Abstract Details

Title Improving Tuberculous Meningitis Diagnostics - A Combined Host and Pathogen Classifier

Topic Infectious Disease

Presentation(s) S28 - Infectious Disease: Chronic Meningitis and the Immunosuppressed (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Background

GeneXpert RIF/MTB Ultra is ~70% sensitive for definite/probable TBM. Definite TBM is microbiologically proven. Probable TBM has negative microbiology but scores >10 points on the case definition scale. 90-98% of mNGS sequencing data reflect host gene expression. Host transcriptomic signatures may differ by pathogen and thus, enhance diagnostic utility. We assessed CSF mNGS and transcriptomics for identifying TBM and other pathogens misclassified as TBM.

Objective

To assess the diagnostic performance of metagenomic next-generation sequencing (mNGS) combined with host differential gene expression for tuberculous meningitis (TBM) versus other causes of meningitis.

Design/Methods

Cohort: 157 HIV-infected Ugandan adults with sub-acute meningitis: Definite (n=15), probable (n=7), and possible (n=53) TBM; non-TB meningitis (n=82).

Method: Unbiased RNA and DNA libraries were sequenced. We performed metagenomic analysis through a custom bioinformatics pipeline. Transcriptomic diagnostic classifier was developed using 22 samples (11 TB + 11 other), which, along with cases with co-infections, were not included in the final analysis.

Results

mNGS was 80% concordant (12/15) against definite TBM with 3 additional cases of TBM detected (1 probable and 2 possible). Host transcriptomics displayed 83% (5/6) sensitivity (inclusive of mNGS-positive TBM), 78% (62/79) specificity, and 98% negative predictive value. Among probable TBM cases the host transcriptomic classifier predicted 71% (5/7) were TBM including the 1 mNGS-positive TBM case. Within possible TBM, mNGS identified 9 other pathogens (4 viral, 2 bacterial, 2 toxoplasmosis and 1 TBM-viral co-infection). The host transcriptomic signature classified 9/53 possible TBM cases as TBM, including the 1 mNGS-positive TBM case.

Conclusions

mNGS and host transcriptomics combined for 77% (17/22) sensitivity against definite/probable TBM. mNGS alone detected TB or alternate pathogens in 19% (10/53) of possible TBM cases. Further optimization of the classifier is required to increase accuracy. The combined assay will be assessed on a validation cohort with results presented at the meeting.

Authors/Disclosures
Prashanth S. Ramachandran, Jr., MBBS (Royal Melbourne Hospital) PRESENTER	Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merk.
	No disclosure on file
Fiona Cresswell	No disclosure on file
Carson M. Quinn, MD (Mass General Brigham)	Dr. Quinn has nothing to disclose.
Prashanth S. Ramachandran, Jr., MBBS (Royal Melbourne Hospital)	Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merk.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Charles Langelier	No disclosure on file
David Meya	No disclosure on file
	No disclosure on file
David R. Boulware, MD, MPH (University of Minnesota)	The institution of David R. Boulware, MD, MPH has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sfunga. David R. Boulware, MD, MPH has received publishing royalties from a publication relating to health care. David R. Boulware, MD, MPH has received personal compensation in the range of $0-$499 for serving as a Study Section with NIH.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cambridge Medical Experts. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. The institution of Dr. Wilson has received research support from Chan Zuckerberg Initiative. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.

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