Pneumonia is one of the most common causes of hospitalization in children in the United States.1–3 It is caused by bacteria, viruses, or simultaneous infection with both types of pathogens. For bacteria, culture-based methods remain the most common way of identifying pneumonia pathogens.
The 2011 national guidelines for the management of community-acquired pneumonia (CAP) published by the Society for Pediatric Infectious Diseases (SEIP) and the Infectious Diseases Society of America (SEIA) recommend obtaining blood cultures in all hospitalized children with CAP. moderate to severe,4 although the classification of moderate disease was not explicitly defined.
Potential benefits of obtaining positive blood culture results in patients with CAP include the possibility of a narrow antibiotic spectrum, prediction of outcomes, and reporting of vaccine efficacy evaluations; but the productivity and impact of blood cultures have not been adequately studied.
In a meta-analysis of smaller studies, blood culture results were rarely positive among children with CAP.5 Additionally, S. pneumoniae remains the most common bacterial organism in culture-positive CAP cases,5–12 and Empirical treatment recommendations already point to this pathogen.
On the other hand, isolation of contaminants from blood cultures is relatively common and can lead to unnecessary exposure to broad-spectrum antibiotics and prolonged hospitalization.13
Thus, although it is recommended by the SEIP and SEIA guidelines for the majority of children hospitalized with CAP, there is clear evidence that demonstrates that the routine use of blood cultures in all children hospitalized with pneumonia is uncertain.9,12, 14 Previous studies were limited by selective collection of cultures, resulting in a lack of culture data in 20% to 65% of children enrolled in the studies of interest.6-10,12,14
The objective of this study was to estimate the prevalence, risk factors, and clinical outcomes of bacteremic CAP among children enrolled in a prospective multicenter study of pediatric hospitalizations for CAP in the United States, which included systematic collection of blood cultures. Associations between positive blood cultures, empiric antibiotics, and modifications in antibiotic therapy were also examined.
| Methods |
> Study population
We analyzed data from the Etiology of Pneumonia in the Community Study (CNSE), a prospective, active surveillance study of children <18 years of age who were hospitalized with CAP at 3 US children’s hospitals from January 1, 2010 to June 30, 2012.15
Data analysis was completed in January 2018. Each hospital’s institutional review board and the Centers for Disease Control and Prevention approved the study protocol.
Children were included in the study if they resided in a predetermined catchment area and were hospitalized in one of the study hospitals with (1) signs or symptoms of acute infection (e.g., fever), (2) evidence of acute respiratory illness (e.g., cough) and (3) evidence of pneumonia on chest x-ray as judged by a study radiologist at each site.
Children with a recent hospitalization (<7 days for immunocompetent children and <90 days for immunocompromised children), residing in an extended care facility, with a tracheostomy tube, cystic fibrosis, severe immunosuppression, or with a clear alternative diagnosis were excluded. of the study.15
Demographic information, medical history, and current illness were collected, and reviews of medical records were performed (medical history, hospital course, antibiotic treatment, clinical results, and laboratory data). Procalcitonin levels were collected in a subset of patients.16
Clinical outcomes included length of stay (DI) in days, intensive care unit (ICU) admission, and severe pneumonia defined by the need for invasive mechanical ventilation (IMV) and/or shock requiring vasoactive medications.
> Definition of bacteremia
Blood cultures were routinely collected at the time of enrollment if they had not been performed previously. All cultures with positive results were made available to the clinical teams.
For the present analysis, children without blood culture data were excluded .
Bacteremia was defined as the isolation of a pathogen by blood culture collected within 72 hours of admission.
The following organisms, when isolated, were identified as contaminants based on expert consensus at the time of the EENC: Aeroccocus , Alcaligenes faecalis , Bacillus , Citrobacter , coagulase-negative staphylococci, Corynebacterium , Enterococcus , Micrococcus , Neisseria subflava , Propionibacterium , Stomatococcus , Streptococcus bovis and Veillonella . The most virulent viridans streptococci ( Streptococcus anginosus , Streptococcus mitis ) were considered pathogenic.
The less virulent viridans streptococci ( Streptococcus salivarius and viridans without further speciation) were considered contaminants when isolated concurrently with another bacterial pathogen. Otherwise, the less virulent viridans group streptococci were considered pathogenic.15
For the purposes of this study, a member of each institution reviewed the medical record of each patient who met the above criteria for bacteremia to confirm that the positive culture result was treated as a true pathogen by the clinical team. Positive culture results not treated as true bacteremia by the clinical team were also excluded from the analyses.
