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C-Reactive Protein Concentration Can Help to Identify Bacteremia in Children Visiting the Emergency Department: A Single Medical Center Experience

Chiu, I-Min MD; Huang, Ying-Hsien MD, PhD; Su, Chih-Min MD; Kung, Chia-Te MD; Li, Chao-Jui MD; Chen, Chih-Ho MD; Tang, Kuo-Su MD; Kuo, Kuang-Che MD

Author Information
doi: 10.1097/PEC.0000000000001453
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Abstract

Blood culture is considered the criterion standard for detecting bacteremia and is among the most frequently requested microbiological tests in the pediatric emergency department (PED).1 A positive blood culture can suggest a definite diagnosis, thus allowing medical professionals to target therapy against specific organisms. Upon receiving a positive blood culture result, clinicians must determine whether the organism represents a clinically significant infection correlated with a great risk of morbidity and mortality.1–4 However, a high rate of negative, false-positive, or contaminated blood cultures were found in children visiting emergency department.5–7 Moreover, overuse of blood culture has been described in relation to a financial burden to our healthcare system.8 Both the high rate of negative blood culture reports and the false-positive culture results, including contaminated blood culture, may result in wasted medical resources, inappropriate use of antibiotics, return emergency department visits, additional diagnostic tests, increased length of hospital stays, and specialty consultations.8,9 Segal and Chamberlain10 explained that in an urban pediatric department in the United States, contaminated blood cultures in 85 children added more than US $78,000 in substantial increases in resource use and hospital charges.

Many studies continue to debate the most appropriate blood cultures in the PED. For example, the Infectious Diseases Society of America, which published guidelines for managing pediatric community-acquired pneumonia (CAP) in 2011,11 recommends obtaining blood cultures in only moderately or severely ill children hospitalized for CAP. Lai et al12 reported that both the yield rate of a true-positive blood culture and the impact of blood culture results on adjusting antibiotic administration were very small in CAP. However, in the practical guidelines for diagnosing and managing skin and soft tissue infections, obtaining blood cultures was only recommended for extensive infections or immune-compromised patients.13

Previous studies on blood culture use of the PED have mainly focused on specific pediatric diseases or immune-compromised patients.14–16 An accurate interpretation of culture results is vital, not only from the perspective of individual patient care but also from the standpoint of hospital epidemiology, insurance costs, and public health. This study's goal was to determine the factors of bacteremia, nonbacteremia, and contaminated blood culture results in the general population visiting the PED, which will help us determine whether routinely obtaining blood cultures in the PED is necessary.

METHODS

Study Design

We conducted a retrospective, cohort study of patients who presented to the PED of the Kaohsiung Chang Gung Medical Hospital in Taiwan during the period of January 1, 2007, through December 31, 2013. The institutional review board of the Chang Gung Medical Foundation approved all medical information, and all patients' and physicians' records were anonymized and deidentified before analysis.

We enrolled all patients younger than 18 years who visited the PED and had a blood culture obtained during the study period. All blood cultures were collected by nurses who followed our institution's standard procedures. Because obtaining 2 sets of cultures was difficult in the pediatric population, 1 set for febrile patients was generally taken in our clinical practice in the PED. All patients were classified into the following 6 groups based on their age at the time of the PED visit: infant group (0–1 years), toddler group (1–3 years), preschool group (3–6 years), primary school group (6–12 years), and teen group (12–18 years).

Inclusive Blood Culture Criteria

The following organisms represent a true infection when isolated from a blood culture: Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, and all bacteria considered as a positive culture.17–20

Exclusive Blood Culture Criteria

Similarly, certain organisms have been found to represent contamination in a significant proportion of cases. These organisms include coagulase-negative staphylococci, Corynebacterium species, Bacillus species other than Bacillus anthracis, and Propionibacterium acnes.17–20 If any doubt arose regarding the potential pathogenicity of one of the species isolated, the research coordinator reviewed the case to determine whether the corresponding blood culture should be included in the registry.

Statistical Analysis

All values in the figures and tables are expressed as mean (SE). Quantitative data were analyzed using the one-way analysis of variance when appropriate, and we adopted the least significant difference test for post hoc testing. We calculated differences in frequencies between groups using χ2 tests. The receiver operating characteristics (ROC) curve method was used to differentiate between groups, and different cut-off points had different sensitivities and specificities for diagnosing a true-positive blood culture. The best cut-off points for accurate diagnosis of a true-positive blood culture using CRP levels were based on the highest sensitivity value plus the specificity identified by the ROC curve. Binary logistic regression will be applied for individual contributing factors after adjusting for age and sex. A two-sided P value less than 0.05 was considered statistically significant. We carried out the statistical analysis using IBM SPSS Statistics for Windows (Version 18).

