Published online August 31, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. 489-496 (doi:10.1542/peds.2007-0252)
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ARTICLE

Routine Cerebrospinal Fluid Enterovirus Polymerase Chain Reaction Testing Reduces Hospitalization and Antibiotic Use for Infants 90 Days of Age or Younger

Rebecca L. King, MDa, Scott A. Lorch, MD, MSCEb,c,d, Daniela M. Cohen, BSa, Richard L. Hodinka, PhDa,c,e, Keri A. Cohn, MDa and Samir S. Shah, MD, MSCEa,c,d,f

a Divisions of Infectious Diseases
b Neonatology
e Clinical Virology Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
c Departments of Pediatrics
f Biostatistics and Epidemiology
d Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The goal was to evaluate the impact of cerebrospinal fluid enterovirus polymerase chain reaction testing on the length of hospitalization and the duration of antibiotic use for infants ≤90 days of age with suspected aseptic meningitis.

METHODS. This retrospective cohort study was conducted at an urban, tertiary-care children's hospital. Data were collected for 478 patients ≤90 days of age for whom cerebrospinal fluid enterovirus polymerase chain reaction testing was performed during the enteroviral seasons of 2000 to 2006. The length of hospitalization and the duration of antibiotic use were assessed.

RESULTS. Cerebrospinal fluid enterovirus polymerase chain reaction test results were positive for 154 patients (34.8%). The mean length of stay was 3.65 days. The median polymerase chain reaction turnaround time was 23 hours. In multivariate analysis, having a positive cerebrospinal fluid enterovirus polymerase chain reaction result was associated with a 1.54-day decrease in the length of stay and a 33.7% shorter duration of antibiotic use. When patients were stratified according to the presence or absence of pleocytosis, both groups demonstrated significant reductions in the length of stay with positive cerebrospinal fluid enterovirus polymerase chain reaction results (1.32 and 1.38 days, respectively). Furthermore, increasing the polymerase chain reaction turnaround time by 24 hours increased the length of stay by 13.6% for patients with positive cerebrospinal fluid enterovirus polymerase chain reaction results.

CONCLUSIONS. Having positive cerebrospinal fluid enterovirus polymerase chain reaction results decreases the length of hospitalization and the duration of antibiotic use for young infants. These results support the routine use of this test during periods of peak enterovirus prevalence.

Key Words: enterovirus • infant • polymerase chain reaction • aseptic meningitis

Abbreviations: CSF—cerebrospinal fluid • LOS—length of stay • PCR—polymerase chain reaction • WBC—white blood cell • CI—confidence interval

Aseptic meningitis is a common pediatric infection, with an estimated 75000 cases occurring in the United States each year.1,2 Nonpolio enterovirus infection accounts for the majority of aseptic meningitis cases in infants ≤90 days of age, with peak incidence during the summer and fall months.3–5 The illness is most often self-limited; complications occur in <10% of cases.6,7 However, it is difficult to distinguish accurately young infants with enterovirus meningitis from those with other sources of infection. Young infants often lack classic signs of aseptic meningitis found in older children5,7–9 and may also lack cerebrospinal fluid (CSF) pleo- cytosis.3–6,10 Therefore, many of these patients are hospitalized to receive empiric, broad-spectrum antibiotic therapy while awaiting bacterial culture results.7,8,11–13

Reverse transcriptase-polymerase chain reaction (PCR)-based testing for enterovirus in CSF offers a solution to this problem by allowing rapid accurate diagnosis of infants with enterovirus meningitis.2,14–17 Previous studies with older children suggested that the use of diagnostic CSF enterovirus PCR testing decreases the hospital length of stay (LOS) and changes management for children ultimately diagnosed as having enteroviral meningitis.5,6,16,18 In addition, several authors have demonstrated the potential for significant cost savings if testing is performed frequently and during periods of peak enterovirus prevalence.4,19–21 However, previous studies failed to adjust for other factors that might have affected LOS.5,6,16 In addition, those studies failed to specify whether enterovirus PCR testing was performed for all infants as part of the initial diagnostic evaluation or was performed later in the course of a complicated hospitalization.5,6,16,18 Finally, no study focused specifically on the impact of CSF enterovirus PCR testing on LOS for patients ≤90 days of age.

