NEW YORK – Eight years after US Food and Drug Administration clearance and CE marking of BioMérieux's BioFire FilmArray ME — the first highly multiplexed rapid syndromic PCR panel to detect pathogens causing brain infections — adoption by clinical laboratories has been steadily increasing.
Now, with a new test from Qiagen recently entering the market, labs have more options yet still grapple with appropriate diagnostic stewardship of syndromic panel tests given that current professional guidelines predate their existence.
Infectious meningitis and encephalitis (ME) can be conclusively diagnosed through the detection of pathogens in the cerebrospinal fluid, potentially enabling targeted therapies. However, CSF sample volumes are often too low for repeated testing, the range of bacteria and viruses that can cause these deadly infections is large, and pathogen concentrations in the tiny samples are often miniscule.
With brain infections, time is also critical — in some cases a causative agent isn't conclusively identified until after a patient has died, and in about one-third of cases no cause is ever determined.
The introduction of rapid multiplex syndromic ME panels in 2015 seemed poised to tackle both the issues of low sample volumes and the need to quickly test for many targets.
BioMérieux's panel obtained FDA de novo clearance that year and the CE mark in 2016, but quickly became the subject of a debate over the appropriate diagnostic stewardship for ME panel testing.
In the wake of a published evaluation of the multicenter clinical trial that supported FDA clearance, some laboratorians asserted that syndromic panels would save lives and improve patient care, while others believed there was simply not enough outcomes data to support their use given the cost and the fact that false negative and false positive results — related to low concentrations of pathogen or contamination during the sample collection, respectively — can be extremely detrimental.
Today, the discussion over the best approach to diagnostic stewardship is ongoing, even as testing adoption increases.
For example, while a survey published in BMC Infectious Diseases last year of 335 pediatric physicians found that 68 percent were currently using the BioFire ME panel at their institutions, three-quarters of these test users reported having no institutional guidelines on when to order the test or how to interpret it, and 58 percent self-reported a lack of knowledge of the test's performance characteristics.
As guidance from the Infectious Disease Society of America on encephalitis has not been updated since it was written in 2008, physicians and labs have instead relied on published literature, in-house evaluations, and best judgements to decide when and how to use these panels on patient samples.
Nevertheless, the adoption of these types of panels seems likely to continue to grow with the market entrance of a CE-marked commercial offering from Qiagen, called the QIAstat-Dx Meningitis/Encephalitis Panel.
The Qiagen ME panel has been shown in two recent studies to be comparable to the BioFire panel in many respects, and it is expected to be submitted to the FDA later this year.
When to restrict testing?
Guidelines are typically codified by professional organizations and updated as the science and practice of medicine evolves. In the case of ME panels, the most applicable guidelines according to experts in the field are from the Infectious Disease Society of America and these have not been updated since 2008.
The IDSA guidelines state, "Nucleic acid amplification tests (such as PCR) should be performed on CSF specimens to identify certain etiologic agents in patients with encephalitis." They then go on to list 63 possible causes of encephalitis. As these guidelines pre-date ME panel technology, they do not include any mention of highly multiplexed PCR or any guidance for labs on diagnostic stewardship of panels.
Institutional guidelines can be used when there are no professional guidelines, and lab directors can create policies on test ordering that both improve patient care and make the best use of limited financial and staffing resources. The lab community also convenes at conferences, in message boards, and through published opinion pieces and studies to collectively arrive at best practices when new technologies are introduced.
This approach can lead to a diversity of strategies, however.
For example, according to online documents, the University of Nebraska Medical Center restricts the use of the BioFire panel to patients who have suspected ME and are either over the age of 2 years old, have more than 10 white blood cells per microliter of CSF, or are immunosuppressed. The lab noted that its retrospective study of 366 CSF samples found this strategy would not miss any clinically significant infections and that subsequent introduction of these criteria led to as much as 53 percent less panel use. The lab also requires that the BioFire ME panel be ordered in conjunction with culture.
The Mayo Clinic, meanwhile, guides its clinicians to test CSF of previously healthy patients for Streptococcus pneumoniae antigens, and perform herpes simplex virus and enterovirus PCR, if these tests are locally available, and to also consider varicella zoster virus PCR testing prior to ordering the BioFire ME panel.
