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.

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.

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.

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.