RESULTS

During the study period, we enrolled a total of 239,459 PED visits, and 21,841 blood cultures were taken. Patients were categorized into the following 3 groups pursuant to the blood culture results. The sex and mean age for each group are provided in Table 1. The most common five pathogens in the bacteremia group were Salmonella entericae (24.7%), Escherichia coli (22.2%), Streptococcus pneumonia (10.8%), S. aureus (8.2%), and gram-negative bacilli-glucose nonfermenting group (7.2%) (Table 2). In the contamination group, the most common results were coagulase-negative staphylococcus (30.2%), Staphylococcus epidermidis (29.2%), Micrococcus (9.1%), Staphylococcus haemolyticus (7.1%), and gram-positive Bacillus (5.7%) (Table 2). The mortality rates in the 3 groups had no significant difference between groups. The lengths of hospital stays were longer in the bacteremia group. The results of culture rate among each group are listed in Table 2. The rates of true bacteremia in each age group were significantly different and highest in the group of younger than 1 year (Table 3).

TABLE 1
TABLE 1:
Rate of Bacteremia, Nonbacteremia, Contamination, and Outcome
TABLE 2
TABLE 2:
Most Common Results of the Bacteremia and Contamination Groups
TABLE 3
TABLE 3:
Bacteremia, Nonbacteremia, and Contamination Rate in Different Age Groups

With clinical characteristics as the secondary outcome of the culture results, the patients' vital signs at presentation and laboratory tests were obtained for further analysis and compared with the blood culture results. The nonbacteremia group and contaminated group were put together and compared with the bacteremia group. As shown in Table 4, statistical significant differences (bacteremia vs nonbactermenia + contaminant) were found regarding patients' initial blood temperature, heart rate, and diastolic blood pressure at initial ED triage (P < 0.001). Systemic blood pressure was lower among the bacteremia group, but it was not statistically significant. Of the laboratory test studies, higher CRP levels and lower hemoglobin levels were observed in the bacteremia group (P < 0.001). We found no statistical difference in total white blood cell, neutrophil count, sugar, serum urea nitrogen, creatinine, aspartate transaminase and alanine transaminase between the groups.

TABLE 4
TABLE 4:
Clinical Characteristics

To more accurately distinguish between these 2 groups, we chose cut-off points for CRP level based on the highest sensitivity and specificity values identified by the ROC curves to determine the clinical utility of the blood culture result. The area under curve (AUC) values of the different age groups with the best cut-off values were calculated and are listed in Table 5. The AUC values are higher in age of 0 to 1 years and 12 to 18 years (0.754 and 0.778, respectively). Before applying logistic regression for clinical utility of the blood culture results, the cut-off value for CRP levels (mg/L) based on the AUC for age groups were 30, 45, 55, 35, and 50, respectively.

TABLE 5
TABLE 5:
Statistical Analysis of CRP Level

An elevated percentage of positive blood cultures was observed in each of the following age groups: 0 to 1 years (odds ratio [OR] = 5.4, 95% confidence interval [CI] = 2.73–10.62, P < 0.001); 1 to 3 years (OR = 3.7, 95% CI = 2.16–6.34, P < 0.001), and 12 to 18 years (OR = 6.3, 95% CI = 1.70–23.47, P = 0.006) (Table 5). We performed binary regression after controlling for potential confounding factors (age, sex, initial body temperature, heart rate, and blood pressure at the emergency department), and significant differences in the bacteremia rate were found in the following age groups: 0 to 1 year, 1 to 3 years, and 12 to 18 years. In these 3 age groups, the bacteremia rate increased from 1.7% to 4.7%, 0.8% to 1.7%, and 0.6% to 1.5%, respectively. Meanwhile, the bacteremia rate in patients with CRP levels below the cut-off value were significantly lower in these groups. According to the CRP cut-off value established in this study, we could reduce the total 21,841 blood culture samples in the PED by 14,108 (64.6%).

