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The Global Pertussis Initiative is an expert scientific forum that publishes consensus recommendations concerning pertussis for many regions of the world. Here, we give recommendations for the primary vaccination of infants in those countries where whole-cell pertussis (wP)- and acellular pertussis (aP)-containing combination vaccines are used in parallel. A selective literature review was performed concerning the influence on safety, immunogenicity, and effectiveness of mixing wP- and aP-containing vaccines for primary immunization of infants. In addition, local data were collected from various countries and the results discussed in a face-to-face meeting. Very few data addressing issues of mixing combination vaccines were identified, and no data were available concerning the effectiveness or duration of protection. It was also found that pharmacovigilance data are scarce or lacking in those countries where they would be needed the most. We then identified frequent problems occurring in low- and middle-income countries (LMICs) where both vaccine types are used. Relying on local knowledge, we give practical recommendations for a variety of situations in different settings. Specific needs for additional data addressing these issues were also identified. International bodies, such as the World Health Organization (WHO), as well as vaccine producers should try to find ways to highlight the problems of mixing wP- and aP-containing combination vaccines with robust data. Countries are urged to improve on their pharmacovigilance for vaccines. For practicing physicians, our recommendations offer guidance when wP- and aP-containing vaccines are used in parallel during primary immunization., Instituto de Biotecnologia y Biologia Molecular

SUMMARYLaboratory tests in adult outpatients with longer lasting coughs to identify a potential causal pathogen are rarely performed, and there is no gold standard for these diagnostic tests. While the diagnostic validity of serological tests for pertussis is well established their potential contribution for diagnosing adenovirus and influenza virus A and B infections is unclear. A sentinel study into the population-based incidence of longer lasting coughs in adults was done in Rostock (former East Germany) and Krefeld (former West Germany). A total of 971 outpatients who consulted general practitioners or internists were included. Inclusion criteria were coughing for ⩾1 week and no chronic respiratory diseases. We evaluated the performance of polymerase chain reaction (PCR) as well as IgG and IgA serology, applying a latent class model for diagnosing infections with adenovirus,B. pertussis, and influenza virus A and B. The adult outpatients first sought medical attention when they had been coughing for a median of 3 weeks. In this situation, direct detection of infectious agents by PCR had a low sensitivity. Modelling showed that additional serological tests equally improved sensitivity and specificity for diagnosis for adenovirus,B. pertussisand influenza virus A and B infections. The combination of serology and PCR may improve the overall performance of diagnostic tests forB. pertussisand also foradenovirus, and influenza virus A and B infections.

Bordetella pertussis-specific antibodies can be detected by enzyme-linked immunosorbent assays (ELISAs) or multiplex immunoassays. Assays use purified or mixed antigens, and only pertussis toxin (PT) is specific for B. pertussis. The interpretation of results can be based on dual-sample or single-sample serology using one or two cut-offs. The EU Pertstrain group recommends that: (i) ELISAs and multiplex immunoassays should use purified non-detoxified PT as an antigen, that they should have a broad linear range and that they should express results quantitatively in International Units per millilitre (IU/ml); (ii) a single or dual diagnostic cut-off for single-serum serology using IgG-anti-PT between 50 and 120 IU/ml should be used, and diagnostic serology cannot be validly interpreted for one year after vaccination with acellular pertussis (aP) vaccines; (iii) IgA-anti-PT should only be used with indeterminate IgG-anti-PT levels or when a second sample cannot be obtained. This group discourages using: (i) other antigens in routine diagnostics, as they are not specific; (ii) micro-agglutination, due to its lack of sensitivity; (iii) immunoblots for pertussis serodiagnosis, as results cannot be quantified; (iv) other methods, such as complement fixation or indirect immunofluorescence, due to their low sensitivity and/or specificity.