In another example, clinical researchers at Geneva University Hospital in Switzerland retrospectively analyzed two and a half years of BioFire ME panel testing and determined that if they had applied restrictions — specifically only performing testing on patients with four white blood cells or more and greater than 50 milligrams of protein per deciliter of CSF or on patients who were older than 18 or immunocompromised — they would not have missed any infections. They also would have saved one-third of the panel tests performed in that time span, according to the study, or a total of 544 tests.
However, the nuances of each lab and patient community mean one size does not always fit all.
Jennifer Dien Bard, director of the Clinical Microbiology and Virology Laboratory at Children's Hospital Los Angeles, has studied the unrestricted ordering of the BioFire ME panel in her pediatric hospital. While she has consulted for BioFire Diagnostics, the studies of the ME panel that she worked on were independent of that, she noted.
Along with her colleagues, Dien Bard published a prospective evaluation in 2018, concluding that although roughly 87 percent of 251 patients tested over one year were negative for all the targets in the panel, the testing also had a low false positive rate, and negative tests agreed with the patient's clinical picture and other testing.
Restrictions — which can include pleocytosis with a defined WBC cutoff, or no repeat testing within seven days, for example — might be best determined using data specific to an institution, Dien Bard said in a recent interview, if any are needed at all.
In a 2020 Journal of Clinical Microbiology study, Dien Bard and her team found pleocytosis and abnormal glucose or protein levels were poor predictors of a positive ME result in pediatric patients, particularly for detection of viral targets.
"Therefore, the only restriction that we currently have in place is on repeat testing within a seven-day interval," she said.
Kevin Messacar, a pediatric infectious disease specialist at Children's Hospital Colorado, also evaluated the use of the BioFire ME panel in his institution.
He and his team found that the panel decreased the time to a patient getting on an antimicrobial therapy targeted to the identified pathogen from 28 hours to 18 hours.
It also led to infectious neurologic diagnoses in 15 percent of cases as opposed to 10 percent before the panel was introduced, and overall decreased patients' time spent on intravenous antimicrobial therapy by 12 hours.
That said, the team also found the panel did not change the time it took for patients to be given antimicrobials to which an organism was susceptible, nor did it impact hospital admissions, whether antimicrobials were started, or a patients' length of stay. The team found that the overall costs of microbiologic testing increased by $100 per patient with the BioFire ME panel, but that the total hospital costs per patient were unchanged.
The study attributed the latter to diagnostic stewardship — namely the lab's policy of restricting the testing to infants older than 2 months, children who are immunocompromised or have encephalitis, and those with more than five white blood cells per microliter of CSF.
"There is no debating that there is a need for diagnostic stewardship when implementing molecular testing of CSF for suspected [central nervous system] disease," Messacar said in an interview, as it is critical to ensure a test is used in appropriate situations but not overused, "which contributes to healthcare costs and risks detection of false positives."
Messacar also said that one size does not fit all, noting that the literature has been evolving as more data is generated on the use of these tests in various settings.
However, "we conduct many lumbar punctures to detect few cases of CNS infection," he said. "Not every CSF from every lumbar puncture needs a rapid molecular syndromic panel [but] certain cases would clearly benefit from more rapid, comprehensive testing than the standard pathogen-specific approach."
To generally assess how clinicians are currently diagnosing ME and to see what challenges they face, Messacar and his colleagues also conducted surveys of pediatric and adult infectious disease doctors.
These surveys "suggested the need for updating the IDSA guidelines for encephalitis, particularly to incorporate diagnostic advances of syndromic panel testing," he said, as well as to include metagenomic next-generation sequencing approaches.
Indeed, physicians surveyed reported that they rely heavily on the 2008 IDSA guidelines for the management of brain infections, and more than 82 percent of respondents said a formal guideline update is needed.
BioFire's head start
Despite syndromic assays exclusion from current professional guidelines, the BioFire FilmArray ME panel has still seen significant uptake among labs.
The BMC Infectious Diseases study noted that while 68 percent of respondents report using the BioFire ME panel in their practice, only 8 percent have used the panel for more than four years. And, the panel also seems to be replacing standard PCR testing, as only 4 percent of the survey respondents reported still using single organism PCR in all scenarios, and 40 percent reported that they no longer use a single organism PCR test at all.