DISCUSSION

In this study, we found that the overall true bacteremia rate is 0.7% in febrile pediatric patients and was higher in infants. This result agrees with previous similar studies conducted in emergency department settings (prevalence = 0.25%–2.1%).21–23 The acceptable blood culture contamination rate should be lower than 2% to 3% as published reports have indicated,20 and the overall contamination rate was 3% in our study. However, the mortality rate was low in all 3 blood culture groups, and we found no significant differences among the 3 groups. Regarding the length of hospital stays, the bacteremia group correlated with longer hospital stays compared with the other 2 groups because of the routine use of antibiotics. Furthermore, length of hospital stays was longer in the contamination group than the nonbacteremia group even in direct comparison (6.3 days vs 4.9 days, P < 0.001). Ambiguous culture results often result in diagnostic uncertainty in clinical management, as well as increased health care costs due to unnecessary treatment and testing.4,6,10,24,25 This finding may be partially explained by prolonged antibiotics use and increased admission rate due to uncertain interpretations of blood culture reports, ultimately resulting in substantial increases in resource use and hospital charges.10,26,27

The body temperature and heart rate also seem to be elevated, as was lower diastolic pressure instead of systolic blood pressure among the bacteremia group, which agrees with the previous consensus describing the pattern of septicemia in children.28 However, the variations in vital signs in the PED can be huge and may not serve as useful indicators for obtaining blood cultures when handling individuals.

We found lower hemoglobin and higher CRP levels in the bacteremia group in this study. Inflammation-related anemia represents a highly prevalent and important clinical problem.29 The anemia of disease is often seen in various inflammatory states, including infections, inflammatory disorders, and certain cancers.30–34 In 2009, Ballin et al35 reported that bacteremia are accompanied by a significant decrease in hemoglobin levels without evidence of hemolytic anemia. Recently, Tacke et al36 described that iron metabolism parameters are strong outcome predictors in intensive care unit patients. In 2000, Krause et al37 found a peptide originally referred to as liver-expressed antimicrobial peptide-1, or LEAP-1, which was later named “hepcidin” based on its hepatic expression and antimicrobial activity. Hepcidin is known to play an important role in blocking the iron flow into plasma.29,38 Furthermore, hepcidin-induced low iron levels were related to both the short- and long-term survival of critically ill patients.39,40 Therefore, we propose that the serum hepcidin is greater in the bacteremia group than in the nonbacteremia group, and this may suggest a reasonable explanation for anemia in this patient cohort.

The risk of bacteremia is higher in infants less than 1 year than in the other age groups in the present study. Elevated CRP levels among children with bacteremia and monitoring CRP level as an indicator of sepsis have both been discussed in previous studies.41,42 We reported different CRP cut-off values for obtaining positive blood cultures in different age groups. The current study has demonstrated that CRP has a better predictive power than white blood cell count. This finding is consistent with the previous systemic review for identifying children with serious infections.43 Buendia et al44 showed that Rochester criteria together with CRP was more cost-effective than Rochester criteria alone in infants with a fever without a source. Therefore, introducing CRP to manage young infants with fever without a source may reduce unnecessary antibiotic treatment and hospitalization.

Continuing education programs related to culture collection or standardized processes for collecting specimens may reduce blood culture contamination, but children have some restrictions, such as 2 separate sets of blood cultures and a greater amount of blood. A review of peripheral blood cultures shows that contamination rates vary significantly between institutions and can approach 6% to 11%.26,45 The accepted blood culture contamination rate in the hospital is between 2% and 3%. Our contaminated blood culture rate in the pediatric ED was acceptable under our institution's standard processes and education programs.

Contaminated blood cultures frequently resulted in a patient receiving antibiotics in our institution because occult bacteremia was suspected in the pediatric population.46,47 In particular, for children admitted in the young infant period (age <120 days) to “rule out sepsis,” additional days in the hospital are a typical occurrence when a blood culture is contaminated. Furthermore, Hall et al8 and Gomez et al25 evaluated the cost of contamination in patients discharged from the ED, but these studies had restricted their populations to previously healthy children.8,25 Our data demonstrated the financial burden of blood culture contamination in the pediatric ED. For children with febrile issues, our study indicated that CRP levels in different age groups could be useful for establishing a benchmark for blood cultures during busy and crowded periods in the pediatric ED. Our results agreed with the previous literature,41,48 but we additionally offered the obvious cut-off level of CRP by patients' age group. Therefore, applying these results may not only reduce necessary blood cultures and children's discomfort but also medical costs and nursing load.

CONCLUSIONS

In short, the overall bacteremia rate was low in febrile children visiting the PED and was remarkably lower in patients older than the age of 3 years. Among the various clinical characteristics observed in the PED, CRP may become a commonly used indicator of when to obtain blood cultures in certain age groups and will help improve the clinical utility of the bacteremia rate of blood cultures in the pediatric department.

ACKNOWLEDGMENTS

The authors thank the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for its statistics work.

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Keywords:

bacteremia; blood culture; CRP; hemoglobin

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.