Simple Spinal Fluid Protein Test Could Curb Unnecessary Meningitis PCR Panels

A rapid molecular panel that detects the genetic fingerprints of viruses, bacteria, and fungi in the fluid surrounding the brain and spinal cord has transformed the workup of suspected meningoencephalitis. Yet the very ease of ordering the FilmArray Meningitis/Encephalitis panel, known as FAME, has created a new problem for hospitals: many of the tests come back negative, consuming laboratory resources and money without changing a single patient’s treatment. A new retrospective study from Medellín, Colombia, published in BMC Infectious Diseases, suggests that two routine measurements already available from every lumbar puncture, the cerebrospinal fluid white cell count and protein concentration, could act as gatekeepers, identifying which samples are actually likely to yield a positive molecular result.

The research team, led by Juan Felipe Morantes Rubiano of Hospital Pablo Tobón Uribe and Universidad Pontificia Bolivariana, reviewed the records of 478 adults with suspected acute meningoencephalitis who underwent FAME testing at two tertiary hospitals in Medellín between 2019 and 2023. The cohort had a median age of 51 years and was 55 percent male. Of these patients, 353 were immunocompetent and 125 were immunosuppressed, a distinction that matters because clinicians have historically been reluctant to apply any restrictive testing rules to patients whose weakened immune systems can blunt the usual inflammatory signals of infection. Overall, only 14.8 percent of the FAME panels returned a positive result, a figure that immediately illustrates the scale of low-yield testing in routine practice.

The study’s design deserves careful attention because it differs from a classic diagnostic accuracy trial. The authors explicitly framed their work as a diagnostic stewardship evaluation rather than an assessment of how well spinal fluid chemistry detects confirmed central nervous system infection. The reason is subtle but important: the FAME panel itself is an imperfect reference standard, capable of missing genuine infections and occasionally detecting latent viruses that are not causing disease. Rather than claiming that routine measurements can diagnose meningoencephalitis, the researchers asked a narrower and more honest question: which cytochemical parameters predict that a FAME panel will come back positive? The target condition was therefore panel positivity, not microbiologically confirmed infection.

The differences between positive and negative cases were striking. Patients with positive panels had a median cerebrospinal fluid leukocyte count of 189 cells per cubic millimeter, compared with just 3 cells per cubic millimeter in those with negative panels. Protein concentration, a marker of blood-brain barrier disruption and inflammation, was also markedly higher in positive cases, with a median of 167 milligrams per deciliter versus 47 milligrams per deciliter. Glucose, which bacteria and viruses consume as they multiply, was lower in positive cases, at a median of 31 milligrams per deciliter compared with 62. Among all the parameters evaluated, protein showed the greatest discriminative capacity, with an area under the receiver operating characteristic curve of 0.793, while opening pressure, the pressure measured when the needle first enters the spinal canal, showed the weakest, at 0.666.

From these data, the team constructed a practical screening rule. Of the 478 tests performed, 287, or 60 percent, were carried out on samples without pleocytosis, defined as fewer than 10 white cells per cubic millimeter of fluid. In this low-cell-count group, the FAME positivity rate was only 5.5 percent. When the researchers added a second condition, requiring protein below 50 milligrams per deciliter, they identified 192 samples, or 40.1 percent of the total, in which positivity fell to just 2.6 percent. In other words, applying a combined threshold of at least 10 leukocytes per cubic millimeter or at least 50 milligrams per deciliter of protein would have flagged the samples most likely to be positive and spared the rest.

The clinical stakes of such a rule depend on what would have been missed. Under a narrow definition of clinically relevant results, meaning a positive test that would actually change patient management, only 0.5 percent of the low-yield samples would have contained such a finding. Under a broader definition, counting any confirmed true positive regardless of its management impact, the figure rose to 1.0 percent. These numbers quantify the trade-off at the heart of diagnostic stewardship: a modest risk of overlooking rare positives in exchange for a substantial reduction in testing that rarely helps. The combined threshold would have increased overall diagnostic yield by 55.4 percent while cutting low-yield testing by 40.1 percent, gains that translate directly into lower costs and faster laboratory turnaround for the samples that matter.