Background and Objectives National guidelines for monitoring bacterial contamination of blood components were introduced in Germany in 1997. Between 1998 and 2002, numerous measures were implemented to prevent bacterial contamination. This study investigates their impact on contamination rates. Materials and Methods Culture-based testing for bacterial detection on a random sample of blood components is part of routine quality control in German blood establishments. Using standardized questionnaires, data from the production periods 1998, 2001 and 2005/2006 were collected and analysed. Results The bacterial contamination rate of RBCs was reduced from 0·157% in 1998 to 0·029% in 2005/2006 (P

Pertussis is an endemic and cyclical disease. But protection from infection and through vaccination is not long-lived. Because of high vaccination coverage among infants the age distribution of pertussis has changed: adults and adolescents are now the main reservoir for Bordetella pertussis. The current recommendations of the German Standing Vaccination Committee (STIKO) are designed to achieve life-long protection, which is feasible with acellular pertussis vaccines. Vaccination of all adults with Tdap instead of dT vaccine is recommended in many countries, because this strategy may reduce the burden of disease in adults and infants, and is cost-effective.

An international meeting on Bordetella pertussis assay standardization and harmonization was held at the Centers for Disease Control and Prevention (CDC), Atlanta, GA, 19-20 July 2007. The goal of the meeting was to harmonize the immunoassays used for pertussis diagnostics and vaccine evaluation, as agreed upon by academic and government researchers, regulatory authorities, vaccine manufacturers, and the World Health Organization (WHO). The primary objectives were (1) to provide epidemiologic, laboratory, and statistical background for support of global harmonization; (2) to overview the current status of global epidemiology, pathogenesis and immunology of pertussis; (3) to develop a consensus opinion on existing gaps in understanding standardization of pertussis assays used for serodiagnosis and vaccine evaluation; and (4) to search for a multicenter process for addressing these priority gaps. Presentations and discussions by content experts addressed these objectives. A prioritized list of action items to improve standardization and harmonization of pertussis assays was identified during a group discussion at the end of the meeting. The major items included: (1) to identify a group that will organize, prepare, maintain, and distribute proficiency panels and key reagents such as reference and control sera; (2) to encourage the development and identification of one or more reference laboratories that can serve as an anchor and resource for other laboratories; (3) to define a performance-based assay method that can serve as a reference point for evaluating laboratory differences; (4) to develop guidance on quality of other reagents, e.g., pertussis toxin and other antigens, and methods to demonstrate their suitability; (5) to establish an international working group to harmonize the criteria to evaluate the results obtained on reference and proficiency panel sera; (6) to create an inventory to determine the amount of appropriate and well-characterized sera that are available globally to be used as bridging reagents for vaccine licensure; and (7) to seek specific guidance from regulatory authorities regarding the expectations and requirements for the licensure of new multicomponent pertussis vaccines.

Within a period of four years the diagnosis of pertussis was made in 169 adults (105 women, 64 men; mean age 35.8 [18-79] years). based on symptoms, specific antibodies and bacteriological examination of nasopharyngeal swabs (in 53). The findings were compared with those obtained in a control group of 2,771 children (1,381 females, 1,390 males; mean age 4.3 years). In the adult the dominant symptom was persisting cough, at times convulsive, while the other symptoms, characteristic in children, of rib retraction and vomiting were significantly less common in adults (retraction: 3% vs 40%; vomiting 12% vs 59%). A history of contact was elicited in only 17% of adults (38% in children). Confirmation of the diagnosis was obtained by growing Bordetella pertussis from a nasopharyngeal swab (6 of 53 patients [11%]; in children 45%), or finding significantly elevated antibody concentration or titre rise of specific antibodies against B. pertussis (IgG: 81% vs 68%; IgA: 91% vs 73%; IgM: 44% vs 72%). Half the adult patients were aged between 20 and 35 years. Contrary to the sex distribution of pertussis in children, significantly more women than men contracted the infection (P less than 0.01). It is concluded that even in adults pertussis should be considered in the differential diagnosis of persisting cough.

