with acellular vaccine at 45% coverage (vaccine efficacy 85%), and (3) vaccination with acellular vaccine at 90% coverage. In the two low coverage scenarios expected annual savings in direct medical costs through prevention of disease were larger for whole-cell than for acellular vaccination (252 vs 216 million DM, respectively). Direct costs for treating the more important adverse events induced by whole-cell vaccination (16.9 million DM annually) did not outweigh the higher direct costs of pertussis infections not prevented with the acellular vaccine and the higher price of the acellular vaccine. However, vaccination with acellular pertussis vaccine rapidly becomes as cost saving as vaccination with whole-cell vaccine as soon as vaccination coverage can be raised from 45% to 52.5% with acellular vaccine. Acellular vaccination is also the superior alternative when considering indirect cost savings resulting from reduction in work-loss due to adverse events., Conclusion: In our simulations, the most cost-effective pertussis prevention strategy was the use of an effective whole-cell vaccine with a high coverage rate. Introduction of the more expensive acellular pertussis vaccines becomes cost saving if at least a 7.5% increase in coverage is achieved. If also non-medical indirect costs to parents resulting from vaccine associated side-effects are accounted for, acellular vaccines may be more cost-effective also in countries with already high whole-cell vaccine coverage. more...

Unlabelled: The objective of this study was to compare the spread of pertussis in children and adults being secondary contacts after household exposure. The study was nested in an efficacy trial of an acellular pertussis vaccine. The spread of the disease was also monitored with respect to gender and antibiotic therapy. A total of 453 index cases, of which 133 were monitored for adult disease, fulfilled the WHO definition of pertussis. They had contacts to 173 unvaccinated children aged 6-47 months, and a total of 101 adults with pertussis were followed. Detection of the bacteria, or a significant increase of specific antibodies confirmed the diagnosis. Secondary spread of the disease was assumed, when a household member coughed for 7 days or more and had laboratory evidence for pertussis. Crude attack rates (AR) were 69% in children and 31% in adults (P < 0.05). AR in children were independent of gender but more women than men (P=0.02) were affected in those households where the index case was a child. Erythromycin treatment of the index case reduced the AR in exposed toddlers from 80% to 57% (P=0.06), and in exposed adults from 40% to 21% (P=0.2). Erythromycin therapy in contacts did not alter the clinical course of the disease significantly., Conclusions: In a household study of pertussis, 69% of children and 31% of adults (more women than men) contracted the disease. Erythromycin reduced the number of infections in household contacts, but did not alter the clinical course in those who contracted pertussis. more...

Unlabelled: With an increasing number of new vaccines available for routine childhood immunization, combination vaccines are needed in order to maintain or achieve a high compliance with recommended immunization programmes. In a prospective, randomized, comparative, multi-centre study, 822 healthy infants were enrolled to receive three doses of either a candidate or a commercially available Haemophilus influenzae type b (Hib) vaccine concomitantly with diphtheria-, tetanus- acellular pertussis (DTaP) vaccine. Study subjects were randomly allocated to one of the following groups: (1) separate, or (2) mixed injection of DTaP and candidate Hib vaccine, or (3) separate injection of DTaP and commercial Hib vaccine. One year later the first 189 study subjects received either separate or mixed injections of the same Hib and DTaP vaccines as booster doses. Evaluation of reactogenicity was based on diary cards completed by parents. Immunogenicity was documented by measuring IgG antibody concentrations in serum samples taken before and 4 weeks after primary and booster vaccination. No serious adverse events occurred and most local and systemic reactions were mild to moderate. Booster doses were more reactogenic than primary doses with all groups. Antibody concentrations against pertussis antigens were similar to those seen with DTaP alone. All but one subject had protective antibody concentrations against diphtheria and tetanus. Primary immune response to the Hib vaccine was significantly lower in the group receiving the mixed Hib-DTaP vaccine, however, > or = 95% of vaccinees had anti-Hib antibody concentrations > or = 0.15 microg/ml and there was a marked booster response (> 100-fold) in all groups., Conclusions: Mixing DTaP and Hib vaccines for primary immunization caused a decrease in anti-Hib antibody response, although after primary immunization as after booster doses, all subjects showed antibody concentrations considered to be protective for invasive Hib disease. Mixing of the vaccines did not result in increased reactogenicity. more...