> Use of antibiotics
Empirical antibiotics were defined as antibiotics initiated in the emergency department or inpatient ward as documented in the patient’s electronic medical record before any culture data were available.
Empiric antibiotics were classified as follows: cephalosporin (with or without a macrolide), cephalosporin plus vancomycin or clindamycin (with or without a macrolide), aminopenicillin, other, and none. A review of the medical history of each patient with bacteremia was performed to obtain additional information on antibiotic management in response to the positive culture result.
For these patients, definitive therapy referred to antibiotics selected after culture data, including speciation and susceptibility testing, were obtained and added to the medical record for viewing by clinicians.
> Statistical analysis
Characteristics of children with and without bacteremia were compared, including age, race and ethnicity, comorbidities, antibiotic exposure before blood culture, temperature, physical examination findings at presentation (e.g., wheezing), concomitant viral detection, procalcitonin level, leukocyte count and radiographic findings.
For bivariate comparisons between children with and without bacteremia, Wilcoxon rank sum or χ tests were used. Binomial exact 95% confidence intervals (CIs) were also calculated.
Associations between bacteremia and clinical outcomes were assessed using Cox proportional hazards regression by time to discharge (DI equivalent) (a hazard ratio < 1 indicated that the discharge rate for patients with bacteremia was lower compared to patients without bacteremia at any particular time point) and logistic regression for ICU admission while adjusting for demographic, clinical, laboratory, and radiographic characteristics.
There were no in-hospital deaths or other censoring events. Firth17 logistic regression (penalized maximum likelihood estimation) was used for VMI and/or shock to minimize potential model overfitting.
To explore the influence of individual pathogens causing bacteremia, we also compared clinical outcomes between children without bacteremia with those with bacteremia caused by specific pathogens, including S. pneumoniae , S. aureus , S. pyogenes , and a group composed of all remaining or "other" pathogens.
| Results |
> Study population
Of the 2358 children enrolled in the EENC, 2143 (91%) had blood cultures and were included in the analysis. The median time from triage to blood culture collection was 2.6 hours (interquartile range [IQR], 1.0–7.3 hours), with 92.5% of cultures collected within 24 hours. and 96.9% within 36 hours.
Of the 461 children who required ICU care, 429 (93.1%) were admitted to the ICU within 1 calendar day of presentation and 450 (98%) within 2 calendar days.
Fifty-three patients had positive blood culture results. Seven (13%) blood culture results met the criteria for a true pathogen but were excluded from the study because the clinical team did not consider them true pathogens.
In these 7 cultures Acinetobacter (n = 1), Moraxella (n = 2), and viridans group streptococci ( S. parasanguinis , n = 2 and S. salivarius , n = 2) grew. The analysis was performed including these pathogens without significant differences in the results, so the data were not reported.
Forty-six (2.2%, 95% CI: 1.6%-2.9%) children had bacteremia treated as true pathogens by the physician in charge of these patients.
The most common pathogens were S. pneumoniae (n = 21, 46%), S. aureus (n = 6, 13%), and S. pyogenes (n = 4, 9%). Other pathogens included viridans group streptococci (n = 8, 17%); group B, C, or G streptococci (n = 2, 4%); Haemophilus influenzae (n = 1, 2%); Fusobacterium (n = 2, 4%); both S. pneumoniae and H. influenzae (n = 1, 2%); and both viridans group streptococci and Moraxella (n = 1, 2%).
The prevalence of bacteremia was similar between children with prior outpatient use of antibiotics (2.2%, CI: 1.3% –3.9%) and those without antibiotics (2.2%, CI: 1.5% – 3.0%).
However, patients who did not receive inpatient antibiotics before culture had a higher prevalence of bacteremia than those who did (2.6%, CI: 1.8% –3.4% vs. 0.82%, CI : 0.2% –2.1%; P = 0.021). Patients admitted to the ICU (4.3%, CI: 2.8% - 6.6%) and those with pleural effusion (8.4%, CI: 5.6% -12.4%) also had a higher prevalence of bacteremia.
The number needed to test a positive isolate was 24 among children admitted to the ICU, 12 for children with parapneumonic effusion, and 91 for children without ICU admission or effusion.
Among 1501 children with vaccine data available, 90% of them without bacteremia and 100% with bacteremia had received at least 3 doses of pneumococcal conjugate vaccine.
> Factors associated with bacteremia
Children with bacteremia were significantly more likely to be male, have a higher P/F ratio (PaO2/FIO2), have a parapneumonic effusion or pleural drainage procedure, and have blood collected before inpatient antibiotics, but significantly less likely to have wheezing or indrawing.