BACKGROUND AND OBJECTIVE: A prospective sentinel study into the population-based incidence of pertussis in adults was done between 2001 and 2004 in Rostock (former East Germany) and Krefeld (former West Germany). PATIENTS AND METHODS: 971 outpatients, who consulted general practitioners or internists, were included. Clinical inclusion criteria were coughing for one week or more and no chronic respiratory diseases. Bordetella infection was diagnosed by PCR on nasopharyngeal swabs and ELISA for serology (IgG-anti-PT, IgA-anti-PT, IgG-anti-FHA, IgA-anti-FHA). RESULTS: We found a total of 97 cases of pertussis in this cohort. The main symptom was coughing for a median of 7-8 weeks. Population-based incidence was estimated in Krefeld at 169 cases/100000 population per year, and in Rostock at 160/100000 per year. Resource use was 120 EUR of direct medical cost and 434 euro of indirect medical cost, not including hospitalization in this study. CONCLUSIONS: Pertussis is a frequent cause of longer lasting cough in German adults, and it causes significant morbidity and costs.

Reinfektionen von gesunden Erwachsenen mit Respiratory-Syncytial-Virus (RSV) und Bordetella pertussis – ublicherweise als Erreger von typischen Kinderkrankheiten angesehen – kommen haufig vor. Die Erkrankungen manifestieren sich meist nur als langer dauernder Husten,wobei das Spektrum der klinischen Prasentation insbesondere bei RSV sehr vielgestaltig sein kann.Zur Diagnostik bietet sich bei beiden Erregern der Nukleinsaurenachweis mittels PCR und/oder der Antikorpernachweis mittels ELISA an. Eine spezifische Therapie ist bei Patienten ohne zusatzliche Risikofaktoren im Allgemeinen nicht erforderlich, die Gabe von Makroliden unterbricht jedoch bei Pertussis die Infektionskette.Zur Pravention sind bei RSV allgemeine Hygienemasnahmen effektiv, eine aktive Schutzimpfung gegen Pertussis wird neben der Impfung von Sauglingen und Kleinkindern auch fur Adoleszente und fur Personal von Kinderkliniken und Gemeinschaftseinrichtungen empfohlen.

The purpose of this investigation was to test the performance of pertussis serology in diagnostic laboratories. The World Health Organization (WHO) Reference Reagent (06/142) and a sample with a low level of antibodies were sent to 200 participants of an external quality assessment (EQA) programme in Germany. The results were reported qualitatively and quantitatively, and were converted into IU/ml when possible. A total of 183 participants reported results. IgG, IgA and IgM enzyme-linked immunosorbent assays (ELISAs) with mixed antigens were used by 111, 110 and 113 participants, respectively, and 69 and 44 participants used IgG and IgA ELISAs with purified pertussis toxin (PT), respectively. IgG, IgA and IgM immunoblots were employed by 62, 63 and 11 participants, respectively. Most tests could distinguish between the positive and negative samples, but quantitative results were reported partly in non-comparable units. Only 37 % of participants used ELISAs that gave results comparable to the expected values in IU/ml and that could be interpreted according to published recommendations.

We assessed the effectiveness of complete and partial pertussis vaccination in Germany--a country where acellular vaccine is predominantly used--for the prevention of cases of pertussis requiring hospitalization. Vaccine effectiveness was estimated by means of a screening method. Vaccine coverage of children born during the period of June 1996 through December 1998 was assessed by a telephone survey. Data from hospitalized children with pertussis in 1997-1998 and from patients with pertussis complications in 1997-2000 were acquired by a nationwide, hospital-based, active surveillance system. Age-adjusted vaccine effectiveness of completed primary vaccination was estimated to be 99.8% (95% confidence interval [95% CI], 98.9-100). After receipt of 1 dose of vaccine, vaccine effectiveness was as high as 68.0% (95% CI, 45.6-81.1), increasing to 91.8% (95% CI, 84.7-95.7) after receipt of the second dose. Vaccine effectiveness was even slightly higher for pertussis with complications. Thus, even after partial vaccination, acellular pertussis vaccine is highly effective in preventing hospitalizations for pertussis.