A new technique for breast imaging is presented. This technique combines radiographic mammography directly with automated ultrasound. The combined examination, which is performed without decompression of the breast, yields the conventional mammography films as well as a complete set of B-mode scans and ultrasound projections. These can be geometrically matched with each other in a definitive manner. A prototype of the device was first used in a pilot study of 50 patients followed by a study of an additional 450 patients with a total of 492 breast lesions, of which 269 were confirmed by histology or cytology. The results show that X-ray and ultrasound are complementary in the detection of cancer. The use of an experimental mode of image interpretation for combined mammography and automated ultrasound reduced the number of mammographically suspicious findings that ultimately turned out to be benign. These results were also confirmed in two blind studies including a total of 160 histologically or cytologically confirmed lesions and 40 cases without lesions. With further technical advancement of the technique aimed at rapid and easy application and confirmation of the results obtained so far, the combination of mammography and automated ultrasound might be introduced into a routine clinical setting. more...

To evaluate the reactogenicity and immunogenicity of a Haemophilus influenzae type b conjugate vaccine (HbOC) and of a tricomponent acellular pertussis vaccine (DTaP) when injected simultaneously into either contralateral arms or into contralateral thighs, 110 infants were enrolled to receive three doses of DTaP at 3, 4, and 5 months and two HbOC doses at 3 and 5 months of age. Administration of either of the two vaccines into arms was associated with significantly more local side effects than administration into thighs. There was no difference in geometric mean concentration (GMC) values for any of the four vaccine antigens between subjects who had been vaccinated into arms or thighs. After immunization, all children had protective antibody titers to diphtheria toxin. While post vaccination the mean anti-tetanus toxoid GMC was > or = 1.25 IU/ml, there was no significant rise as compared to the GMC before vaccination. GMCs of antibodies against the various pertussis antigens were similar to those observed before with the same DTaP vaccine. The simultaneous administration of DTaP and HbOC was safe and immunogenic irrespective of the site of vaccine administration, but significantly more local reactions occurred when vaccines were injected into arms. more...

Following concerns about the safety and reactogenicity profile of diphtheria, tetanus and whole cell pertussis vaccines (DTwP), new and less reactogenic alternatives were developed over the last two decades. The new diphtheria, tetanus and acellular pertussis vaccines (DTaP) no longer consist of the whole bacterial cell but of either extracts or of a few highly purified components. While it soon became clear that DTaP vaccines are significantly less reactogenic than DTwP vaccines, their efficacy was disputed and remained unproven. First studies and epidemiological data from Japan suggested vaccine efficacy rates (VE) of about 80%; however, the first blinded clinical trial from Sweden documented a much lower VE. Worldwide, seven large DTaP efficacy trials have recently been completed. Our own efforts included a large safety trial with 22505 vaccinees and, nested in this setting, a prospective household contact study. Typical WHO-defined pertussis developed in 7 of 112 DTaP vaccinated children following household exposure as compared to 96 cases in 173 children not vaccinated against pertussis. Thus, vaccine efficacy was calculated to be 88.7% (95% CI 76.6 to 94.6). The median duration of spasmodic cough in the few children vaccinated with DTaP who did start coughing was 17 days as compared to 35 days in unvaccinated children. No waning of protection was observed. None of the confounding variables analyzed influenced study results in favour of DTaP. Following administration of more than 67000 DTaP doses, 153 serious adverse events were reported. Eight events were considered possibly related and five were considered related to the study vaccine. According to additional study results from the other trials it can be concluded that DTaP vaccines, like DTwP vaccines, are safe and effective. The choice between DTwP and DTaP should be based on acceptance of the reactogenicity profile, coverage rates achieved, costs and other factors in each individual country. more...