The objectives of this study were to evaluate the impact of CSF enterovirus PCR testing on hospital LOS and duration of antibiotic use for infants ≤90 days of age. Because previous studies showed this test to be routinely cost-effective during periods of peak enterovirus prevalence, we chose to limit this cohort to infants who had enterovirus PCR testing performed as part of their initial evaluations during the enteroviral season.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design and Setting
This retrospective cohort study was performed at the Children's Hospital of Philadelphia (Philadelphia, PA), an urban, tertiary-care children's hospital. The Committee for the Protection of Human Subjects of the Children's Hospital of Philadelphia approved this study, with a waiver of informed consent requirements.

Study Population
Patients who underwent CSF enterovirus PCR testing were identified by using clinical virology laboratory records. Infants ≤90 days of age were eligible for inclusion if they underwent evaluation through lumbar puncture between June 1 and October 31, 2000 to 2006, and had CSF enterovirus PCR testing performed within 48 hours after hospitalization. At our institution, infants ≤56 days of age routinely undergo lumbar puncture during evaluation for fever. There is more variability among attending physicians regarding evaluation of febrile infants 57 to 90 days of age. To minimize the impact of selection bias, patients were excluded if they were diagnosed as having herpes simplex virus infection or a serious bacterial infection, such as bacterial meningitis, bacteremia, or urinary tract infection. We expected that infants with herpes simplex virus infection or a serious bacterial infection would be less likely to undergo CSF enterovirus PCR testing and that those conditions, which prolong hospital LOS, would affect patients with negative enterovirus PCR results disproportionately, leading to biased results.

Study Definitions
The enteroviral season was defined as June 1 through October 31 for each year during the study period. We considered elevations in CSF white blood cell (WBC) counts in 3 ways: (1) as a continuous variable; (2) as ≥8 WBCs per mm3, based on literature reports suggesting that CSF WBC counts greater than this value have high sensitivity in identifying children with bacterial meningitis12,22,23; and (3) using previously published criteria for CSF WBC counts, that is, >22 WBCs per mm3 for infants ≤4 weeks of age and >15 WBCs per mm3 for infants >4 weeks of age.24 We defined traumatic lumbar puncture on the basis of the presence of >500 red blood cells per mm3.25

Bacterial meningitis was defined on the basis of either the isolation of a bacterial pathogen from the CSF or, for patients who received antibiotics before evaluation, the combination of CSF pleocytosis and bacteria detectable in the CSF with Gram staining. Bacteremia was defined on the basis of isolation of a known bacterial pathogen from blood cultures, excluding isolates that reflected commensal skin flora. Urinary tract infection was defined on the basis of growth of a single known pathogen meeting 1 of 3 criteria, as follows: (1) ≥1000 colony-forming units per mL for urine cultures obtained through suprapubic aspiration, (2) ≥50000 colony-forming units per mL for specimens obtained through catheterization, or (3) ≥10000 colony-forming units per mL for specimens obtained through catheterization in association with positive urinalysis results.26 Hyponatremia was defined as a serum sodium level of <131 mmol/L.

