Low Rates of Culture-Confirmed Invasive Bacterial Infections
Low Rates of Culture-Confirmed Invasive Bacterial Infections
We have established a minimum population-based estimate of childhood, culture-confirmed invasive bacterial infection and described the characteristics of children who developed invasive bacterial infection over a 3-year period. By conducting the study within a defined geographical region, we are able to provide robust estimates of culture-confirmed invasive bacterial infection in a large and ethnically diverse cohort, representing 15% of the total childhood population in England. Inclusion of all children with a positive blood/CSF culture in the surveillance also allowed us to collect extensive clinical and microbiological data.
There are limited data published on the epidemiology of childhood invasive bacterial infections in countries with established national vaccination programmes. Several large studies have highlighted the low bacteraemia rates in the postvaccine era in children. In the UK and the Netherlands, for example, serious bacterial infections were identified in 12–25% of previously healthy children attending the Emergency Department. Bacteraemia and meningitis, however, represented only 1% of these infections. Although our cohort was restricted to only blood/CSF culture-confirmed cases representing the more severe end of childhood infection, we were able to collect detailed information on cases and responsible pathogens in different age groups and with different risk factors. Our strict inclusion criteria also allow us to compare rates with other population-based studies, including historical rates. In <5-year-olds, for example, our rates of 13.8/000 000 and 2.6/100 000 for culture-confirmed invasive bacterial infections and meningitis, respectively, are far lower than 36/100 000 and 25/100 000 for invasive Hib disease and Hib meningitis alone (which were both diagnosed through culture only), just before routine Hib vaccination was introduced in the UK in 1992.
Another important finding is that HA-invasive bacterial infection accounted for a third of all invasive bacterial infection and also two-thirds of children with community-acquired invasive bacterial infections had co-morbidities. HA infections are associated with prolonged hospitalisation, increased healthcare costs and significant long-term morbidity and mortality. In common with other reports, we found that HA-invasive bacterial infections were responsible for 60% of all invasive bacterial infection among premature infants. A previous study using data linkage by Blackburn and colleagues noted that approximately 50% of all invasive bacterial infection in infants under 1 year of age was HA. In addition, the Health Protection Agency recently reported an overall prevalence of HA infections in children of 5.4% (95% CI 3.9% to 7.5%) in England, with infants aged 1–23 months having the highest HA infection rates (8.2%) (http://www.hpa.org.uk/Publications/InfectiousDiseases/AntimicrobialAndHealthcareAssociatedInfections/1205HCAIEnglishPPSforhcaiandamu2011prelim/). Both studies indicate a worrying trend of rising HA infection rates in this population, which is exacerbated by increasing antimicrobial resistance among pathogens causing HA infections. Early recognition and prompt management is essential in children with suspected invasive bacterial infections in order to improve these outcomes. These include goal-directed therapy, bacterial cultures prior to commencing antibiotics and evidence-based broad spectrum empiric antibiotic use with de-escalation as soon as possible.
The remarkably low invasive bacterial infection rates in England, however, are in contrast to the rapidly rising trends in paediatric hospital admissions, predominantly for infection in infants. Since the early 2000's, the number of infants admitted to hospital has continued to rise year-on-year, such that 36% of infants had at least one hospital admission in the first year of life, with the majority of healthy infants admitted for less than 1 day, mainly for minor acute infections. The 2013 National Institute of Health and Care Excellence (NICE) guidance addresses the difficult task of identifying invasive bacterial infections in young children presenting to the emergency department with a febrile illness. However, accurate estimates of invasive bacterial infections in the UK are lacking. Rates of childhood invasive bacterial infections that were used to develop the recent NICE guidance, for example, are based on data from the 1980s and our data suggest they significantly overestimate the current population risk of invasive bacterial infections. If our estimate of 1% of hospital admissions is correct, this would have a major impact for policy-makers in the assumptions made about the investigations and management of children presenting with suspected infection.