Pathogen adaptation has been proposed to contribute to the resurgence of pertussis. A striking recent example is the emergence of isolates deficient in the vaccine component pertactin (Prn). This study explores the emergence of such Prn-deficient isolates in six European countries. During 2007 to 2009, 0/83 isolates from the Netherlands, 0/18 from the United Kingdom, 0/17 Finland, 0/23 Denmark, 4/99 Sweden and 5/20 from Norway of the isolates collected were Prn-deficient. In the Netherlands and Sweden, respectively 4/146 and 1/8 were observed in a later period (2010–12). The Prn-deficient isolates were genetically diverse and different mutations were found to inactivate the prn gene. These are indications that Prn-deficiency is subject to positive selective pressure. We hypothesise that the switch from whole cell to acellular pertussis vaccines has affected the balance between ‘costs and benefits’ of Prn production by Bordetella pertussis to the extent that isolates that do not produce Prn are able to expand. The absence of Prn-deficient isolates in some countries may point to ways to prevent or delay the spread of Prn-deficient strains. In order to substantiate this hypothesis, trends in the European B. pertussis population should be monitored continuously.

Pertussis vaccination of infants has dramatically reduced disease, complications and deaths in infancy and early childhood. But there is still a major public health challenge — to deal with the morbidity and economic burden of illness in older children, adolescents and adults. Furthermore, it is these groups that form a major source of infection for non-immunised and partially immunised infants who are at high risk of severe complications. Adult-type acellular pertussis vaccine confers safe and effective protection against pertussis. There are several strategies to consider for immunising older individuals. Universal vaccination of all age groups would be the best available strategy for protecting individuals. It would also reduce the potential for transmitting the disease to other susceptibles, particularly infants. However, such a policy may be difficult both logistically and economically at this time. More easily achievable as a first step would be a strategy of universal adolescent booster vaccination combined with a programme targeted at adults most likely to have contact with very young babies including healthcare and childcare workers, parents and close family contacts. There is also potential for offering vaccination to adults (and their carers and close contacts) whose medical conditions or advanced age may place them at increased risk of more severe pertussis disease. Specific details of immunisation programmes must be made on a country by country basis depending on local circumstances.

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 (

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.

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. 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.

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.

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 ≥ 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, micro-biological 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.

The isolation of a strain of Bordetella for which the species could not be determined but which most closely resembled Bordetella avium is reported. The strain was isolated in mixed culture from an ear swab of a patient suffering from chronic otitis media. The bacterium showed the typical biochemical reactions of Bordetella avium but differed in antimicrobial resistance pattern, protein and fatty acid composition, and DNA-DNA and DNA-rRNA hybridization. Further studies will clarify the taxonomic status of this strain within the Bordetella-Alcaligenes ribosomal RNA cluster.

Whooping cough can be caused by either Bordetella pertussis or Bordetella parapertussis. Although the two species share an almost complete DNA identity, Bordetella parapertussis does not produce pertussis toxin, which is thought to be the main virulence factor of Bordetella pertussis. In order to elucidate the role of pertussis toxin in causing the typical symptoms of whooping cough, clinical information from 33 patients with culture-positive Bordetella parapertussis infection was collected and compared to that from 331 patients with infection caused by Bordetella pertussis. Isolated strains of Bordetella parapertussis lacked pertussis toxin expression, as was demonstrated by negative tests for histamine sensitization. This was further substantiated in vivo by a significantly lower leukocyte count in the parapertussis group as compared to the pertussis group. Frequencies of typical symptoms of whooping cough, such as paroxysmal coughing, whooping and vomiting, were almost identical in the two groups. Nocturnal coughing and contact anamnesis were noted more often in the Bordetella pertussis group. Children in the parapertussis group were significantly more often vaccinated with whole-cell pertussis vaccine than children infected with Bordetella pertussis. The results indicate that pertussis toxin may not play a decisive role in causing the typical symptoms of whooping cough, such as paroxysmal coughing, whooping and vomiting.