All historical data, vital signs, and clinical findings were obtained from the initial presentation at our institution. A patient was defined as hypoxic if the patient received supplemental oxygen or if the percutaneous oxygen saturation level was <93%. Tachypnea was defined as a respiratory rate of >70 breaths per minute.27 We defined fever as a temperature of >38.0°C. We defined history of fever as a report of a tactile temperature or recorded temperature of >38.0°C at home. Hypothermia was defined as a temperature of <36.1°C, which was <5th percentile among our study population. Hypotension was defined as systolic blood pressure of <63 mm Hg.28

CSF Enterovirus PCR Testing
Enteroviral RNA was extracted from CSF by using an automated MagNAPure LC instrument and total nucleic acid isolation kit (Roche Diagnostics, Indianapolis, IN) and was detected with qualitative real-time TaqMan PCR. The primers and probe were from a portion of the enterovirus genome that codes for the 5'-nontranslated region. Amplification and detection were completed by using either an ABI Prism 7000 sequence detection system or a 7500 real-time PCR system (Applied Biosystems, Foster, CA). Positive and negative control samples, consisting of primary rhesus monkey kidney cells infected with echovirus 11 and uninfected A549 human lung carcinoma cells, respectively, were processed with each batch of clinical samples, from extraction of nucleic acids through detection of amplified product. Specimens and control samples were tested singly and were considered positive when the generated fluorescence signal at the threshold cycle value exceeded a defined threshold limit. Appropriate no-template controls were included in each reaction plate. A human albumin gene was amplified as an internal positive control for human nucleic acid, to ensure that negative results were not attributable to poor nucleic acid extraction or inhibition of the PCR assay. Because we used automated, magnet bead-based, extraction technology, blood contamination of the CSF from traumatic lumbar punctures would not be expected to affect the PCR yield.29

Data Collection
Data were abstracted from the medical charts of study patients and entered into a standardized data collection form. Information collected included demographic data, vital signs, clinical and historical findings at presentation, notable clinical events during hospitalization, empiric antibiotic use, imaging studies performed, and results of laboratory testing. Dates and times of admission, discharge, antibiotic dosing, CSF enterovirus PCR collection, and result reporting were also obtained. Laboratory values, imaging studies, and clinical events were included only if they occurred within 48 hours after hospitalization, except for electrocardiograms, which were included if performed within 72 hours, and echocardiograms, which were included if ordered within 72 hours, because of commonly encountered delays in obtaining these studies. Variables calculated from laboratory data included CSF/serum glucose ratio and CSF absolute neutrophil count. Calculated variables included LOS, duration of antibiotic use, time from hospital admission to PCR result, time from PCR result to discharge, and PCR turnaround time, which was defined as the time (in hours) between CSF collection and CSF enterovirus PCR result availability.

Data Analyses
Data were analyzed by using Stata 9 (Stata Corp, College Station, TX). Continuous variables were described by using mean, median, range, and interquartile range values. Dichotomous variables were described by using counts and percentages. The primary outcome considered was LOS. Duration of antibiotic use was evaluated as a secondary outcome by using similar methods. Spearman's correlation coefficient was used to assess the relationship between hospital LOS and duration of antibiotic use.

Univariate analyses were conducted to identify factors associated with LOS. Multivariate linear regression was performed to identify factors associated independently with LOS. Building of the multivariate model began with inclusion of the variable positive CSF enterovirus PCR result, on the basis of our a priori hypothesis of an association between positive CSF enterovirus PCR results and LOS. Other variables were considered for inclusion in the multivariate model if they were associated with LOS in univariate analyses (P < .20). In addition, risk factors were considered for inclusion in the model if they were confounders of the association between positive CSF enterovirus PCR results and LOS.30 These variables were included in the final multivariate model if they remained significant after adjustment for other factors or if their inclusion in the model resulted in a ≥15% change in the effect size of the primary association of interest (positive CSF enterovirus PCR result and LOS), regardless of statistical significance.31 Statistical significance was determined a priori as a 2-tailed P value of <.05.

Because the LOS variable had a skewed distribution, we considered the data in 2 additional ways. First, we excluded from analysis patients whose LOS was >14 days, which was >95th percentile for our study population. Second, we repeated our analysis by using logarithmically transformed LOS values.

Subsequently, we assumed that test results not available before discharge had no impact on the decision to send the patient home; therefore, we repeated the analysis and included only patients who had PCR results available before discharge. Finally, we considered that a child with pleocytosis might be less likely to have the discharge decision based on PCR results alone. To evaluate this, we repeated our analysis and stratified patients according to the presence or absence of pleocytosis.

