Given the similarity in symptomology, it is often difficult to distinguish bacterial and viral infections of the central nervous system based on clinical presentation alone. As a result, obtaining a rapid and accurate diagnosis is important for proper patient management. Andrew Hemmert and Jeremy Gilbreath of BioFire Diagnostics review the current landscape for diagnostic testing of cerebrospinal fluid (CSF) in acute CNS infections.
Analysis of patient CSF is crucial for diagnosis and management of CNS infection. For cases of acute meningitis or encephalitis, CSF is obtained via lumbar puncture (LP). Clinical findings such as cell count, glucose and protein concentrations can provide clues regarding infection. These differential indicators are useful to aid in diagnosis, but because of overlap between etiologies, they are not sufficient to guide targeted therapy.
The standard method for diagnosis of bacterial meningitis is Gram stain and CSF culture. Other methods for detection and identification of bacterial pathogens such as direct antigen testing or polymerase chain reaction (PCR) are not yet commonly used as first line diagnostics, but have recognised value in patients with clinical findings consistent with a bacterial CNS infection who have negative Gram stain and culture results.
In contrast to bacterial detection, PCR has become the gold standard for detecting viruses associated with aseptic meningitis or encephalitis. In some cases, serological testing may be more appropriate for suspected arbovirus infections since immunocompetent patients may not have these viruses in their CSF at the time of presentation.
In addition to these single-target viral detection assays, a rapid commercial multiplex PCR test for the detection of 14 pathogens received FDA clearance for use as an aid to diagnosis of meningitis or encephalitis in October 2015. The addition of this type of panel-based syndromic testing to CNS disease allows detection of a wide range of pathogens in a clinically actionable time frame and has demonstrated high diagnostic value with other infectious disease syndromes.
Benefits of a rapid turnaround time
Due to the potential severity of CNS disease, early and effective treatment is critical to reducing morbidity and mortality; however, many current diagnostic methodologies are technically cumbersome or time-consuming to perform. CSF culture has a turnaround time (TAT) of 24-48 hours and TATs for standard PCR tests can range from a few hours to several days, depending on whether the test is performed in-house or has to be shipped to a reference lab. Given the approximate one hour sample-to-answer run time with the commercial multiplex test mentioned above, a STAT result could be reported within 1.5-2.0 hours of specimen collection. Beyond providing a STAT result, improving TAT can likely improve antimicrobial stewardship, infection control practices and healthcare costs associated with CNS infections.
A study on identification of blood culture pathogens reported a decrease in time to appropriate targeted therapy for patients infected with vancomycin-resistance enterococci when using a rapid, multiplex PCR system. For CNS infections, a similar narrowing of antimicrobial therapy could potentially be made if an appropriate diagnosis was made within a few hours. A rapid diagnosis also has the potential to benefit infection control practices as well as community outbreak notification.
Reductions in the scope of diagnostic testing required to make a definitive diagnosis have the potential to reduce length of hospitalisation and overall healthcare costs. Rapid identification of blood culture pathogens using a commercially available multiplex panel reduced the length of hospitalisation and cost of care for patients whose cultures tested positive for contaminating bacteria. Based on the multiple studies that have already demonstrated cost savings, reduced length of hospitalisation and reduced exposure to unnecessary antibiotics associated with molecular testing for early identification of pathogens in CSF, it is hypothesised that faster results through multiplex PCR testing will also have an impact on CNS disease.
Increasing diagnostic yield
Negative Gram stains are observed in 90% of patients presenting with acute meningitis reporting to A&E. Because no underlying cause can be readily identified, patients are often unnecessarily hospitalised and treated with empiric antimicrobial therapy, thus creating a significant healthcare burden. Recent studies have demonstrated that performing additional CSF PCR tests will increase the diagnostic yield in culture or Gram-stain-negative acute meningitis cases.
Advances in molecular technology may be ushering in a new era of diagnostics for acute meningitis and encephalitis. In addition to the new multiplex PCR system, other techniques such as next-generation sequencing have great promise to increase diagnostic yield. Faster and more comprehensive results could lead to improved patient outcomes through decreased TAT for diagnosis and better antimicrobial stewardship. The healthcare community should work together to determine when these new tests are most appropriate to balance diagnostic yield with laboratory costs.