Perhaps the most consequential finding concerns immunosuppressed patients, a group usually excluded from restrictive testing guidelines because clinicians fear that their blunted inflammatory responses will produce false reassurance. In this cohort, the negative predictive value of the combined threshold was 97.4 percent overall and 96.0 percent in immunosuppressed patients, with a confidence interval of 86.5 to 98.9 percent for the latter group. That suggests the rule may be applicable even to patients with compromised immunity, though the authors caution that one clinically significant case in this subgroup would have been missed under the broader definition. The finding is hypothesis-generating rather than definitive, and the researchers emphasize that prospective validation is required before such thresholds are adopted into clinical pathways.

The concept of diagnostic stewardship, as opposed to antimicrobial stewardship, is gaining traction in infectious diseases. The idea is to intervene at the moment a test is ordered rather than after a result returns, ensuring that expensive diagnostics are directed at patients in whom they are most likely to change outcomes. Molecular syndromic panels like FAME test for a fixed menu of pathogens, including herpes simplex viruses, enteroviruses, cryptococcus, and several others, and each run carries a significant cost. When the pre-test probability of a positive result is low, as it evidently is in the majority of samples in this study, the marginal value of the panel diminishes. Simple, cheap cytochemical measurements performed on the same spinal fluid sample can serve as an inexpensive triage layer.

The study also illustrates the methodological caution needed when evaluating syndromic diagnostics. Because FAME served as the reference standard, the analysis cannot distinguish between true infections that the panel missed and latent viral detections that the panel flagged without clinical consequence. Herpes simplex virus DNA, for example, can persist in cerebrospinal fluid after treatment, and latent infections can produce positive results that do not reflect active disease. The authors’ decision to define their target as panel positivity rather than confirmed infection keeps the conclusions within defensible bounds, and their framing of the results as hypothesis-generating reflects that restraint. Any future implementation would need to weigh the rare missed positives against the systemic benefits of reduced testing, ideally through prospective studies that follow patients longitudinally.

For hospitals confronting the economics of molecular diagnostics, the Colombian data offer a concrete starting point for local evaluation. The thresholds involved, 10 leukocytes per cubic millimeter and 50 milligrams per deciliter of protein, are not exotic measurements but values already reported in every cerebrospinal fluid analysis, making implementation straightforward wherever FAME testing is available. The authors, who also included Laura Restrepo Álvarez, Andrea Mazo Cañola, Juan Pablo Villa Franco, Santiago Atehortúa Muñoz, Jorge Hernando Donado Gómez, and Paulina González Obando, received no direct monetary funding and declare no competing interests. If prospective validation confirms their findings, the humble spinal fluid cell count and protein level, measurements that have been part of neurology for more than a century, may become the first filter in a smarter, more sustainable diagnostic pathway for one of medicine’s most urgent syndromes.

Subject of Research: Cerebrospinal fluid cytochemical parameters as predictors of FilmArray Meningitis/Encephalitis panel positivity for diagnostic stewardship

Article Title: Cerebrospinal fluid cytochemical parameters as predictors of FilmArray Meningitis/Encephalitis panel positivity: a diagnostic stewardship approach in immunocompetent and immunocompromised patients

Article References: Morantes Rubiano, J. F., Restrepo Álvarez, L., Mazo Cañola, A., Villa Franco, J. P., Atehortúa Muñoz, S., Donado Gómez, J. H., & González Obando, P. (2026). Cerebrospinal fluid cytochemical parameters as predictors of FilmArray Meningitis/Encephalitis panel positivity: a diagnostic stewardship approach in immunocompetent and immunocompromised patients. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14575-x

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14575-x

Keywords: meningitis, encephalitis, cerebrospinal fluid, FilmArray, diagnostic stewardship, molecular diagnosis, pleocytosis, CSF protein, immunocompromised patients, diagnostic accuracy, BMC Infectious Diseases, Colombia