Vicki Harder, senior global product manager at BioFire, said that since its introduction, the ME panel "has experienced tremendous success with panel adoption."
While BioMérieux does not break out individual panel sales figures, the BioFire FilmArray installed base has grown from a total of 2,500 units in 2015 to 23,500 units in 2022. For 2023, BioMérieux has said it is targeting organic sales growth of between 8 percent and 10 percent excluding sales of respiratory panels, and that this increase is expected to be driven in part by "solid growth" of BioFire non-respiratory panels.
With an eight-year head start, the BioFire FilmArray ME assay has also been the subject of numerous studies demonstrating its value in improving patient management, Harder noted.
"I don't think lack of updated IDSA guidelines have impacted panel adoption, but updated guidelines would certainly be supportive in understanding evidence-based practices, including treatment for the specific pathogens on the panel," she said.
Harder is under the impression that there is growing momentum in the clinical community to have the IDSA guidelines updated, "considering so much has evolved in this disease space since 2008."
Since the body of literature on the overall positive impact of the BioFire ME panel continues to grow, the firm expects those outcomes would be considered in future guidelines, "and have a positive impact," she said.
In terms of diagnostic stewardship, BioFire also believes that this is an important consideration when labs adopt new testing, Harder said.
"It's not surprising there was a lot of discussion around this when the BioFire ME panel launched because it was a major step forward in infectious disease diagnostics for this syndrome," she said.
She and her team have seen many research publications come out since the panel launched that propose different stewardship considerations, and over the years, "the understanding in this area has evolved significantly," she said.
Beyond implementation, Harder said another important diagnostic stewardship consideration is offering testing that provides high value, and one path to this outcome is increasing diagnostic yield, she said, or the number of positive cases found with a given assay.
Many research publications have demonstrated the BioFire ME panel significantly increases diagnostic yield compared to standard of care, Harder said, and the panel has also "brought increased recognition to etiologies that were previously underappreciated, such as human parechovirus."
Indeed, a surprising cluster of 23 parechovirus meningitis cases among newborns in Tennessee last year was detected by the BioFire ME panel, with authors of a report concluding that rapid detection by multiplex molecular panels can limit antibiotic administration and improve patient management.
Qiagen's offering
Qiagen leapt into the syndromic testing space with the acquisition of Stat-Dx in 2018. The firm launched the QIAstat-Dx multiplex syndromic panel system along with a CE-IVD-marked respiratory panel in Europe two months later, and obtained FDA clearance the following year. Qiagen added a SARS-CoV-2 target to the respiratory panel early in the COVID-19 pandemic while it continued to develop panels for gastrointestinal diseases and meningitis/encephalitis. The company has since launched the GI panel in Europe and submitted it to the FDA.
According to Nadia Aelbrecht, VP of the syndromic testing franchise at Qiagen, the QIAstat-Dx ME panel was CE marked and launched last year in Europe and the firm expects to submit it for 510(k) clearance to the FDA later in 2023.
Aelbrecht, who joined Qiagen in December and formerly worked in the molecular IVD business at BioMérieux and Roche Diagnostics, highlighted in a recent interview that, "a lot of clinicians really like syndromic testing because it gives them an answer much faster."
So far, the Qiagen ME panel has also fared well in two recent studies comparing it to the BioFire offering.
A study published in Diagnostics in March by a team in France concluded that the performance characteristics of the Qiagen ME panel were close to those of the BioFire panel.
Using contrived samples, the team observed three false positive results out of 48 Qiagen panel tests as compared to one out of 37 BioFire panel tests. The researchers noted that two of the Qiagen false positives had very high Ct values and that these and the BioFire false positive indicated a likely contamination, considering that suspensions of the pathogens detected had been prepared in the same part of the lab shortly before the testing. "These results are a reminder of the vulnerability of [point-of-care syndromic PCR] assays to contaminations," the team concluded.
A study published in Microbiology Spectrum last month by a team in Finland compared the two ME assays using clinical samples and contrived samples. The evaluation determined the systems were "comparable," having a 100 percent combined positive agreement and a 94 percent combined negative agreement.