Bordetella pertussis infection is mostly diagnosed by serological tests, such as by enzyme-linked immunosorbent assays (ELISAs) or by immunoblots. We compared immunoblots from five different manufacturers. Immunoblots from Euroimmun, Mikrogen, Trinity Biotech, Viramed and Virotech were used. All kits except the kit from Trinity Biotech measured IgG and IgA antibodies separately. The kits were used according to the kit inserts. Various reference preparations from the World Health Organization (WHO), the National Institute for Biological Standards and Control (NIBSC) and the Center for Biologics Evaluation and Research/Food and Drug Administration (CBER/FDA) were analysed. Patient sera with high antibody titres in ELISA, sera from patients with compatible clinical symptoms and sera from vaccinees were compared. An algorithm for interpreting quantitative values for IgG and IgA anti-pertussis toxin (PT) from in-house ELISAs was used as a reference. The sensitivity and specificity of the assays was variable when comparing the qualitative results of immunoblots with expected values of reference preparations and ELISA interpretation of patient sera. The interpretation of semi-quantitative reading of the immunoblots did not compare well to the ELISA results. Adenylate cyclase toxin as an additional antigen in two immunoblots did not effectively distinguish between infection and vaccination. Due to the lack of quantification of antibody concentrations, IgG and IgA immunoblots are of limited value in the serological diagnosis of pertussis.

National guidelines for monitoring bacterial contamination of blood components were introduced in Germany in 1997. Between 1998 and 2002, numerous measures were implemented to prevent bacterial contamination. This study investigates their impact on contamination rates.Culture-based testing for bacterial detection on a random sample of blood components is part of routine quality control in German blood establishments. Using standardized questionnaires, data from the production periods 1998, 2001 and 2005/2006 were collected and analysed.The bacterial contamination rate of RBCs was reduced from 0·157% in 1998 to 0·029% in 2005/2006 (P0·001). While the contamination rate of apheresis PCs remained nearly unchanged over the years, it dramatically decreased for pooled PCs by 70% to a contamination rate of 0·158% (P=0·001) within the last observation period, similar to that of apheresis PCs. The contamination rate of plasma decreased from 0·100% in 1998 to 0·019% in 2005/2006 (P=0·002).Precautionary measures significantly reduced bacterial contamination rates of blood components. Long-term monitoring with standardized methods is appropriate to evaluate the cumulative effect of contamination-preventing measures.

Pertussis is an endemic and cyclical disease. But protection from infection and through vaccination is not long-lived. Because of high vaccination coverage among infants the age distribution of pertussis has changed: adults and adolescents are now the main reservoir for Bordetella pertussis. The current recommendations of the German Standing Vaccination Committee (STIKO) are designed to achieve life-long protection, which is feasible with acellular pertussis vaccines. Vaccination of all adults with Tdap instead of dT vaccine is recommended in many countries, because this strategy may reduce the burden of disease in adults and infants, and is cost-effective.

Antibody decay after a single dose of acellular pertussis vaccine containing 25 microg of pertussis toxin (PT), 25 microg of filamentous hemagglutin (FHA), and traces of pertactin (PRN) was monitored in health-care workers. Blood was sampled 4 weeks (n = 246), 1 year (n = 187), 2 years (n = 53), 3 years (n = 134), and 4 years (n = 37) after vaccination. IgG anti-PT, IgG anti-FHA and IgG anti-PRN were measured by ELISA. Peak median antibodies to PT, FHA, and PRN were 314, 785, and 84 EU/ml respectively. IgG anti-PT decreased to a median of 29% (76 EU/ml), 18% (64 EU/ml), 19% (58 EU/ml), and 20% (63 EU/ml) of the peak value after 1, 2, 3, and 4 years respectively. IgG anti-FHA decreased more slowly, but showed similar decay patterns. In German health-care workers antibodies to pertussis antigens decayed rapidly within the first year after vaccination, but remained stable after 2, 3, and 4 years. This observation may have implications for the timing of booster vaccinations in adults.