In a secondary analysis, we examined the association between PCR turnaround time and LOS for all study patients and for the subset of patients with positive enterovirus PCR test results. Demonstrating a positive correlation between LOS and PCR turnaround time would support our hypothesis that having a positive test result in a short time directly affects the decision to discharge a patient. For this, we performed linear regression analysis of logarithmically transformed LOS values and PCR turnaround times.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Enrollment and Demographic Data
The medical charts for 478 (89%) of 538 infants for whom CSF enterovirus PCR testing was performed during the study period were available for review. Patients were excluded because of the presence of serious bacterial infection (which occurred in 3.1% of enterovirus-positive patients and 8.5% of enterovirus-negative patients; n = 32) and herpes simplex virus infection (n = 4); the remaining 442 infants were included in the analysis. The median patient age was 29 days (interquartile range: 13–49 days). There were 261 male patients (59.1%) in our population. The racial distribution included patients classified as black (46.5%), white (39.0%), Hispanic (2.5%), Asian/Pacific Islander (1.8%), American Indian (0.2%), or other (10.0%). Seizures occurred in 48 patients (10.8%). Six patients had abnormal echocardiograms. One patient died; the patient did not have enteroviral infection.

CSF Enterovirus PCR Results
CSF enterovirus PCR tests were positive for 154 patients (34.8%). Of all patients, 242 (54.8%) had CSF WBC counts of ≥8 WBCs per mm3, and 185 (41.9%) met the criteria for pleocytosis. Among patients with positive CSF enterovirus PCR results, 123 (79.8%) had CSF WBC counts of ≥8 WBCs per mm3, and 109 (70.8%) met the more-stringent criteria for pleocytosis. Traumatic lumbar puncture occurred in 181 patients (42.6%). The mean LOS for the study population was 3.65 days (range: 0.13–35.58 days); 17 patients had LOS of >14 days. For patients with positive CSF enterovirus PCR results, the median LOS was 2 days. The median time from hospitalization to PCR result was 27 hours (interquartile range: 19–45 hours), and the median PCR turnaround time was 23 hours (interquartile range: 17–30 hours). Differences in the median LOS according to year were not statistically significant either overall or when stratified according to enterovirus PCR result.

Impact on LOS
Results of the univariate analysis are shown in Tables 1 and 2. In our multivariate model, we explored the association between positive CSF enterovirus PCR results and LOS with various restrictions on the population (Table 3). Irrespective of those restrictions, positive CSF enterovirus PCR results were associated with significantly shorter LOS. When enterovirus-positive and enterovirus-negative patients were compared, there was no difference in either the PCR turnaround time (median: 23 hours for each group; P = .53) or the proportions of enterovirus-positive (88%) and enterovirus-negative (83%) patients with results available before discharge (P = .20, {chi}2 test). This ensured that differences in LOS were not attributable to differences in PCR result availability. Because CSF WBC count was significant in our final multivariate model, it might be that the presence or absence of pleocytosis affected LOS. To explore this, we stratified our population according to CSF WBC count by using 2 different thresholds. When patients were stratified according to the presence or absence of pleocytosis, both groups demonstrated significant reductions in LOS with positive CSF enterovirus PCR results, after adjustment for the presence of hypoxia, hypotension, hypothermia, and seizure. The reduction was 1.32 days (logarithmically transformed P < .001) for patients with pleocytosis and 1.38 days (logarithmically transformed P = .008) for those without pleocytosis. The magnitude of the reduction was similar when a CSF WBC threshold of ≥8 WBCs per mm3 was considered.