Among a subset of 502 children with procalcitonin obtained at enrollment, the procalcitonin level was significantly higher in children with bacteremia.
Other characteristics, including initiation of outpatient antibiotics before hospitalization and concomitant viral detection, were not significantly different between the 2 groups.
> Clinical results
Bacteremic children had a median ID of 5.8 days compared with 2.8 days in children without bacteremia (adjusted hazard ratio: 0.79, CI: 0.73-0.86).
Bacteremia was also associated with higher odds of ICU admission (43% vs 21%; adjusted odds ratio (aOR): 5.12; CI: 3.82–6.84) and of IMV and/or shock (30 % vs. 8%; aOR: 5.28; CI: 2.41–11.57) compared to those without bacteremia.
In exploratory analyzes comparing clinical outcomes among children with bacteremia caused by specific pathogens, median DI ranged from 3 days for S. pneumoniae to 15 days for S. aureus .
Children with S. aureus and S. pyogenes bacteremia had a marked increase in the frequency of ICU admission (100% and 73%), IMV and/or shock (67% and 75%) compared to children with S. pneumoniae bacteremia (27% ICU, 18% IMV and/or shock).
The most common empiric antibiotic options (before reporting positive blood cultures) among children with bacteremia included vancomycin or clindamycin plus a third-generation cephalosporin (43%), monotherapy with a third-generation cephalosporin (26%), or other coverage broad spectrum with ≥ 3 agents (15%). Only 3 (7%) children were treated with an aminopenicillin alone.
This was significantly different in children without bacteremia, who most frequently received monotherapy with a third-generation cephalosporin (55%) followed by vancomycin or clindamycin plus a third-generation cephalosporin (17%), no therapy (15%), and monotherapy with aminopenicillin (6%).
In children with bacteremia, empirical therapy was extended in 11 (24%) children with an initial report of a positive culture but before final speciation of the culture. After final speciation and availability of antibiotic susceptibility data, definitive therapy was reduced compared with empirical therapy in 31 children (67%), unchanged in 14 children (30%), and expanded in 1 child with Streptococcus viridans (2%) isolated in culture.
Among S. pneumoniae isolates , 5% were resistant to penicillin and 9% to clindamycin. Among S. aureus isolates , 67% were resistant to methicillin, but none to clindamycin.
| Discussion |
In this study, the authors demonstrated that bacteremia was infrequently detected among more than 2000 children hospitalized in the United States with clinically and radiographically confirmed CAP. S. pneumoniae accounted for half of the bacteremia cases; S. aureus and S. pyogenes were less frequent.
Children with bacteremia had more severe clinical outcomes, including longer IDs, more frequent ICU admissions, IMV, and/or shock.
Most children with bacteremic pneumonia received empiric broad-spectrum antibiotics, although therapy was reduced to two-thirds of these children after the bacterial pathogens were characterized.
The authors of previous studies have found a prevalence of bacteremia in children with CAP that varied from 1.1% to 7.1%.6–10,12,14,18,19
A recent meta-analysis by Iroh Tam et al.5 reported a pooled prevalence of 5.1%. The prevalence of bacteremia of 2.2% in the present study was lower than that reported by Iroh Tam5 but within the range of other reports. However, a potential limitation of previous studies is that culture data were only available for a portion of all enrolled children (median: 47%, IQR: 34%–64%).
Given that cultures were obtained at the discretion of the treating clinician in most studies, blood cultures were probably obtained more frequently in those with more severe disease or who had not yet received antibiotics,8,12 overestimating the prevalence of bacteremia.
Murtagh Kurowski et al.19 found a similar prevalence (2.5%) using routine blood culture collection as part of a quality improvement methodology, but cultures were only available for 79% of patients.
In contrast, >90% of children had blood cultures collected in the present study, and children with blood cultures were not different from those without cultures, suggesting that the sampled population was unbiased.
Several factors likely contribute to the low prevalence of positive blood culture results in pediatric pneumonia. These include the high burden of viral etiologies of pneumonia,15 the use of antibiotics before taking cultures,20 the limited sensitivity of culture methods,21,22 and the marked decrease in the prevalence of bacterial CAP after the introduction of the pneumococcal conjugate vaccine and the vaccine against H. influenzae type B.5
The authors found that bacteremia was less frequently detected in children who had received inpatient antibiotics before cultures were obtained (0.8% vs. 2.5%, P = 0.021).