A prospective sentinel study into the population-based incidence of pertussis in adults was done between 2001 and 2004 in Rostock (former East Germany) and Krefeld (former West Germany).971 outpatients, who consulted general practitioners or internists, were included. Clinical inclusion criteria were coughing for one week or more and no chronic respiratory diseases. Bordetella infection was diagnosed by PCR on nasopharyngeal swabs and ELISA for serology (IgG-anti-PT, IgA-anti-PT, IgG-anti-FHA, IgA-anti-FHA).We found a total of 97 cases of pertussis in this cohort. The main symptom was coughing for a median of 7-8 weeks. Population-based incidence was estimated in Krefeld at 169 cases/100000 population per year, and in Rostock at 160/100000 per year. Resource use was 120 EUR of direct medical cost and 434 euro of indirect medical cost, not including hospitalization in this study.Pertussis is a frequent cause of longer lasting cough in German adults, and it causes significant morbidity and costs.

The global epidemiology of pertussis has recently been reviewed (12, 15). Bordetella pertussis continues to circulate even in populations where high vaccination coverage of infants and children is achieved (15, 23), because the protection after natural infection wanes after 10 to 15 years and protection after vaccination lasts for 6 to 10 years (15). A significant increase of pertussis cases was observed in the United States, in Europe, and in other countries with high vaccination coverage, making pertussis a reemerging disease. Transmission of the disease in highly vaccinated populations occurs mainly from adolescents and adults to infants or among older vaccinated children, adolescents, and adults (15). Thus, most cases of pertussis are now observed in unvaccinated infants, older schoolchildren, adolescents, and adults. In outbreak situations asymptomatic carriage has been observed in up to ∼50% (12).

The incidence of pertussis requiring hospitalization in children younger than 16 years was estimated by the use of an active surveillance-system. Of special interest were differences between West and East Germany following different vaccination strategies before reunification. In 1997 and 1998, 754 pertussis cases required a total of 11,151 hospital inpatient days. The incidence of hospitalized pertussis was 2.68/100,000 person years and this was significantly higher in East than in West Germany. In East Germany an unusually high percentage of hospitalized cases was found in children aged 6-15 years (45% versus 13% in West Germany). The difference between the regions may be due either to a different perception of the disease or to an increased immunity induced by prior disease or vaccination. In East Germany, pertussis was rare until reunification but it has increased significantly since then. Older children may thus represent a population at risk of pertussis having not had previous exposure to pertussis antigens.

Between 1 November 1993 and 31 October 1996, admissions to paediatric departments for Bordetella pertussis complications were reported to a nationwide, hospital-based active surveillance system. The case definition included pertussis complicated by pneumonia, apnoea requiring assisted ventilation, seizures, encephalopathy or a combination of these. Two hundred sixteen cases of pertussis complications were registered. 57.4% of them were in infants, 50.9% of them less than 6 months old. There were five deaths, three previously healthy children died. At the time of hospital admission, 106 cases would have been eligible for at least three doses of pertussis vaccine, only four (3.8%) had received the recommended number of immunisations. From the second quarter of 1995, the reported number of cases declined. The decrease coincides with an improvement of pertussis vaccination coverage between 1992 and 1995 due to an increased use of acellular vaccines. The reduction of complicated pertussis was observed even in age-groups too young for the recommended vaccinations. The observed decrease could be due to the increase in vaccination coverage with interruption of the chain of transmission to the younger age-groups, to a cyclic decrease in pertussis cases, or to a combination of both. Continued surveillance will provide information on the epidemiological trend of hospitalisations for pertussis complications in the first European country to have introduced vaccination with acellular vaccines on a large scale.