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  		TABLE 1 Univariate Regression Analysis of Patient Characteristics Associated With Changes in LOS

 

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  		TABLE 2 Univariate Regression Analysis of Laboratory and Radiologic Study Results Associated With Changes in LOS

 

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  		TABLE 3 Multivariate Linear Regression Model Showing Changes in LOS (From Baseline) Associated With Various Factors

 
Next, we explored the relationship between LOS and PCR turnaround time (Fig 1). Through linear regression analysis, we demonstrated a 13.6% (95% confidence interval [CI]: 5.4%–21.8%; logarithmically transformed P = .001) increase in LOS for every 24-hour increase in PCR turnaround time among patients with positive enterovirus PCR test results.


Figure 1
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  		FIGURE 1 Relationship of PCR turnaround time and LOS (logarithmic scale) for patients with positive CSF enterovirus PCR results (n = 154).

 
Impact on Antibiotic Use
In our study population, 90.5% of all patients and 93.5% of those with pleocytosis received ≥1 dose of intravenously administered antibiotics within 48 hours after presentation. The median duration of antibiotic use for the entire study population was 1.79 days, and that for patients with pleocytosis was 1.74 days. Antibiotic use duration correlated with hospital LOS (Spearman correlation coefficient: 0.69; P < .001); the correlation was most pronounced for the subset of patients without CSF pleocytosis. Acknowledging this correlation, we were interested in quantifying the change in duration of antibiotic use associated with positive CSF enterovirus PCR results. After adjustment for hypotension, hypothermia, hypoxia, seizure, and CSF WBC count, having a positive CSF enterovirus PCR result reduced the duration of antibiotic use by 33.7% (95% CI: 17.3%–50.2%; logarithmically transformed P < .001) for all patients. The reduction for the cohort of patients with LOS of ≤14 days was 33.4% (95% CI: 16.8%–49.9%; logarithmically transformed P < .001), and that for the cohort with LOS of ≤14 days and results available before discharge was 40.9% (95% CI: 23.7%–58.1%; logarithmically transformed P < .001). The reduction in antibiotic use was most pronounced for patients with CSF pleocytosis (56.5% reduction; 95% CI: 32.6%–80.4% reduction; logarithmically transformed P < .001).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We found that the use of CSF enterovirus PCR testing during periods of peak enterovirus prevalence reduced the hospital LOS and duration of antibiotic use for infants ≤90 days of age who were ultimately diagnosed as having enteroviral meningitis. Our study is unique in that it examined specifically the effect of PCR testing on hospital LOS, controlling for other factors that might affect LOS. In addition, it is the first study to demonstrate the impact of this test in a large cohort of young infants ≤90 days of age.

Previous studies demonstrated significantly shorter LOS and duration of antibiotic use for patients with positive CSF enterovirus PCR test results than for those with negative test results.6,16 However, those studies compared enterovirus-positive and enterovirus-negative patients directly and failed to control for conditions present in the enterovirus-negative patients that might have affected their LOS and use of antibiotics. It is possible that patients with negative enterovirus PCR test results had other conditions or clinical findings that prolonged their LOS, independent of the PCR results. Robinson et al18 compared clinical and financial data for hospitalized children with enterovirus meningitis whose enterovirus PCR results were available within 24 hours (n = 11) and those whose results were available >24 hours after specimen collection (n = 30). Although the total hospital charges were less among the patients with PCR results available within 24 hours, there was no significant difference in the duration of antibiotic use or the hospital LOS between the 2 groups. In a secondary analysis that extended the cutoff time to 36 hours, the LOS was 0.44 days shorter (P = .05) for those with the shorter enterovirus PCR turnaround time.18 Only limited conclusions about the utility of routine PCR testing can be drawn from that study, because only patients with positive CSF enterovirus PCR results were included. The diagnosis is not known before testing, and the true impact of routine testing depends on the prevalence of enteroviral disease. Our study, which was conducted during periods of peak enterovirus prevalence, found that positive CSF enterovirus PCR test results for infants ≤90 days of age were associated with shorter LOS and duration of antibiotic use, even after adjustment for potentially confounding variables.