Objectives: The primary objective was to assess the nature and incidence of adverse events after a fourth dose of a tricomponent acellular pertussis-diphtheriatetanus vaccine given in the second year of life after primary vaccination with the same vaccine at 3, 4, and 5 months of age. A secondary objective was to analyze the immunogeniecity of the booster vaccination., Design: Of the 5361 children enrolled (aged 14 to 28 months), adverse reactions were specifically solicited from the first 1863 enrollees for the first 4 days after vaccination and then were unsolicited for the remainder of the 4 weeks of follow-up (group 1). In the next 3498 subjects, safety and reactogenicify were entirely unsolicited for this 4-week period (group 2). Immunogenicity was analyzed by means of prebooster and postbooster serum antibody titers for all vaccine components in a random subgroup of 197 children from group 1., Results: Soliciting symptoms elicited reports of at least one symptom in 1314 of 1809 children in group 1 (72.6%), including 993 (54.9%) with local and 885 (48.9%) with general symptoms during the first 4 days after vaccination. When symptoms were gathered in an unsolicited fashion, only 580 of 3498 children in group 2 (16.6%) had a reported symptom during this time, consisting of 344 (9.8%) local and 319 (9.1%) general symptoms, respectively. An unsolicited symptom, areactive edematous swelling of the whole thigh, occurred in 62 children (1.1%), with 45 and 17 reports in groups 1 and 2, respectively. The vast majority of all reported symptoms were mild to moderate, and all children recovered without sequelae. Fourteen serious adverse events were reported, but none was considered to be related to the vaccination. Immunogenicity analysis showed a vaccine response to pertussis toxin in 99.5% of subjects, to filamentous hemagglutinin in 98.5%, and to pertactin (69 kd outer membrane protein) in 99%. All subjects had postvaccination antibody titers of 0.1 IU/ml or greater against diphtheria and tetanus toxoids. more...

The aim of this study was the investigation of the specific cell-mediated (CMI) responses induced by DTaP and to compare these data to immunity after natural infection. The ability of peripheral blood T-lymphocytes to respond to the pertussis related antigens pertussis-toxin (PT), filamentous haemagglutinin (FHA), and Pertactin (PRN) was investigated in 40 children before vaccination and at different times after vaccination with DTaP (Infanrix) by measurement of antigen-specific proliferation, lymphocyte phenotype, cytokine production and expression of activation markers (CD25, HLADR). Similar investigations were performed in children 4-6 weeks after recovery from natural pertussis. DTaP created a specific T-cell-response to PT, FHA and PRN that increased continually, depending on the progress of the vaccination schedule. In contrast to waning antibody titres, CMI was stable even between the post-basic vaccination and the pre-booster period. The magnitude of CMI after DTaP equalled those after natural infection. Measurement of cytokine-pattern showed induction of IFN-tau-producing T-helper-1-cells with lower stimulation of IL 10-producing T-helper-2-cells for DTaP and natural infection. Our data indicate that DTaP-vaccination induces a potent immune response to PT, FHA, and PRN at least equivalent to CMI after natural infection. The finding of a preferential T-helper-1-induction after DTaP and natural infection suggests a role of IFN gamma-activated macrophages in the protective response against B. pertussis-induced disease. more...

Unlabelled: The lack of an adequate immune response to the major polysaccharide of the Haemophilus influenzae type b (Hib) capsule (polyribosyl ribitol phosphate) (PRP) in very young infants (< 18 months) can be overcome by conjugating PRP to a T-cell dependent carrier protein. We studied whether administration of a tetanus-PRP conjugate vaccine reconstituted with a diphtheria-tetanus-acellular pertussis-hepatitis B (DTPa-HBV) vaccine as a three dose primary course at 3, 4 and 5 months of age induced PRP-specific immunological memory, by examining the anti-PRP response to a dose of unconjugated PRP given with the DTPa-HBV booster approximately 1 year later. The unconjugated PRP elicited protective anti-PRP antibody levels (> or = 0.15 microgram/ml) in all but 3 of the 369 vaccinees, including 13 infants who failed to demonstrate a measurable immune response after the primary course. In a sub-cohort of 54 subjects all had anti-PRP levels > or = 0.5 microgram/ml within 7-14 days of the booster showing a rapid anamnestic type response. Both primary and booster responses were predominantly IgGl indicating a T-cell dependent response. The DTPa-HBV components elicited protective anti-diphtheria, anti-tetanus and anti-HBs antibody levels in > or = 98.5% of vaccinees, and immune responses to each of the acellular pertussis vaccine components in 92.3%-97.3% of subjects., Conclusion: The tetanus-PRP conjugate vaccine not only elicited a good primary humoral response, but also induced immunological memory so that the infants were able to mount a large and rapid immune response to subsequent exposure to plain PRP, indicating that protection against circulating wild-type Hib had been generated. Successful induction of immunological memory occurred even when there was no measurable humoral anti-PRP response to the primary course. Tetanus-PRP conjugate vaccine can be used in combination with DTPa-HBV vaccine, when administered separately or as a single injection in the same syringe, in primary immunisation schedules at 3, 4 and 5 months of age. more...

