Faster Results, Better Care? Impact of Meningitis/Encephalitis Syndromic Panel Testing on Pathogen Detection and Hospital Outcomes Beyond CSF Culture: A Literature Search for Diagnosticians

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive narrative review of syndromic meningitis/encephalitis (M/E) panels, with a primary focus on the BioFire FilmArray® M/E panel. The topic is clinically relevant and timely, and the review summarizes a broad body of literature on diagnostic performance, clinical outcomes, and stewardship implications. However, the manuscript is overly descriptive, lacks a clear critical framework, and would benefit from tighter structure, stronger synthesis, and clearer positioning of conclusions. Major revision is recommended.

1. Introduction

1. The Introduction is informative but lengthy; it would benefit from clearer framing of the specific clinical question(s) this review aims to answer.
2. The rationale for focusing predominantly on the BioFire FilmArray® M/E panel, rather than other commercial or emerging syndromic platforms, should be stated more explicitly.

1. Results and Discussion

1. Diagnostic performance data are extensively summarized, but the section would benefit from greater synthesis rather than repetition of individual study findings.
2. False-positive and false-negative results (e.g., HHV-6, HSV, Cryptococcus, Listeria) are well discussed, yet a concise comparative table or summary figure highlighting high-risk pitfalls would improve clarity.
3. The discussion of clinical outcomes (LOS, antimicrobial duration) is comprehensive but sometimes contradictory; stronger emphasis on contextual modifiers (age, immune status, stewardship presence) is needed.

III. Conclusion

1. The Conclusion appropriately emphasizes speed and stewardship benefits but should be more cautious in framing clinical impact, particularly for bacterial and fungal infections.
2. Future directions would benefit from prioritization, focusing on diagnostic stewardship models, LMIC applicability, and algorithm-guided testing, rather than broad technological speculation.

Author Response

* Comment 1:

The Introduction is informative but lengthy; it would benefit from clearer framing of the specific clinical question(s) this review aims to answer.

Reply:

Thank you for this valuable comment. We revised the Introduction to explicitly state the clinical questions guiding this narrative review. We added a concluding paragraph that clearly frames the population of interest, the diagnostic intervention (FilmArray® M/E panel), the comparator (conventional CSF–based methods), and the key clinical and hospital outcomes evaluated, including diagnostic yield, turnaround time, length of stay, and antimicrobial and antiviral use.

 

* Comment 2:

The rationale for focusing predominantly on the BioFire FilmArray® M/E panel, rather than other commercial or emerging syndromic platforms, should be stated more explicitly.

Reply:

Thank you for this valuable comment. We added sentences that explained the reason for the focus on the BioFire in the Introduction. 

* Comment 3:

Diagnostic performance data are extensively summarized, but the section would benefit from greater synthesis rather than repetition of individual study findings.

Reply:

We thank the reviewer for this helpful comment. We agree that the diagnostic performance section contains a large amount of data, reflecting the heterogeneity of available studies and pathogen-specific performance of the M/E panels. Our intention was to provide a comprehensive overview of sensitivity, specificity, and false-positive/false-negative patterns across pathogens and populations.

* Comment 4:

False-positive and false-negative results (e.g., HHV-6, HSV, Cryptococcus, Listeria) are well discussed, yet a concise comparative table or summary figure highlighting high-risk pitfalls would improve clarity.

Reply:

Thank you for this suggestion. We added a third concise comparative table summarizing high-risk false-positive and false-negative pitfalls of the M/E panel (including HHV-6, HSV-1/2, Cryptococcus neoformans, and Listeria monocytogenes), along with the error type and key clinical implications. This provides an at-a-glance summary to improve clarity and support cautious result interpretation. Given that the order of tables has changed, Table 2 became Table 3, and the new table was named Table 2.

* Comment 5:

The discussion of clinical outcomes (LOS, antimicrobial duration) is comprehensive but sometimes contradictory; stronger emphasis on contextual modifiers (age, immune status, stewardship presence) is needed.

Reply:

We added an explanatory paragraph explaining that LOS, antimicrobial duration is center specific, depends on context and on population to decrease the fact that it seems contradictory. More emphasis is provided for age, immune status and stewardship presence with citations from research articles. Kindly refer to paragraphs: 3.4, 3.6, 3.8.

* Comment 6:   

The Conclusion appropriately emphasizes speed and stewardship benefits but should be more cautious in framing clinical impact, particularly for bacterial and fungal infections.