The goal of our investigation was to define a population of children for whom this test should be ordered as part of the initial diagnostic evaluation. When we stratified our population according to the presence or absence of CSF pleocytosis, both groups demonstrated significant decreases in LOS for patients with positive PCR results. Therefore, it would not be beneficial to restrict testing on the basis of CSF WBC counts for young infants. Furthermore, pleocytosis is an unreliable indicator of the presence of enteroviral meningitis in this age group.3–6,10,32 We maintain that this test should be considered for all young infants presenting with suspected meningitis during the enteroviral season.

When we restricted our population to patients whose PCR results were available before discharge, the LOS was even shorter for those with positive enterovirus PCR results. This again supports the idea that, when results are available rapidly, they play a key role in discharge decisions. To explore this point more thoroughly, we evaluated the relationship between PCR turnaround time and LOS. This concept was addressed in previous studies, which showed a positive correlation between enterovirus PCR turnaround time and LOS.5,18 Stellrecht et al5 demonstrated that the median LOS among enterovirus-negative patients remained constant over a 4-year time period, whereas the median LOS for 31 enterovirus-positive patients <3 months of age showed a decrease over the same time period. The authors attributed this decrease in LOS over time to a corresponding decrease in PCR turnaround time at their institution.5 Our study also demonstrates that there is a positive correlation between these 2 variables and specifically that each 24-hour delay in PCR result availability increases the LOS significantly. This finding emphasizes the causal relationship between PCR testing and LOS and highlights the importance of performing enterovirus PCR testing daily during periods of peak enterovirus prevalence. Although we did not examine cost savings specifically in this study, a cost analysis model published by Nigrovic and Chiang4 demonstrated that routine use of CSF enterovirus PCR testing would result in significant cost savings during periods of peak enterovirus prevalence if results were available within 24 hours.

This study has several limitations. By including only infants with enterovirus PCR tests sent during the study period, we might have introduced selection bias. Although some patients who did not have CSF enterovirus PCR testing performed might have had overt manifestations of serious bacterial infection and thus warranted exclusion, others might have appeared well or lacked pleocytosis. If those who appeared well or lacked pleocytosis were less likely to have enterovirus PCR testing performed, then the LOS for those with negative enterovirus PCR results would be even shorter and the absolute effect of positive enterovirus PCR results would be less than found in this study. We think that such bias is minimal, because our finding that one third of infants with positive CSF enterovirus PCR results lacked pleocytosis is similar to the findings of previous enterovirus meningitis studies in this population. It is also possible that the negative PCR test results prolonged the hospital LOS beyond what occurs in the absence of such testing, while clinicians searched for an alternative diagnosis. Hamilton et al16 found that the LOS among PCR-negative patients increased from 1.97 days to 2.44 days over 2 consecutive enteroviral seasons. This was attributed to greater clinician concern regarding bacterial infection when the PCR results were negative as clinicians became more familiar with the PCR test. However, the median LOS for PCR-negative patients did not change over time in our study. Clinical judgment should always be a factor in the decision to perform enterovirus PCR testing and in the interpretation of test results, because positive CSF enterovirus PCR results do not exclude the possibility of concomitant bacterial infection. Lastly, because this study was conducted at a single center, its generalizability depends on the extent of regional variation in the treatment of young infants.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our study found that having positive CSF enterovirus PCR results available rapidly decreases the LOS significantly for patients ≤90 days of age who do not have evidence of concomitant serious bacterial or herpes simplex virus infection. Individual centers need to assess whether their laboratory capacity permits such frequent CSF enterovirus PCR testing and whether their patient volume makes such frequent testing cost-effective. Additional prospective studies of the utility of CSF enterovirus PCR testing during low-prevalence periods are required before the routine use of such tests outside the enteroviral season is encouraged.


   FOOTNOTES
 
Accepted Apr 18, 2007.

Address correspondence to Samir S. Shah, MD, Room 1526, North Campus, Division of Infectious Diseases, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail: shahs{at}email.chop.edu

Dr Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 DISCUSSION
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 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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