The finding that two-thirds of the community-acquired invasive bacterial infection episodes now occur in children with co-morbidities is also new. The risk factors (especially presence of a central line) and pathogens responsible for community-acquired infection in children with co-morbidities were similar to those with HA-invasive bacterial infection. While national empiric prescribing guidelines are in place for fever in children with malignancy, no such guidance exists for children with other co-morbidities. The British National Formulary for Children (BNF-C) currently recommends ceftriaxone for all children with suspected invasive bacterial infection but does not differentiate between previously healthy children and those with co-morbidities, even though the pathogens responsible and their antimicrobial susceptibility profile are very different. Further studies are needed to evaluate whether children with co-morbidities other than malignancy who become unwell in the community might benefit from more broad-spectrum empiric antibiotic therapy.
Our study has limitations. First, we only included children with blood/CSF culture-confirmed invasive bacterial infection. However, the inclusion of cases with negative blood/CSF cultures but positive cultures from other sterile sites is unlikely to significantly increase the estimated rates. Similarly, local hospital microbiology departments generally do not perform blood/CSF PCR-testing for invasive bacterial infection. A national PCR-testing service is available, but only for meningococcal septicaemia/meningitis and for pneumococcal meningitis/empyema. Given that nearly all children with suspected invasive bacterial infection in England are hospitalised and have blood cultures taken prior to initiating empiric intravenous antibiotic therapy, there are unlikely to be many cases of PCR-positive, culture-negative cases in our cohort. During 2009–2011, for example, there were only nine PCR-positive tests for N meningitidis from 141 blood/CSF samples submitted for testing by all participating sites. Our case definition also does not include non-bacteraemic infections such as osteomyelitis, pneumonia or urinary tract infections, which may cause significant morbidity in children. In Australia, urinary tract infections and pneumonia were each responsible for 3.4% of almost 16 000 febrile illness episodes in children aged <5 years during 2004–2006 and the new NICE guidelines include urinalysis as part of the investigation algorithm for young children with a febrile illness.
Another limitation is that we were unable to compare population rates for invasive bacterial infections in healthy children and in those with co-morbidities because we do not have denominator data for childhood co-morbidity prevalence in SWL. A recent UK study estimated that 1.8% of children aged 2–15 years had co-morbidities associated with an increased risk of invasive pneumococcal disease in England. Even if the true number of children with invasive bacterial infection in our cohort were doubled and taking an exaggerated estimate of 5% childhood co-morbidity prevalence, the incidence of invasive bacterial infections in previously healthy children would still remain low at 13/100,000 population.
Discussion
We have established a minimum population-based estimate of childhood, culture-confirmed invasive bacterial infection and described the characteristics of children who developed invasive bacterial infection over a 3-year period. By conducting the study within a defined geographical region, we are able to provide robust estimates of culture-confirmed invasive bacterial infection in a large and ethnically diverse cohort, representing 15% of the total childhood population in England. Inclusion of all children with a positive blood/CSF culture in the surveillance also allowed us to collect extensive clinical and microbiological data.
There are limited data published on the epidemiology of childhood invasive bacterial infections in countries with established national vaccination programmes. Several large studies have highlighted the low bacteraemia rates in the postvaccine era in children. In the UK and the Netherlands, for example, serious bacterial infections were identified in 12–25% of previously healthy children attending the Emergency Department. Bacteraemia and meningitis, however, represented only 1% of these infections. Although our cohort was restricted to only blood/CSF culture-confirmed cases representing the more severe end of childhood infection, we were able to collect detailed information on cases and responsible pathogens in different age groups and with different risk factors. Our strict inclusion criteria also allow us to compare rates with other population-based studies, including historical rates. In <5-year-olds, for example, our rates of 13.8/000 000 and 2.6/100 000 for culture-confirmed invasive bacterial infections and meningitis, respectively, are far lower than 36/100 000 and 25/100 000 for invasive Hib disease and Hib meningitis alone (which were both diagnosed through culture only), just before routine Hib vaccination was introduced in the UK in 1992.