The aim of this study was to evaluate factors that influenced the spread of pertussis in secondary contacts after household exposure. The data were acquired during a prospective household-contact study into the efficacy of an acellular vaccine. The spread of the disease was monitored with respect to various case definitions of pertussis, socio-economic factors, household composition, and antibiotic therapy. A total of 453 index cases had contact with 173 unvaccinated children aged from 6 to 47 months. Depending on the clinical case definition, the attack rates (AR) in children with a laboratory-confirmed Bordetella infection increased from 55% for the WHO definition to 69%, when a less stringent definition was used. AR in children were independent of age and gender. The social status of the family had no significant influence on the AR in children. Erythromycin treatment of the index case reduced the AR from 64% to 51% (p = 0.08). These factors should be taken into consideration when studies into the secondary prevention of pertussis by acellular vaccines are initiated. more...

After concern about the safety of diphtheria-tetanus toxoid-whole cell pertussis vaccines (DTPw), the recommendation to vaccinate children with DTPw was withdrawn in 1974 in the former West Germany. This led pertussis cases to increase to an estimated 100,000 annually. Despite renewal of the vaccination recommendation in 1991, vaccine use remained low. The German health care structure assures regular contact between most children and pediatricians. This enabled the conduct of a large efficacy trial with a diphtheria-tetanus toxoid-acellular pertussis (DTPa) vaccine. Because a placebo-controlled trial was not ethically possible, a prospective household contact study with a blinded clinical follow-up was done. Possible study participants were screened by their pediatrician, who also initiated diagnostic procedures. Clinical follow-up was done by another locally based but independent and blinded physician. Vaccine efficacy was calculated to be 89% (95% confidence interval, 76.6%-94.6%). None of the identified confounding factors biased results in favor of the DTPa vaccine. more...

Pertussis was a major childhood disease in parts of West Germany in 1990. Before a prospective household contact trial into the efficacy of an acellular pertussis vaccine was undertaken, the epidemiology of the disease was studied in one area. This study showed that pertussis had an annual incidence of 4%-6% in the first 6 years of life. During the trial, a total of 1223 pertussis cases were diagnosed by laboratory methods. Isolation rates of Bordetella organisms varied by the pediatrician who did the nasopharyngeal swab and decreased with time required for swab transport. Analysis of the serologic results showed that if IgG and IgA anti-pertactin antibodies had been considered, overall sensitivity would have been only marginally increased. Several pertussis patients had antibodies to parapertussis antigens, indicating a lack of complete cross-protection. The serologic response in secondary household contacts differed by vaccination status. However, this difference was unlikely to have influenced the point estimate of efficacy of the acellular vaccine. more...

Objectives: To assess the safety and tolerability of 12 lots of SmithKline Beecham Biologicals' diphtheria-tetanus-tricomponent acellular pertussis vaccine (DTaP) in a large cohort of 22,000 vaccinees, with detailed analyses of reactivity, immunogenicity, and immune response to pertussis toxin in subsets., Methods: In a prospective, double-blind, multicenter trial in Germany, 22,505 healthy infants received three vaccinations of DTaP at age 3, 4, and 5 months. Serious adverse events were followed for 1 month after each vaccination, and neurologic events for 1 year or longer. Serum IgG antibodies were assayed before vaccination and 1 month after vaccination., Results: After 67,000 doses, 153 serious adverse events (0.23%) were reported, 8 considered possibly related, and 5 related to vaccination, including 1 hypotonic-hyporesponsive episode. Incidence rates of sudden infant death syndrome (7; 0.01%) or acute neurologic events (20; 0.030%) were no higher than expected and not considered to be related to vaccination. Redness and swelling of 20 mm or greater occurred after 44 (0.6%) and 40 (0.6%) of the 7270 doses, respectively, and high fever (> 39.5 degrees C) in 6 (0.08%) subjects within 48 hours of vaccination. In the immunogenicity analysis of 580 infants, 98% responded to pertussis toxin, 96% to filamentous hemagglutinin, and 98% to pertactin. In an additional 5712 infants, the response rate to pertussis toxin was 99%., Conclusions: In a large cohort of 22,505 infants vaccinated, SmithKline Beecham Biologicals' tricomponent DTaP vaccine was shown to be safe, well-tolerated, and immunogenic for all component antigens. more...

