Association of the FilmArray Meningitis/Encephalitis Panel With Clinical Management

Subjects

Children 0 to 18 years old who had a CSF culture or ME panel obtained within 48 hours of admission were included. Subjects were identified through a search of the e-health records. Exclusion criteria included patients who died during hospitalization because of a noninfectious cause, who never received antibiotics, who had lumbar puncture (LP) to evaluate a noninfectious etiology, who had a repeat LP in known meningitis, or who had a history of central nervous system surgery. LP to evaluate a noninfectious cause was determined through review of the history and physical (H&P). If no infectious etiology was listed in the assessment in addition to no antimicrobial agents started, the patient was excluded. Excluded conditions included malignancy, pseudotumor cerebri, intractable epilepsy, maternal syphilis, autoimmune encephalitis, and Guillain Barré syndrome.

Data Collection

Manual chart review included the attending physician’s initial H&P or consult notes, laboratories, imaging, and medication administration record using a standardized form among 3 reviewers. The lead author reviewed 10% of other reviewers’ charts to assess for agreement in coding. If a diagnostic study was not performed, it was assumed that the provider did not base clinical management on the study, and therefore it was classified as a negative result. Presenting symptoms were presumed to be negative results if not listed in documentation.

Outcomes

The primary outcome measure was LOS measured in hours on the basis of encounter start and end times. Secondary outcome measures included total time on antibiotics in hours from the time the first antibiotic dose was administered at our institution to the last dose administered, including antibiotics prescribed at discharge. For antibiotics prescribed at discharge, the duration was estimated on the basis of dosing instructions. Antibiotics were coded by class. Time to narrowing antibiotics was defined as the time from the first antibiotic dose at our institution to the time at which monotherapy or dual therapy for a specific organism was initiated. If patients were continued on the same monotherapy throughout their course, they were excluded from the time to narrowing analysis. Acyclovir was measured in intravenous or oral doses received at our institution or at discharge. This method was used to avoid creating artificial differences in hours on therapy due to different dosing regimens. Prophylactic dosing of antimicrobial agents was not included.

Covariates

Age was stratified into <30, 30 to 90, and >90 day groups. The admission department was noted, as were illness markers, including prematurity (birth before 37 weeks’ gestation); Streptococcus agalactiae status; non-neurologic focal symptoms (respiratory, acute otitis media, pharyngitis, vomiting, diarrhea, dysuria, or skin infection); neurologic symptoms (altered mental status, seizure, or abnormal neurologic examination); sick contacts; and HSV concern (concerning lesions on examination or HSV exposure). The presence of renal dysfunction as noted in the problem list or admission laboratories was noted. Immunosuppression, including immunodeficiency, neutropenia, and active chemotherapy or immunomodulator use, were recorded. All brain imaging reports during the admission were reviewed for changes consistent with an infectious process, including dural enhancement or thickening; leptomeningeal enhancement; restricted diffusion; or multifocal T2 weighted MRI image hyperintensities concerning for encephalitis, lenticulostriate vasculopathy, mastoiditis, empyema, or abscess. Pediatric Risk of Mortality (PRISM) III scores were collected for all PICU admissions.

Laboratories

Initial serum white blood cells (WBCs), bands, creatinine, blood urea nitrogen, liver function tests, C-reactive protein (CRP), and procalcitonin were noted. Serum WBCs were classified as normal or abnormal by using age-specific guidelines.¹⁰ Less than one-third of patients had bands, CRP, or procalcitonin reported, so these were excluded in final analysis. CSF studies included WBCs, neutrophil percentage, red blood cells (RBCs), glucose, protein, Gram-stain, culture, enterovirus PCR, HSV PCR, and the ME panel. HSV PCR was performed via sendout laboratory during business hours by using a Simplexa Direct Kit. CSF culture, ME panel, and enterovirus PCR were performed 24 hours per day every day at our institution.

The LP was classified as bloody if it had >1000 RBCs based on laboratory-reported cutoffs. Other infectious workup recorded included urine, blood, and respiratory cultures within 48 hours of admission as well as respiratory PCR panel results. Bacterial cultures obtained at outside facilities and recorded within the H&P were also included. Urine cultures with colony count <10 000 or multiple flora and blood cultures with coagulase-negative Staphylococcus and Bacillus species results were categorized as likely contaminants.¹¹ Bacterial meningitis was classified by the presence of CSF culture or ME panel result positive for a bacterial pathogen.

Statistical Analysis

Descriptive statistics were used to define the study groups. Fisher’s exact test was used to compare categorical measures, and the Mann-Whitney U test was used for nonparametric continuous variables. Because of the extreme skewness of LOS and antibiotic times, model assumptions were not met when the outcomes were considered as count or time to event data. Thus, LOS was dichotomized into <36 and ≥36 hours on the basis of data that most true-positive bacterial culture results are identified within 36 hours; thus being a likely critical time point if the management decision was based solely on cultures.^12,13 Accordingly, antibiotic time was categorized as 0 (single dose), 1 to 35, and ≥36 hours. Logistic regression was used to model LOS and time to narrowing antibiotics. A cumulative logit model was used to analyze antibiotic time. Univariate analyses were done of possible covariates on the basis of clinical judgement to evaluate for association with longer LOS or antibiotic time. Age group, previous antibiotic use, neurologic symptoms, abnormal serum WBCs, admission location, and positive culture results were evaluated as possible confounders. No immunocompromised patients and only 1 patient with abnormal imaging stayed <36 hours, limiting their inclusion in the model. Year was not included in the model as a result of multicollinearity concerns because it was strongly associated with ME panel obtainment but not outcome measures. Negative binomial regression was selected to model acyclovir dose because it is a count variable with a large number of 0 values. Age group, HSV concern, admission location, abnormal serum WBCs, neurologic symptoms, and positive culture results were evaluated as possible confounders. A 2-sided value of P < .05 was considered statistically significant.