Reply:

We thank the reviewer for this important observation. We agree that while the M/E panel consistently demonstrates advantages in turnaround time and antimicrobial stewardship, its direct impact on downstream clinical outcomes—particularly for bacterial and fungal infections—is more variable and context dependent. We revised the Conclusion to further temper statements regarding clinical impact, particularly for bacterial and fungal infections, and to more clearly distinguish stewardship benefits from hard clinical outcomes such as length of stay.

* Comment 7:  

Future directions would benefit from prioritization, focusing on diagnostic stewardship models, LMIC applicability, and algorithm-guided testing, rather than broad technological speculation.

Reply:

The sections in the Future Directions section were prioritized in the following way: (1) diagnostic stewardship models, (2) LMIC implementation, and (3) algorithm-guided testing using CSF biomarkers. We removed redundant general sentences in the diagnostic stewardship models, strengthened LMIC applicability by highlighting context-specific implementation needs (limited evidence outside high-income settings, local epidemiology adaptation, and the need for reflex/add-on testing for non-panel pathogens and for cryptococcosis confirmation where relevant), and added for the algorithm-guided testing section with biomarkers that future studies should validate the lactate-guided triage pathway in different subgroups.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors provide a comprehensive review of the performance and clinical utility of the  BioFire FilmArray® Meningitis/Encephalitis (M/E) panel. There are several items that need to be modified and improved before this is ready for publication. Most notably, the methods section needs to be expanded to more fully understand the manuscript search methodology and review process. Also, it is unclear if this is a review of just the Biofire panel or the Biofire and Qiagen panel. If both products are discussed the abstract and introduction needs to be changed to reflect this wider scope. Finally, there are typos and grammatical errors sprinkled throughout the document that makes the material difficult to follow. Additional specific details are listed below.

• Page 2, 1^st full paragraph, typo - and may have doesa low sensitivity
• Methods – greater detail is needed about the search methodology – For example, was there a date limitation? How many articles were originally identified by these search terms? How were articles selected for inclusion in this manuscript?
• It would be helpful to have a short description of the FilmAr-ray® M/E panel as background information. Who is the manufacturer, what are the claims, what viruses/bacteria does it detect, how is it currently used, etc. Figure 2 is helpful in this regard and should be moved earlier in the article.
• Results – figure 1. I wouldn’t describe this as detection capacity. Detection capacity suggests the types of pathogens detected and the limit of detection. Suggest changing this to workflow or something similar.
• Page 5, section 3.2, last paragraph talks about the QI-Astat-Dx M/E Panel. This is the first time this assay is mentioned. I thought this review was about the Biofire FilmArray? Please remove this discussion or alter the scope of the article to describe that the intent of the article is to review the performance of multiple rapid diagnostic platforms. QIAstat is also mentioned on page 7 and page 12.
• Minor point – I would split section 3.8 age-related variations and economic impact into two different sections.
• Throughout the paper there are grammatical modifiers used that sound like marketing material (abstract - provides a revolutionary advancement, page 10 - its remarkably faster turnaround time, page 11 - offer a revolutionary influence on outcomes) rather than providing an impartial review of the literature. Review and remove usage of these modifiers.
• Formatting and English in sections 4.1.1 and 4.1.2 is of lower quality than the rest of the manuscript. Review and edit to improve readability.
• Section 4.3.1 – make sure to use mNGS instead of the typo mGNS in this section.

Comments on the Quality of English Language

See the section on comments and suggestions for authors.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

1. This is an interesting study and the authors need to improve the following point. I think this is a systematic review and why did the authors choose as a research article category?
2. Why did the author. Choose Film array only and there are many other syndromic testing panel eg Qiastat ME panel. Please add the justification for choosing Film array only.
3. For the systematic study, the authors must add the diagram for selection of the stusy in this manuscript. For eg, How many studies were found in Pubme using search word etc. Please add this flow diagram at the revised manuscript.
4. Please also add the cross checking of procedures for searching on the web.
5. The Table-1 described that the sensitivity, specificity, NPV, PPV of different stdies. The diagnostic tests evaluation can vary on the prevalrnce of the pathogens. The studies described in Table-1 must describe the study place for more understanding of the reviewer.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I think this revision addressed previous comments and could be published

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed my comments and I feel this is now ready for publication.