Objective: To evaluate the efficacy of a three-dose primary vaccination with a diphtheria-tetanus tricomponent acellular pertussis vaccine against "typical" pertussis, defined as a spasmodic cough of 21 days or longer with confirmation of Bordetella pertussis infection by culture or serology., Design: Passive monitoring for suspected first household (index) cases of typical pertussis in six areas in Germany comprising 22,505 children vaccinated with study vaccine at 3, 4, and 5 months of age. Blinded, prospective follow-up of household contacts of index cases for incidence and progression of pertussis., Setting: Six areas in Germany with a high incidence of pertussis., Subjects: Four hundred fifty-three households with index cases comprising 360 evaluable contacts eligible for analysis of vaccine efficacy., Main Outcome Measure: Vaccine efficacy from attack rates of pertussis in household contacts classified by vaccination status., Results: Of the 173 nonvaccinated household contacts, 96 developed typical pertussis, compared with seven of 112 contacts vaccinated with acellular pertussis vaccine. Vaccine efficacy was consequently calculated to be 88.7% (95% confidence interval, 76.6% to 94.6%). Protection did not wane until at least the time recommended for booster vaccination. None of the analyzed potential confounding factors--age, socioeconomic status, erythromycin treatment, household composition, center effect, and selection bias--influenced study results in favor of the vaccine., Conclusions: Under conditions of intense household exposure, primary vaccination with acellular vaccine protected against pertussis until at least the time recommended for booster vaccination. The vaccine can be expected to be equally or more effective in settings with lower infectious pressure. more...

Venous occlusion plethysmography is a well-established noninvasive procedure for the investigation of venous outflow disorders. Various different sensor systems are available for the purpose, e.g. photoplethysmography, strain-gauge plethysmography and impedance plethysmography. The technique of microwave volumetry described in this paper is based on the interaction of the electromagnetic fields within the loss medium, tissue, and uses an air-filled resonant cavity as a sensor. As in the case of a microwave oven, this is excited by a high-frequency generator, but involves the use of far less power. As the volume of the measured objects (foot, arm) increases, the losses in the resonator also increase and can be analysed in a computer. The results can be represented in the form of a classical venous occlusion curve. more...

There is increasing evidence that pertussis occurs frequently in adults, but there is limited information on the clinical course of this disease beyond childhood. A household contact study on the efficacy of an acellular pertussis vaccine was used to study the symptoms of pertussis in adults. Among 257 patients with pertussis identified in 121 families during a two-year period in one study center with a low whole-cell pertussis-vaccine uptake, 79 (30.7%) were adults, aged 19-83 years (mean age: 36 years) with a 1:1.8 male to female ratio. Ninety-one percent of the adults suffered from coughing (mean duration: 54 days), and in 80% this cough lasted > or = 21 days. Whoops were rare (8%), whereas cough followed by vomiting and/or choking (53%) and cough disturbing sleep (52%) were common. This is the first report to describe sweating attacks as symptom of pertussis (14%). Pharyngeal symptoms (37%), influenza-like symptoms (30%), sneezing attacks (22%), hoarseness (18%), sinus pain (16%) and headaches (14%) were also observed. Various complications were seen in 23% of the patients. In order to minimize the spread of the organism, microbiological diagnostics should be vigorously applied to all symptomatic contacts of a patient with pertussis but also to all patients with long lasting cough-irrespective of age. more...