The role of Acinetobacter baumannii in infections in ventilated preterm infants was evaluated in 15 colonized infants (11 male, 4 female) in a pediatric intensive care unit. These cases were randomly matched by birth weight and gestational age with ventilated non-colonized controls (8 male, 7 female). Case records were reviewed for signs and symptoms of infection. Colonized infants were ventilated significantly longer (p0.05) than controls, and had body temperatures of37 degrees C for a significantly longer period of time (p0.05). No other parameter of infection differed significantly between the groups. The duration of intensive care treatment did not differ between cases and controls, nor did the weight gain during intensive care treatment. No fatalities occurred in either group.

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 wasor = 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.

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.

Bordetella pertussis is the only bacteria] species which is known to produce pertussis toxin (PT); however, both Bordetella bronchiseptica and Bordetella parapertussis contain regions homologous to the ptx genes of B. pertussis that encode the toxin subunits. After finding that several children with B. parapertussis infections exhibited modest antibody titers to PT, we examined the ptx genes of both B. parapertussis and B. bronchiseptica to determine whether they would encode stable, functional proteins even though their promoters are thought to be inactive under the conditions that have been examined. We inserted a functional promoter directly upstream of the ptx-ptl region of both species and examined culture supernatants of the resulting strains for PT activity. Biologically active PT was found in the culture supernatants of both engineered species. The toxin encoded by the B. parapertussis ptx genes appeared more labile in culture supernatants than did toxin produced by either B. pertussis or the engineered strain of B. bronchiseptica. This lability might be due to the lack of a full-length S2 subunit. We also investigated the ptl genes of these species, which are necessary for the secretion of this toxin, and found that both B. bronchiseptica and B. parapertussis contain at least certain of these genes, including ptlE and ptlF. Moreover, B. bronchiseptica appeared to contain all essential ptl genes since the introduction of a functional promoter directly upstream of the ptx-ptl region resulted in both production and efficient secretion of toxin. These results indicate that despite a number of amino acid changes in the sequences of the toxins, the toxins encoded by B. bronchiseptica and B. parapertussis are active.

Acellular vaccines against pertussis could be developed because various virulence factors of B. pertussis have been characterized. Acellular pertussis vaccines should retain the efficacy but have lower side effects, as compared to the conventional whole-cell vaccine. Lacking any correlate of antibacterial resistance, the efficacy of the vaccines had to be tested in large field trials. Such trials have been conducted and are being conducted in various European and in one African country. These trials used different designs, and various different vaccines were tested. All available efficacy data show that acellular pertussis vaccine can effectively protect against typical pertussis. It also seems probable that the efficacy of vaccines, which contain more than two pertussis components may be better than a vaccine containing pertussis toxoid or pertussis toxoid with filamentous hemagglutinin. A three-component acellular pertussis vaccine has been licensed for use in primary vaccination in infants in Germany in early 1995.

We report a fatal infection with influenza A virus in a 13-year-old child who had been vaccinated against influenza. Influenza A virus RNA was detected by PCR in lungs, bronchi and myocardium. A penicillin-sensitive strain of Staphylococcus aureus was also isolated from her bronchi. This case indicates that a primary viral pneumonia with influenza A virus complicated by a bacterial superinfection with S. aureus can run a fatal course even in a vaccinated child.

The current concepts about sexually transmitted diseases (STD)--excluding syphilis and viral STD--are presented in a condensed form. The focus of attention is directed to complications or sequelae of these infections, and to the epidemiology of STD.