Another important finding is that HA-invasive bacterial infection accounted for a third of all invasive bacterial infection and also two-thirds of children with community-acquired invasive bacterial infections had co-morbidities. HA infections are associated with prolonged hospitalisation, increased healthcare costs and significant long-term morbidity and mortality. In common with other reports, we found that HA-invasive bacterial infections were responsible for 60% of all invasive bacterial infection among premature infants. A previous study using data linkage by Blackburn and colleagues noted that approximately 50% of all invasive bacterial infection in infants under 1 year of age was HA. In addition, the Health Protection Agency recently reported an overall prevalence of HA infections in children of 5.4% (95% CI 3.9% to 7.5%) in England, with infants aged 1–23 months having the highest HA infection rates (8.2%) (http://www.hpa.org.uk/Publications/InfectiousDiseases/AntimicrobialAndHealthcareAssociatedInfections/1205HCAIEnglishPPSforhcaiandamu2011prelim/). Both studies indicate a worrying trend of rising HA infection rates in this population, which is exacerbated by increasing antimicrobial resistance among pathogens causing HA infections. Early recognition and prompt management is essential in children with suspected invasive bacterial infections in order to improve these outcomes. These include goal-directed therapy, bacterial cultures prior to commencing antibiotics and evidence-based broad spectrum empiric antibiotic use with de-escalation as soon as possible.
The remarkably low invasive bacterial infection rates in England, however, are in contrast to the rapidly rising trends in paediatric hospital admissions, predominantly for infection in infants. Since the early 2000's, the number of infants admitted to hospital has continued to rise year-on-year, such that 36% of infants had at least one hospital admission in the first year of life, with the majority of healthy infants admitted for less than 1 day, mainly for minor acute infections. The 2013 National Institute of Health and Care Excellence (NICE) guidance addresses the difficult task of identifying invasive bacterial infections in young children presenting to the emergency department with a febrile illness. However, accurate estimates of invasive bacterial infections in the UK are lacking. Rates of childhood invasive bacterial infections that were used to develop the recent NICE guidance, for example, are based on data from the 1980s and our data suggest they significantly overestimate the current population risk of invasive bacterial infections. If our estimate of 1% of hospital admissions is correct, this would have a major impact for policy-makers in the assumptions made about the investigations and management of children presenting with suspected infection.
The finding that two-thirds of the community-acquired invasive bacterial infection episodes now occur in children with co-morbidities is also new. The risk factors (especially presence of a central line) and pathogens responsible for community-acquired infection in children with co-morbidities were similar to those with HA-invasive bacterial infection. While national empiric prescribing guidelines are in place for fever in children with malignancy, no such guidance exists for children with other co-morbidities. The British National Formulary for Children (BNF-C) currently recommends ceftriaxone for all children with suspected invasive bacterial infection but does not differentiate between previously healthy children and those with co-morbidities, even though the pathogens responsible and their antimicrobial susceptibility profile are very different. Further studies are needed to evaluate whether children with co-morbidities other than malignancy who become unwell in the community might benefit from more broad-spectrum empiric antibiotic therapy.
Our study has limitations. First, we only included children with blood/CSF culture-confirmed invasive bacterial infection. However, the inclusion of cases with negative blood/CSF cultures but positive cultures from other sterile sites is unlikely to significantly increase the estimated rates. Similarly, local hospital microbiology departments generally do not perform blood/CSF PCR-testing for invasive bacterial infection. A national PCR-testing service is available, but only for meningococcal septicaemia/meningitis and for pneumococcal meningitis/empyema. Given that nearly all children with suspected invasive bacterial infection in England are hospitalised and have blood cultures taken prior to initiating empiric intravenous antibiotic therapy, there are unlikely to be many cases of PCR-positive, culture-negative cases in our cohort. During 2009–2011, for example, there were only nine PCR-positive tests for N meningitidis from 141 blood/CSF samples submitted for testing by all participating sites. Our case definition also does not include non-bacteraemic infections such as osteomyelitis, pneumonia or urinary tract infections, which may cause significant morbidity in children. In Australia, urinary tract infections and pneumonia were each responsible for 3.4% of almost 16 000 febrile illness episodes in children aged <5 years during 2004–2006 and the new NICE guidelines include urinalysis as part of the investigation algorithm for young children with a febrile illness.
Another limitation is that we were unable to compare population rates for invasive bacterial infections in healthy children and in those with co-morbidities because we do not have denominator data for childhood co-morbidity prevalence in SWL. A recent UK study estimated that 1.8% of children aged 2–15 years had co-morbidities associated with an increased risk of invasive pneumococcal disease in England. Even if the true number of children with invasive bacterial infection in our cohort were doubled and taking an exaggerated estimate of 5% childhood co-morbidity prevalence, the incidence of invasive bacterial infections in previously healthy children would still remain low at 13/100,000 population.
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