PID-ARI.net - a pediatric infectious diseases network on acute respiratory infections and the added value of a multilevel research network.

BACKGROUND: PID-ARI.net was one of three infectious disease epidemiological research networks funded by the German Ministry of Education and Research (BMBF). Its objectives were to strengthen the national initiative on infectious diseases epidemiology and to focus on a health care problem of high relevance. PATIENTS AND METHODS: A research network on the epidemiology of ARI in children was formed to generate data on several levels. Key structure was a centrally organized active surveillance system in three areas of Germany from north to south. RESULTS: In the 6 years of funding by the BMBF, an integrated research network with a known population denominator was formed. In the laboratory-based surveillance of up to 19 respiratory pathogens, 18,899 samples were analyzed. The added value is utilization of data on time, place, person and pathogen of a disease episode at several levels - from surveillance and online publication via a website to descriptive, analytical and molecular epidemiology and further specialized projects. Its wide age range including children up to 16 years of age, an extensive panel of pathogens, a known population denominator and the diversity of 3 distant geographical areas should considerably reduce vulnerability due to bias. CONCLUSIONS: Active surveillance systems for ARI are superior to passive systems. If a surveillance system such as the one used in PID-ARI.net is part of a research network which can utilize the data on several levels, the expenditure for such a system should be worthwhile and such a system would be an asset to any health care system.

Lower respiratory tract disease in children: constant pathogens - constant management?!

BACKGROUND: This study analyses the pathogens of acute lower respiratory tract infections (LRI) in children in a German community hospital over six years. Against this background the adoption of new diagnostic and therapeutic guidelines for the LRI management and of RSV-cases in particular is studied. METHODS: 1054 children aged zero to 36 months hospitalized with LRI were prospectively included in the surveillance studies "Parainfluenzavirus (PIV) and Respiratory syncytial virus (RSV) infections in Germany [PRI.de] 1999-2001" and the "pediatric infectious diseases network on acute respiratory tract infections" [PID-ARI.net] for the time period of October 2002 until June 2005. The nasopharyngeal aspirates (NPA) of these children had been analysed for RSV, PIV 1,2,3 and influenzavirus (IV)-A, -B. In 2003/2004 the national guideline on how to diagnose and treat RSV-disease (bronchiolitis) changed. Data on LRI cases severity and especially those regarding the clinical management of RSV-infections were compared to see differences following the release of the guideline. RESULTS: 84% of the children were between zero and 24 months old. 34% of the NPA specimens were positive for RSV, 7.7% for PIV 1,2,3 and 4.7% for IV-A, -B. Epidemiological findings did not differ substantially between the two studies. Clinical management of RSV-LRI, especially drug use, did not change except for the lower rate of x-ray examination (p<0.01). CONCLUSION: The spectrum of causing agents in LRI of children remained quite stable over of six years. Diagnostic and therapeutic concepts remain also stable in a situation where new guidelines were introduced, but not reinforced.

The descriptive epidemiology of severe lower respiratory tract infections in children in Kiel, Germany.

BACKGROUND: Lower respiratory tract infections (LRI) inflict a high burden of disease in children worldwide. Longitudinal, descriptive epidemiological data on different forms of LRI are urgently needed to differentiate this burden, compare population-based incidence rates between countries and to recognize trends. PATIENTS AND METHODS: From July 1996 to June 2000, all children hospitalized with LRI, i. e. laryngo-tracheo-bronchitis (LTB), bronchitis, wheezing bronchitis-bronchiolitis (WBB), bronchopneumonia and pneumonia, in the municipal area of Kiel, Schleswig-Holstein, Germany, were analyzed by cross-sectional studies. Naso-pharyngeal aspirates (NPA) were analyzed by an in-house 9-valent multiplex-RT-PCR. RESULTS: In the 4-year observational period, 1 072 children aged 0 to 16 years (median 23 months) were hospitalized with LRI: 12 % (median 28 months) with LTB, 11 % (median 17 months) with bronchitis, 28 % (median 13 months) with WBB, 26 % (median 26 months) with bronchopneumonia and 22 % (median 47 months) with pneumonia. The prevalence of chronic underlying conditions (20 %) and low gestational age (13 %) varied in the different forms of LRI. The cumulative incidence rate of LRI rose steadily over the 4 years. The highest fraction was contributed by WBB, while pneumonia declined. The highest incidence rate ratio was attributable to respiratory syncytial virus (RSV, 0.46) and to children under 2 years of age. CONCLUSIONS: LRI, especially obstructive forms of LRI, are increasing in Germany as described earlier for the USA, UK and Sweden. The major burden is carried by children under 2 years. RSV is the single pathogen with the highest impact.