Infections with hepatitis virus A, B, C, D or E can also be observed during pregnancy. Furthermore, pregnant carriers of hepatitis B virus, occurring at various frequencies in different populations, represent an important source of infection. The course and the outcome of hepatitis A, B, C and D do not seem to be significantly affected by pregnancy. A fulminant hepatitis E, however, which is observed only rarely in Europe, can be induced by pregnancy and labor. Fetal malformations have not been attributed to any hepatitis virus. A perinatal transmission of hepatitis B virus often occurs, whereby the circulating HBe antigen or the amount of viral DNA in blood can be used as prognostic markers. Perinatal transmission of hepatitis C virus has also been documented; its frequency, however, seems to be less than 10%. A general screening of pregnant women for HBs antigen is suitable in interrupting transmission of hepatitis B virus. Children born from hepatitis B virus carriers should receive a postpartal passive-active immunization.

In a period of nine months (May 1991 to January 1992), 39 infants were colonized with Acinetobacter baumannii in a paediatric intensive care unit. Colonization was observed mainly in premature infants, weighing between 680 g and 2,000 g, who were artificially ventilated. Shortly after birth, A. baumannii was isolated regularly from tracheal washings, and less frequently from other material, such as gastric juice, catheter tips, and umbilical swabs. In older children or adults, the bacteria were found only in very low frequency. In the intensive care unit, A. baumannii could be isolated from tap water, sinks, water traps of the ventilation devices, the inner wall of incubators, and from the hands of medical personnel. Patients strains of A. baumannii, and those isolated monitoring the intensive care unit had an identical biochemical profile and a similar pattern of antimicrobial resistance, as well as a similar reaction in other typing methods. Anti-infective measures are discussed.

Each vaccine is normally rated according to its efficacy and to the frequency and severity of unwanted side effects. The efficacy of whole-cell pertussis vaccines is beyond doubt, its frequent side effects, however, stimulated research into less reactogenic acellular vaccines. Several acellular pertussis vaccines of different composition have been developed. All of these produced significantly less local and systemic side effects, as compared to the conventional whole-cell vaccine. Various epidemiological data strongly suggest the efficacy of these vaccines. An equivalence of protective efficacy between whole-cell vaccines and acellular pertussis vaccines can, however, only be documented in controlled field trials, which are now ongoing in several countries.

Due to a low acceptance of active immunisation against Bordetella pertussis, whooping cough continues to be a frequent childhood disease in parts of Germany. The age distribution in the lower Rhine area showed a peak incidence at 4.3 years of age, whereas 11% of all cases were observed in infants, and 6% were observed in adults. A significant sex difference was not found in children suffering from pertussis; in adult patients, however, women were more often affected. Whooping cough occurred during the whole year, its peak incidence was found during early winter. In children, paroxysmal coughing fits, vomiting and whooping were the primary symptoms of disease; adults and infants, however, developed these symptoms only in reduced frequency. About 25% of all cases showed an atypical course, and could only be diagnosed by laboratory tests. While leukocyte count and ESR did not have diagnostic significance, a combination of microbiological and serological tests showed a high diagnostic sensitivity and specificity. In contrast to the former GDR and to most European neighbours, the former Federal Republic overrated the side effects of active vaccination as compared to the various risks of natural infection. This resulted in a decline of vaccine acceptance to less than 10% in several areas of the former FRG. It is anticipated that the altered recommendation in favour of vaccination, and especially the future application of acellular vaccines with less side effects, will result in the elimination of whooping cough in all areas of Germany.

Mackaness' original article about cellular resistance to infection, published in 1962, is recalled. These experiments laid the foundation of the analysis of immune mechanisms against infection with facultatively intracellular microorganisms. Based on a simple murine model with Listeria monocytogenes, an array of data was compiled during three decades, clarifying the mechanism of inborn resistance and acquired immunity to this type of parasites. The idea of various immune cell populations cooperating via cytokines was developed and experimentally proven. Different forms of immunodeficiencies were conceived in the same model, and therapeutic approaches were evaluated. Thus, thirty years after the first publication, Mackaness' concept of cell-mediated immunity to infection is solidly based on experimental data, and is an integral part of our understanding of the mammal immune system.