The 2011 SEIP and SEIA pediatric CAP guideline recommends obtaining blood cultures in all hospitalized children with moderate to severe CAP,4 although there is no agreed upon definition of moderate CAP in children.
The presence of pleural effusion on chest radiography is a factor consistently shown to be associated with bacteremic pneumonia, both in this study and in other reports.9,12,23,24
Previous studies support obtaining cultures in children with stroke, need for ICU care, central line(s), younger age, immunocompromise, or chronic medical conditions.7,24
The authors did not find a difference in bacteremia based on age or comorbidities, but the data suggest that blood culture performance could be improved by focusing on children who require ICU admission or who have pleural effusion on chest x-ray. , as the majority (76%) of bacteremic children are still identified.
Additionally, in a previous study of children presenting to the emergency department with CAP, researchers found the need to culture 909 children to identify a positive isolate.25
Here the authors estimated a culture needed number of 24 for children admitted to the ICU and 12 for children with parapneumonic effusion, compared with 91 for children admitted to acute care without effusion. Therefore, obtaining blood cultures in each of these clinical scenarios seems prudent.
The values of the biomarker procalcitonin , associated with bacterial disease,16 were higher in children with bacteremia in this study. Therefore, this information could influence decisions around cultivation if the results are available quickly.
Risk stratification tools may also be useful in identifying children with moderate to severe pneumonia who are at increased risk for bacterial CAP.26
Empiric broad-spectrum antibiotics were commonly used before culture results were available in children who ultimately demonstrated bacteremia, and included coverage for S. aureus more frequently than in nonbacteremic children, probably due to more severe disease in their presentation.
However, penicillin-susceptible S. pneumoniae was the most common etiology of bacteremic CAP, and definitive antibiotic therapy was eventually reduced to two-thirds of bacteremic children.
Frequent use of a cephalosporin in both groups was likely because these data were collected from 2010 to 2012, before widespread adoption of the SEIA recommendation for aminopenicillin monotherapy in CAP.
These findings were similar to those reported by Neuman et al.,10 in which it was demonstrated that the majority of pathogens recovered in children with bacteremic CAP were sensitive to penicillin.
Taken together, these 2 studies support the 2011 SEIP and SEIA guidelines recommendation for the use of narrow-spectrum aminopenicillins in children hospitalized with suspected bacterial CAP.4
Although limited by the small sample size, this analysis examining outcomes by pathogen suggested that children with S. aureus and S. pyogenes bacteremia experience increased morbidity, including longer IDs, higher frequency of ICU admission, VMI and/or shock, compared to children with S. pneumoniae .
Several limitations should be kept in mind when interpreting the results of this study. Although this is one of the largest and most comprehensive studies to date in which researchers
have evaluated the microbiological etiology and burden of bacteremic CAP in US children, the sample size of children with bacteremia was limited. This precluded more robust analyzes to examine risk factors associated with bacteremia as well as pathogen-specific analyses.
Because a quarter of the children received inpatient antibiotics before blood culture collection, the prevalence of bacteremia may have been underestimated and certain risk factors may not have been identified due to misclassification bias.
However, sensitivity analyzes excluding patients who received antibiotics before obtaining cultures did not differ substantially, suggesting a limited impact of this bias.
The use of blood cultures instead of the more sensitive whole blood polymerase chain reaction is also likely to result in an underestimation of the true prevalence of bacteremia.15
Furthermore, cultures were not obtained in all patients. However, if selection bias exists, the influence on the results is probably minimal given the low percentage (8%) of patients without culture data.
The authors were unable to determine the rate of false-positive blood culture results, the relationship between timing of ICU admission and positive blood culture results, the specific S. pneumoniae serotypes that caused bacteremia, or differences in cultures obtained. for clinical versus research purposes due to lack of availability of this data.
Finally, this study was conducted at 3 tertiary care children’s hospitals in the United States, and these findings may not be generalizable.
| Conclusions |
Blood culture results identified a causative pathogen in only 2.2% of children hospitalized with CAP, and results were positive more frequently in those with parapneumonic effusion on chest x-ray and in those with severe disease requiring in-patient care. the ICU. Penicillin-susceptible S. pneumoniae was the most common cause of bacteremic CAP in this study, supporting the existing recommendation for empirical use of narrow-spectrum aminopenicillins for the majority of children hospitalized with suspected bacterial CAP.
In an era with widespread pneumococcus vaccination and low prevalence of bacteremia in the United States, children admitted with CAP who have pleural effusion or require ICU care may represent a high-yield population for identification of bacteremia.