Population-based incidence of severe pneumonia in children in Kiel, Germany.

BACKGROUND: Elaborated data on the descriptive epidemiology of community-acquired pneumonia (CAP) are a prerequisite to estimate the impact of new vaccines. PATIENTS AND METHODS: From July 1996 to June 2000, all children (0-16 years) admitted to one of the two pediatric hospitals in Kiel and being resident in the municipal area of Kiel were investigated by cross-sectional studies and prospective testing using a 9-valent in-house m-RT-PCR method. RESULTS: In the 4-year period, 514 children were included (mean age 46, median 40 months): 279 were diagnosed with bronchopneumonia (BPN, median age 26 months), 235 with pneumonia (PN) (47 months); within the latter 69 cases had lobar PN (55 months), 41 atypical PN (51 months) and 28 parapneumonic effusions (74 months). An underlying chronic condition was present in 22.8 % and 10.1 % were born prematurely. The population-based incidence rates (per 100,000 per year) were on average 300 for children 0-16 years, 163 for BPN, 136 for PN, 53 for lobar PN, 24 for atypical PN and 16 for parapneumonic effusions. The rate was stable or slightly declined over the observation period. 61 % of infants and 45 % of children under 5 years of age have to be hospitalized having contracted CAP. The highest fraction of 34 and 25 %, respectively, was attributable to RSV. Viruses were not diagnosed significantly more often in BPN than in PN, if stratified by age. CONCLUSION: The incidence and the admission rate of severe CAP is lower than in the USA. The high rate of empyema warrants enhanced surveillance as an indicator for antibiotic resistance or changing impact of pneumococcal serotypes. Misclassification, also with ICD codes, is a major issue. Well analyzed epidemiological recruitment areas are a valid tool to generate precise data in Germany.

RSV-prevention in children guided by a web-based early warning system.

BACKGROUND: Passive immunization with palivizumab is expensive and requires considerable logistic effort. So far 5 monthly injections from November to March are recommended. The RSV season onset and its duration, however, shows considerable variation. In many countries on the northern hemisphere a dual rhythm is described. METHOD: A web-based early warning system within the research network PID-ARI.net is in place since 2002. The surveillance data are published online weekly via www.pid-ari.net. This enables physicians to carry out interventions, like passive immunization for RSV, synchronously with the epidemiology of a given pathogen instead of a rigid schedule. The surveillance of PID-ARI.net is based on a 19 valent multiplex RT-PCR on naso-pharyngeal aspirates. The samples are provided by hospitals and offices in Freiburg, Mainz and Schleswig-Holstein (north, middle, south of Germany). Children with lower airway infections are prospectively enrolled. RESULTS: In the time period from July 1999 to June 2003 with 20 months of recommended palivizumab application, 5 months (25 %) would have been not on target. In two seasons the start of the vaccine campaign would have been too early (waste of two months). In one season the application would have started one month too late and in two seasons the vaccine campaign would have been stopped two months too early leaving the vaccinees on risk for acquiring RSV. CONCLUSIONS: The web-based early warning system of PID-ARI.net is the first, pathogen-specific, comprehensive and fast surveillance-system for airway pathogens in Europe. It facilitates the epidemic-synchronous use of the passive immunization with palivizumab and by this increases its efficiency and should safe costs.

Evaluation of a multiplex reverse transcriptase PCR ELISA for the detection of nine respiratory tract pathogens.

BACKGROUND: A multiplex reverse transcription (RT) polymerase chain reaction combined with a microwell hybridization assay (m-RT-PCR-ELISA) was previously developed to detect nine different microorganisms: enterovirus (EV), influenza virus type A (IVA) and type B (IVB), respiratory syncytial virus (RSV), parainfluenzavirus type 1 (PIV1) and type 3 (PIV3), adenovirus (AV), Mycoplasma pneumoniae (Mpn), Chlamydia pneumoniae (Cpn) in a single test. These organisms do not usually colonize the respiratory tract of humans, but, if present, it may be assumed they are involved in respiratory disease. OBJECTIVES AND STUDY DESIGN: The m-RT-PCR-ELISA was tested on (i) culture supernatants of unknown contents, (ii) by determining the analytical sensitivity of 10-fold serial dilutions of culture supernatants and (iii) by determining clinical sensitivity in a retrospective study on 411 clinical specimens. The specimens were re-tested in parallel by m-RT-PCR-ELISA versus the gold standard culture and immunfluorescence, and versus individual RT-PCR. RESULTS: (i) The 9-valent m-RT-PCR-ELISA shows 83% to 100% concordant results on 103 culture supernatants containing different organisms. (ii) The analytical sensitivity was as follows: higher sensitivity of the 9-valent m-RT-PCR-ELISA in comparison to culture in the cases of PIV3, IVA and IVB (factor 10) and AV and EV (factor 100), and lower sensitivity in case of RSV and PIV1 (factor 10). (iii) The agreement with the gold standard in the kappa statistic was excellent for RSV (kappa = 0.937), IVA (kappa = 0.940), very good for PIV1 (kappa = 0.914), IVB (kappa = 0.907) and satisfactory for PIV3 (kappa = 0.410). For AV, EV and Mpn the m-RT-PCR-ELISA preliminary could be qualified as very good, based on the data derived on culture supernatants. Information about the validity for Cpn is limited. CONCLUSION: The m-RT-PCR-ELISA is a feasible, sensitive and specific method for detection of a broad spectrum of organisms. It is suitable for individual as well as epidemiological diagnosis.