Organ perfusion with bloodless solutions is an established clinical method for protecting the heart against ischemic damage. In our study, we evaluated the effects of intraischemic bloodless brain perfusion on postischemic ultrastructural neuronal changes in a model of severe incomplete forebrain ischemia produced by hemorrhagic hypotension combined with temporary carotid occlusion in the rat. Four groups of rats were compared. During an ischemic insult of 30 min, the brains of two groups were perfused via both external carotids with either a normosmolar normothermic magnesium-enriched perfusate (MgSO4, 30 mM; NaCl, 37 mM; mannitol, 180 mM; n = 10) or a normothermic normal saline solution (n = 9) at a rate of 6 ml/h. Two other groups (ischemia without perfusion, n = 8; no ischemia and no perfusion, n = 7) served as controls. After 30 min of ischemia, withdrawn blood for hemorrhagic hypotension was reinfused, the carotid arteries reopened, and the brains reperfused for 2 h. After perfusion-fixation, qualitative and quantitative evaluation of postischemic cell changes of hippocampal CA1 neurons was performed by electron microscopy. Brain perfusion with the magnesium-containing solution significantly protected neurons against ischemic cell changes and provided an ultrastructural pattern similar to that seen in the nonischemic control group. In contrast, brain perfusion with normal saline solution did not result in neuronal protection. We conclude that intraischemic intracarotid brain perfusion with magnesium-enriched perfusate protects hippocampal neurons significantly against ischemic cell changes in the early reperfusion period after transient severe forebrain ischemia. more...

Fungal infections continue to be a major problem in the management of immunocompromised patients. Despite its formidable toxicity and treatment failures, amphotericin B is still the drug of choice for most of these infections. One strategy for reducing the toxicity of amphotericin B and thus permitting administration of higher doses is that of using less toxic formulations. Entrapping amphotericin B into liposomes or binding it to other substances reduces its toxicity to host cells, whereas the selective binding of amphotericin B to ergosterol preserves its toxicity to fungal cells. Adding fungus-specific antibodies to such liposomes may further increase the efficiency of drug targeting. The initial unpublished data from controlled clinical trials of various liposomal preparations of amphotericin B are less encouraging than anticipated, but additional trials are needed for a proper evaluation. Another strategy for improving efficacy of amphotericin B is that of bringing it directly into contact with the body sites most likely to be infected. Intranasal delivery of amphotericin B for prevention of invasive aspergillosis has been evaluated in at least three different clinical trials with conflicting results; no controlled trials are available. Prophylactic administration of low doses of amphotericin B as an aerosol was the most effective of the regimens tested in an animal model of pulmonary aspergillosis and was also judged to be effective in a clinical trial using historical controls. Independent of the route of administration, in both an animal model was various clinical studies, early administration of amphotericin B was more effective than late administration.(ABSTRACT TRUNCATED AT 250 WORDS) more...

Detection of hearing impairment in early childhood is difficult. We serially recorded transient evoked otoacoustic emissions (TEOAEs) to search for signs of ototoxicity in term, healthy newborns and compared the results to a second group of term babies treated for perinatally acquired bacterial infection with ampicillin plus either cefotaxime or plus aminoglycoside. At initial evaluation, in the group of 45 healthy children born at term, well reproducible emissions were observed in all but two children. In each of these two, initially well reproducible TEOAEs were detected in one ear only. At the time of the second recording (mean at day 8.5) excellent emissions were seen in all ears of all children. Similarly, in the second group receiving ampicillin plus either cefotaxime or plus aminoglycoside, the height of emissions as well as TEOAE-reproducibility was equal or even increased at the time of the second evaluation in all 17 patients. In the following group of 59 patients, all receiving ampicillin plus aminoglycoside, again TEOAEs were equal or improved at the time of follow-up examinations. In all patients, a reduced general condition tended to be associated with less reproducible TEOAEs. We conclude that at conventional doses in low-risk infants, aminoglycosides are unlikely to cause ototoxicity and that in early childhood serial TEOAE-recording may be useful for evaluation of inner ear function. more...

The incidence of shunt infections and possible risk factors was investigated by chart analysis. From 1986 to 1989 350 shunt procedures were performed including 273 ventriculoperitoneal shunts and 75 ventriculoatrial shunts. Twenty-eight infectious episodes (8%) occurred in 25 patients during a median follow-up time of 20 months. For 204 patients the follow-up time could be prolonged until September 1992. In these patients no infectious episodes occurred in the extended observation period. In 24 cases (85.7%) a causative organism could be isolated. The infecting organisms were gram-positive cocci in 22 cases (78.6%) and gram-negative bacilli in two cases. The main signs and symptoms were fever, shunt malfunction and meningeal irritation, and with VP-shunts only, abdominal pain. Twenty-four infectious episodes were treated with antibiotics and immediate removal of the shunt. The remaining were managed with antibiotics only. The risk for shunt infection did not correlate with age or sex of patients, nor with the etiology of hydrocephalus, type of shunt implanted or perioperative antibiotic prophylaxis. However, a trend showing a higher risk for shunt infections with prolonged operation time was noticed. The infection rate was 13.6% for an operation lasting more than 90 minutes versus 5.2% for procedures of less than 30 minutes duration. more...