In the study, the Qiagen system had an error rate of about 6 percent compared to no erroneous results for the BioFire system, which led the Finnish team to conclude that the FilmArray ME assay was "more reliable."
On the other hand, the authors noted that using the QIAstat-Dx analyzer was as simple as using the FilmArray analyzer, but the handling of the ME assay cassette with the Qiagen system was "faster and easier" than the FilmArray ME cassette because the sample is pipetted directly into the cassette with the QIAstat-Dx.
The authors also noted that, unlike the FilmArray ME panel, QIAstat-Dx displays Ct values and PCR amplification curves.
Dien Bard of Children's Hospital Los Angeles said this feature might be of interest to some microbiology lab directors, but also warned against making specific decisions using Ct values on a qualitative test result, "as a positive with a high Ct value does not translate to an insignificant result," she said.
BioFire's Harder said that "each competitor in the field will have unique features that will appeal to different customers," but noted that the higher failure rates of the Qiagen ME test in the Microbiology Spectrum article are "an important factor to many clinicians."
Regarding the two studies, Marti Juanola, Qiagen's associate director for medical affairs in the syndromic testing franchise, said that every publication is welcomed by the firm, "especially when it comes from an external user who thinks QIAstat-Dx could be a good solution for the lab."
The ease of use of QIAstat-Dx could also be a distinct advantage, he said. "It is literally just pipetting the CSF into the cartridge; there are no additional steps required."
Both Aelbrecht and Juanola said that the evidence is building for improved clinical outcomes for syndromic testing but added that it takes time for labs to get up and running with new assays before they can generate data to publish.
Qiagen is now aiming to grow the presence of QIAstat-Dx in more countries, Aelbrecht said, citing a recent regulatory clearance and launch in Japan of the firm's respiratory panel.
The firm also plans to debut its CE-marked high-volume QIAstat-Dx Rise instrument in the US later this year, she said, which can automatically load and unload up to 18 samples at a time and has the option of priority testing of urgent samples. The firm is also developing QIAstat-Dx panels for antimicrobial resistance in blood culture-positive samples and lower respiratory tract infections, and it received breakthrough device designation from the FDA for its in-development complicated urinary tract infection panel, Juanola noted.
Overall, the lab community seems to be increasingly embracing syndromic testing, and Qiagen's Aelbrecht said the case is growing for positive patient and hospital impacts of rapid syndromic panels generally.
For Qiagen's respiratory and gastrointestinal panels, which have been commercially available for a longer time than the ME panel, there is also growing evidence that these can decrease the length of hospital stay, decrease unnecessary antibiotic use, and help get patients on effective therapy more quickly, Aelbrecht said.
Other benefits
For ME, the literature so far exclusively evaluates the BioFire panel and shows a trend toward decreased length of stay and antimicrobial use and a quicker time to effective therapy.
Still, other potential benefits of ME syndromic testing are a bit unexpected.
For example, a 2018 study from the UK suggested that patients with viral meningitis can have increased pain, anxiety, and depression for nearly one year after their illness. Speeding up diagnosis could lead to faster administration of appropriate treatment, potentially improving these long-term patient outcomes.
Use of ME panels in rural and isolated communities can also potentially reduce costs of transporting patients to medical centers. Furthermore, ME infections are most common among children and students, and in this population, there is also a less-studied but important variable of increased patient satisfaction.
The ME test is, "an extremely emotional assay, because the physician is not only facing patients but also facing parents," Qiagen's Aelbrecht said. Rapid testing can be a relief for clinicians in these cases, she said, because they can potentially give parents a definitive result and then treat appropriately.
Whether the availability of new panels will now change the trajectory of syndromic ME testing adoption is unclear, however.
Dien Bard speculated that institutions that are already testing using other multiplexed panels on the QIAstat-Dx may expand to include the ME panel. But "every institution and microbiology laboratory director have specific reasons for implementing a test and … considering switching from one platform to another," she said.
As the QIAstat-Dx panel appears to perform quite similarly to the BioFire ME panel, "I would speculate that the concerns that limited the adoption of the BioFire ME panel would still exist with the QIAstat-Dx panel," Dien Bard added.
And while there still is no consensus in the field on stewardship, "this is certainly not unique to just the ME panel and is the case for many other molecular diagnostic tests for infectious diseases," she also said.