Variables explaining the duration of hospitalization in children under two years of age admitted with acute airway infections: does respiratory syncytial virus have a direct impact?

BACKGROUND: Duration of hospitalization is influenced by many factors. It is an important parameter for quality of care. So far it is unknown, whether respiratory syncytial virus (RSV) etiology itself contributes to the time in hospital. METHOD: Children under 2 years of age admitted with a lower respiratory tract infection in 3 hospitals (1 tertiary and 2 secondary centers) in northern Germany were included in an unmatched, hospital-based case-control study. Cases were children tested positive for RSV by multiplex RT-PCR. One control group consisted of children tested negative for RSV in the multiplex-RT-PCR and a second control group consisted of patients in whom no PCR was done. Since only 4 to 5% in the latter group and thus 2% of the study population were misclassified, this group could be involved in the analysis. RESULTS: The median days of hospitalization was 7 days; 9 days in the RSV-positive group, 8 and 6 days in the RSV-negative and non-PCR group, respectively. The time in hospital was diminishing over the 4 year observation period. Duration of hospitalization was best predicted by--young age, presence of an underlying condition, disease entity--being pneumonia or bronchiolitis, prematurity, earlier epidemiologic year and intercostal retractions. Not predictive were: RSV-etiology, center, duration of illness, wheezing, C-reactive protein level and consolidation on the chest x-ray (all on admission). CONCLUSIONS: RSV-etiology is influencing the duration of hospitalization only indirectly via its predilection for the very young age and certain underlying conditions--not by RSV itself. In spite of considerable variation of patient populations between secondary and tertiary care facilities and locally different care practices, the treatment center pre se did not influence the duration of hospitalization significantly. Further rationalization of treatment is, however, possible.

Burden of disease in hospitalized RSV-positive children in Germany.

BACKGROUND: In spite of a large amount of data from other countries, those on the burden of disease attributed to respiratory syncytial virus (RSV) in Germany are lacking and are urgently needed. METHOD: In a population-based cross-sectional study from July 1996 to June 1999 150 children from birth to 16 years of age hospitalized in Kiel and tested positive for RSV by polymerase chain reaction were investigated. Stepwise linear and logistic regression models were applied to predict a bacterial co-infection as well as the duration of hospitalization. RESULTS: Pneumonia (54 %) and wheezing bronchitis (including bronchiolitis, 27 %) were the predominating diagnoses; 25 % had an underlying condition. Four patients needed nasal continuous airway pressure and one intermittent mandatory ventilation; none died. According to the surrogate markers CRP and immature neutrophil fraction, 20 % to 30 % were suspected to have a bacterial co-infection on admission; antibiotics were prescribed in 65 % of the patients. The average duration of hospitalization was 9 days and was best predicted by young age, the presence of an underlying condition, intercostal retractions and high CRP on admission. CONCLUSIONS: Bacterial co-infection is the major confounder in burden of disease analyses in RSV. The decision not to administer antibiotics to children hospitalized with RSV can be risky, particularly when there is considerable diagnostic uncertainty. Within the realm of current clinical practice, complications and deaths related to RSV are rare in Germany.

Seasonality of respiratory syncytial virus-positive hospitalizations in children in Kiel, Germany, over a 7-year period.