The use of a pulse oximeter to monitor arterial oxygen saturation (SaO2) is considered accurate and reliable in the range of 90% to 100%. However, differing reports exist about the accuracy with desaturation. Thus, the suitability of pulse oximetry in desaturated patients was evaluated using a Nellcor N-100 oximeter. In 56 children with cyanotic congenital heart disease, the pulse oximeter reading was compared with the direct measurement of SaO2 by a CO-oximeter OSM 3. The influence of high hematocrit values on the accuracy at low saturation was also investigated. All oxygen saturation measurements (two per child) were carried out after induction of anesthesia (ketamine, fentanyl, pancuronium) during a "steady state" before the surgical procedure. The results indicate that at low levels of saturation (SaO2 below 80%), pulse oximetry is not as accurate as at higher saturations, and overestimates the true value. Bias and precision between saturations measured by the pulse oximeter and the CO-oximeter were 5.8 and 4.8 in the group with a saturation below 80%, and 0.5 and 2.5 in the group with a saturation over 90%, respectively. Because the margin of safety for a patient is small when arterial saturation levels are under 80%, it is advisable under this condition to check the SaO2 measurements by a CO-oximeter. High hematocrit levels did not seem to be responsible for impaired accuracy of pulse oximetry at saturation values below 80%. more...

Eight children and young adults with cancer were evaluated serially using pure tone audiometry as well as registration of click-evoked otoacoustic emissions (EOAE) 1 day prior to therapy as well as after various numbers of doses of cisplatinum. A reduction of EOAE-amplitudes following cisplatinum therapy was observed in all patients. This reduction tended to recover after the end of cisplatinum administration. Since EOAE are believed to result from cochlear bio-mechanical processes, the reduced emissions are interpreted as signs of cochlear dysfunction. We conclude, that EOAE testing may be a simple, non-invasive method that may detect early, transient functional impairment of hearing due to ototoxic agents such as cisplatinum, even in children. Further controlled trials are needed. more...

In Germany, infectious diseases cause little mortality, but they are responsible for a large proportion of morbidity. In order to obtain data about the relevance of infectious diarrhea, the charts of 1337 outpatients, hospitalized for this disorder in the time between 1986-1989 at the Children's Hospital, Johannes Gutenberg University Mainz, were analyzed. Sixty-seven percent of patients were younger than one year. An offending organism could be isolated in 42.1% of patients, with Rotaviruses being the leading cause of diarrhea (415 cases), followed by Salmonella spp. (130 cases). Rotavirus-disease was mainly seen in winter, Salmonella-disease in late summer and in autumn. Severe courses of diarrhea were rare, no patient died. Mean duration of hospitalization was 7 days, independent from the offending organism. Infectious diarrhea is a common disorder in children in Germany, which may lead to hospitalization especially during infancy. Additional epidemiological studies are needed in order to develop effective control measures. more...

According to official statistics, infectious diseases only play a minor role in German children. To test this assumption, 1685/3405 charts of a private pediatrician were randomly chosen for further evaluation. 1112/1685 children had been seen in the office during the study period, 934 of them because of an infectious disease (83%). 700/934 charts were further reviewed in a standardized fashion. Pharyngo-tonsillitis was the most frequent diagnosis (18.6%), followed by (non-obstructive) bronchitis (18.5%), infectious diseases of the skin (10.2%) and Otitis media (9.9%). Typical "childhood diseases" (measles, mumps, rubella, varicella) only played a minor role. For some diseases age-specific as well as seasonal changes in incidence could be observed. These data suggest that infectious diseases largely contribute to the morbidity in German children. Prospective epidemiological trials are needed to obtain reliable data for appropriate public health decisions. more...