Commentary: The First Fully Automated Molecular Diagnostic Panel for Meningitis and Encephalitis: How Well Does It Perform, and When Should It Be Used?

Abstract

Meningitis and encephalitis are potential infectious disease emergencies. The laboratory evaluation of suspected meningitis/encephalitis (ME) is complex, in part because the differential diagnosis is broad and the associated clinical signs and symptoms are not organism specific. Clinicians typically prioritize laboratory workup based on host factors, the duration of symptoms, and potential environmental exposures; but cerebrospinal fluid (CSF) indices in combination with multiple microbiologic tests are generally required to exclude infection or identify a potential pathogen.CSF Gram stain with culture has been the diagnostic "gold standard" for acute bacterial meningitis for nearly a century. However, both methods have a limited sensitivity that may be further reduced in patients who have received antibiotics (1). As a result of these limitations, there has been much interest in the development of standardized molecular diagnostic tests for bacterial central nervous system (CNS) infections. Molecular assays have the potential to be more rapid than culture and are potentially less affected by prior antimicrobial therapy. Until recently, there were no commercially available molecular assays for the diagnosis of bacterial ME marketed in the United States. In contrast, nucleic acid amplification tests are the diagnostic standard for most viral CNS infections. U.S. Food and Drug Administration (FDA)-approved PCR assays have been available for enteroviruses (Xpert EV; Cepheid, Sunnyvale, CA) and herpes simplex viruses (Simplexa HSV 1&2 Direct; Focus Diagnostics, Cypress, CA) for years. Some clinical laboratories have also developed their own PCR assays for CNS pathogens, while others may send testing out to a reference laboratory, which potentially delays time to actionable results.In October 2015, the FDA cleared the first multiplex PCR panel for the detection of CNS pathogens. The fully automated FilmArray ME panel (BioFire Diagnostics LLC, Salt Lake City, UT) simultaneously detects and identifies 14 bacterial, viral, and yeast pathogens in about an hour directly from 200 l of CSF. The components of the FDA-approved FilmArray ME multiplex panel are listed as follows. In this issue of the Journal of Clinical Microbiology, Leber and colleagues report the results of a large multicenter trial designed to support FDA clearance of the ME panel (2). Residual cerebrospinal fluid (CSF) specimens obtained as a part of routine clinical care were tested at 11 different sites in the United States. The ME panel test performance was assessed through comparisons to conventional culture for bacteria or with PCR followed by sequencing for the viral and yeast targets. Discordant results across methods were resolved by repeat molecular analysis (when possible) combined with a blind review of study subject demographic, clinical, and laboratory information.A total of 1,560 prospectively collected CSF specimens were enrolled in the study over 8 months. There was 84.4% positive and Ͼ99.9% negative agreement between the ME panel and conven...

Comparison of antibiotic and acyclovir usage before and after the implementation of an on-site FilmArray meningitis/encephalitis panel in an academic tertiary pediatric hospital: a retrospective observational study

“…This might raise the question if using in-house PCR assays for HSV, enterovirus and HHV-6 instead of using the mPCR, may be more cost effective in some institutions. Some authors even implied that the sensitivity of a singleplex assay to detect viral agents is greater than that of a mPCR [15,17,44]. However, this approach involves the risk of missing a viral pathogen and requires a certain level of medical experience.…”

“…mPCR) on empiric treatment. Quick verification or exclusion of the presence of organisms may enable clinicians to early optimize antimicrobial therapy and hence possibly reduce therapy-associated complications and healthcare costs [15][16][17][18]. In a previous study conducted at our institution we retrospectively analyzed all patients receiving mPCR testing over the period of one year [19].…”

Childhood Central Nervous System Infections: Are We under Estimating the True Burden?

“…In the absence of fever, stiff neck, and altered mental status allowed clinicians to exclude meningitis with 99 to 100% confidence. 7 Overall, the classical triad of meningitis with fever, neck stiffness, and altered mental state in our study was 46.1%. A study conducted in patients of 16 years and older found that the triad of fever, neck stiffness, and altered mental state was observed in only 44 to 46%.…”

“…Fifty CSF samples stored in a À 70°C freezer (40 suspected meningitis and 10 suspected encephalitis) were tested using meningitis/encephalitis (ME) panel for FilmArray multiplex polymerized chain reaction (PCR) system. It targets 14 potential pathogens 7,8 CSF parameters including differential cell count, protein concentration, and glucose ratio in CSF and blood were used to aid the etiological diagnosis. 10 Further, depending on clinical suspicion, magnetic resonance imaging (MRI) or computed tomography or ultrasound scan of brain of the infants was performed, to detect space-occupying lesions and to assess structural malformations.…”

Rapid Molecular Panels: What Is in the Best Interest of the Patient? A Review of Patient Outcome Studies for Multiplex Panels Used in Bloodstream, Respiratory, and Neurological Infections

“…Of note, in their clinical trial, Leber et al also reported false-positive results for S. pneumoniae, S. agalactiae, and E. coli and a false-negative result for S. agalactiae. Others who have reviewed these results have remarked that institutions using FilmArray ME may wish to consider implementing clinician counseling by clinical laboratories and/or ASP to ensure that positive and negative results are interpreted appropriately [29].…”