BACKGROUND: Elaborate, long-term data on the rhythm, seasonality and severity of the yearly respiratory syncytial virus (RSV) epidemics in Germany are lacking. PATIENTS AND METHODS: A longitudinal investigation was undertaken of children from birth to 16 years of age admitted with an RSV infection in the two pediatric hospitals in Kiel between July 1994 and June 2001. To compare the severity of the individual seasons, the incidences and the proportion of RSV-positive hospitalized children aged 0 to 2 years from the denominator area of Kiel were compared. RESULTS: During the 7-year period, the nasopharyngeal aspirates of 2,367 children were investigated; RSV was detected in 384 (16.2%). The seasons from 1994/95 to 1996/97 started late (December to January) and ended between March and May. Since 1997/98 it seems that a late season is followed by an early season (start in September to October) in a 2-year pattern. CONCLUSION: No fixed rhythm of the RSV season can be identified as yet. Ascertainment bias is unlikely to explain the differences in rhythm. The incidence of RSV-positive hospitalizations seems to be increasing.

The incidence of influenza-associated hospitalizations in children in Germany.

Since new vaccines and anti-viral drugs for influenza have become available, collation of actual and country-specific epidemiological data is essential. Since respiratory syncytial virus (RSV) is a well known paediatric airway pathogen and some epidemiological data exist already, a comparison between influenza and RSV seems warranted. From July 1996 to June 2001 the naso-pharyngeal aspirates (NPA) of children from birth to 16 years of age, admitted to one of the two paediatric hospitals in Kiel, Germany, were investigated by a nine-valent multiplex reverse transcriptase PCR assay. NPA were investigated in 60.8 % of 3,469 children admitted with an acute respiratory tract infection. Community-acquired or nosocomial infections (in parentheses) due to influenza A were diagnosed in 122 (10) children, due to influenza B in 14 (2) and due to RSV in 325 (24) cases. Patients with influenza A (median 752 days) and influenza B (median 966 days) were older than patients with RSV (median 168 days). The spectrum of disease presentation was broader in influenza than in RSV. In each winter, admissions with influenza were less common than those with RSV. Influenza B only occurred in 2 of the 5 years. The cumulative, population-based incidences per 100,000 children 0-16 (0-5, >5-16) years of age were 53 (123, 22) for influenza A, 16 (30, 9) for influenza B and 165 (453, 4) for RSV. Cardiac conditions and asthma were the major risk factors for admission to hospital with influenza A (RR 9.8, 4.1) and RSV (8.5, 2.1) infections. Underlying conditions were most common in influenza B. Low gestational age doubled the risk for admission to hospital with influenza A infection, but did not show a dose-effect relationship as in RSV. The burden of influenza-positive hospitalizations was about one third that of RSV. The incidence was similar to reports from the United States. Targeting children with underlying conditions, especially cardiac conditions and asthma in the German immunization programme is appropriate, as long as no policy for vaccination of the general paediatric population exists.

Incidence of respiratory syncytial virus-positive hospitalizations in Germany.

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.

Candida arthritis in a premature infant treated successfully with oral fluconazole for six months.

INTRODUCTION: Candida arthritis in premature infants is a rare condition mainly treated with parenteral amphotericin B. CLINICAL PICTURE: Arthritis 9 weeks after birth. The infection resulted out of colonisation at birth and fungaemia at day 6 and day 13 of life. TREATMENT: Oral fluconazole for 6 months (5 mg/kg/day after loading with 7 mg/kg/day). OUTCOME: Full remission. CONCLUSIONS: Oral fluconazole is an alternative to parenteral amphotericin B in the treatment of premature infants, but proof of absorption and an extended treatment period according to prematurity might be warranted.

Epidemiological investigation of nine respiratory pathogens in hospitalized children in Germany using multiplex reverse-transcriptase polymerase chain reaction.

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.

Postoperative Mycobacterium avium osteomyelitis confirmed by polymerase chain reaction.

UNLABELLED: An 18-year-old male with Escobar syndrome developed Mycobacterium avium osteomyelitis after corrective osteotomy. After three surgical interventions the infection reappeared a fourth time. Repeated attempts at microbiological diagnosis of the granulomatous lesions by microscopy and culture for conventional bacteria and Mycobacteria did not reveal any organism. The diagnosis of Mycobacterium avium finally was achieved by polymerase chain reaction. Extensive immunological work-up did not reveal signs of immunodeficiency. The patient was treated successfully by a combined surgical and chemotherapeutic approach consisting of clarithromycin, ethambutol and ciprofloxacin. CONCLUSION: Polymerase chain reaction may be especially useful for clinical situations with a low bacterial load, especially for fastidious and slow growing pathogens like Mycobacteria. In our patient a combination of surgical therapy with a triple regimen containing clarithromycin proved successful for treatment of a localised infection with M. avium in a supposedly immunocompetent host.

Rapid identification of nine microorganisms causing acute respiratory tract infections by single-tube multiplex reverse transcription-PCR: feasibility study.

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.

Safety and efficacy of acellular pertussis vaccines: the Mainz study and other recent studies.

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.