Ignite Creation Date:
2024-06-16 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06439810
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-04
First Post:
2024-05-28
Brief Title:
Diagnostic Utility of Mycobacterium Tuberculosis Cell-free DNA
Sponsor:
Chinese University of Hong Kong
Organization:
Chinese University of Hong Kong
Study Overview
Official Title:
Diagnostic Utility of Mycobacterium Tuberculosis Cell-free DNA MTB cfDNA in Tuberculous and Non-tuberculous Pleural Effusion
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MYDNITE
Brief Summary:
Tuberculosis TB is one of the major global health threats and is the second leading infectious cause of death after COVID-19 in 2022 Extrapulmonary TB EPTB amongst which tuberculous pleuritis TBP is one of the most common subtypes poses additional obstacles to global TB control due to its difficulty in diagnosis
The diagnosis of TBP is challenging The ideal way of confirming TBP is by direct detection of TB bacteria or its specific component in the pleural space However the performance of available diagnostic tests is far from satisfactory and no single test can achieve multiple diagnostic goals simultaneously including high detection sensitivity high specificity to exclude other diseases low invasiveness and detection of drug resistance The inability to diagnose TBP early leads to unnecessary invasive pleural procedures and delayed curative treatment There is a pressing need for a better diagnostic test to diagnose TBP confidently
When TB bacteria die or break down the DNA materials shed into the pleural space forming Mycobacterium tuberculosis cell-free DNA MTB cfDNA which may aid in diagnosing TBP However only limited literature explored this aspect and the sensitivity rates reported were still suboptimal due to the scarcity of DNA materials in the pleural fluid Based on a small patient cohort our group has recently developed a new laboratory assay measuring MTB cfDNA to overcome this problem with a superior diagnostic performance to conventional tests This assay can potentially capture the genes harbouring drug resistance towards anti-TB medications
There are three aims in this research proposal First the diagnostic accuracy of the new MTB cfDNA assay in diagnosing TBP will be determined using a large cohort containing pleural fluid samples of various causes from countries with different TB burdens Second the clinical and laboratory factors determining the pleural fluid MTB cfDNA level will be identified Third the ability of the assay to capture different anti-TB drug-resistance genes will be explored
This new diagnostic method will significantly enhance the pickup rate of TBP benefit patients with less invasive procedures shorter hospital stays and timely treatment
The diagnosis of TBP is challenging The ideal way of confirming TBP is by direct detection of TB bacteria or its specific component in the pleural space However the performance of available diagnostic tests is far from satisfactory and no single test can achieve multiple diagnostic goals simultaneously including high detection sensitivity high specificity to exclude other diseases low invasiveness and detection of drug resistance The inability to diagnose TBP early leads to unnecessary invasive pleural procedures and delayed curative treatment There is a pressing need for a better diagnostic test to diagnose TBP confidently
When TB bacteria die or break down the DNA materials shed into the pleural space forming Mycobacterium tuberculosis cell-free DNA MTB cfDNA which may aid in diagnosing TBP However only limited literature explored this aspect and the sensitivity rates reported were still suboptimal due to the scarcity of DNA materials in the pleural fluid Based on a small patient cohort our group has recently developed a new laboratory assay measuring MTB cfDNA to overcome this problem with a superior diagnostic performance to conventional tests This assay can potentially capture the genes harbouring drug resistance towards anti-TB medications
There are three aims in this research proposal First the diagnostic accuracy of the new MTB cfDNA assay in diagnosing TBP will be determined using a large cohort containing pleural fluid samples of various causes from countries with different TB burdens Second the clinical and laboratory factors determining the pleural fluid MTB cfDNA level will be identified Third the ability of the assay to capture different anti-TB drug-resistance genes will be explored
This new diagnostic method will significantly enhance the pickup rate of TBP benefit patients with less invasive procedures shorter hospital stays and timely treatment
Detailed Description:
Tuberculosis TB remains a key infectious disease burden globally According to the Global TB Report by the World Health Organization WHO in 2023 TB is the second leading infectious cause of death after COVID-19 in 2022 Extrapulmonary TB amongst which tuberculous pleuritis TBP is one of the most common subtypes poses additional obstacles to global TB control due to its difficulty in diagnosis There is a large geographical variation in the incidence of TBP with the proportion of TBP among all TB patients ranging from 22 to 314 An increasing incidence of TBP was noted in two large retrospective Chinese cohort studies
The paucibacillary nature of TBP leads to its diagnostic challenge Despite being a gold standard diagnostic test the diagnostic sensitivity of pleural fluid Mycobacterium tuberculosis MTB culture is suboptimal It varies between 70 and 750 depending on the culture medium and HIV status Its long turnaround time of around 4 to 8 weeks also impairs its clinical practicality Commercial PCR techniques such as Xpert MTBRIF or Xpert Ultra are rapid and specific tests with positive results However their utilities are limited by suboptimal sensitivity Pleural biopsy for histology and combined histology culture might raise the sensitivity to 66 and 79 but this procedure is more invasive than thoracentesis Pleural fluid adenosine deaminase ADA is the most commonly studied biomarker with diagnostic sensitivity and specificity of 093 and 090 at a cutoff of 40 UL Its cutoff range may vary with patient characteristics age comorbid illness The difficulty in diagnosing TBP therefore leads to delayed initiation of anti-TB treatment Empirical anti-TB treatment may be initiated based on compatible clinical presentations without confirmatory diagnostic microbiological results bearing the risk of treatment toxicities eg hepatotoxicity This suggests an unmet clinical need for a better diagnostic tool for TBP
Detecting MTB cell-free DNA cfDNA in the pleural fluid may solve the above problems It is a potential diagnostic tool with minimal invasiveness and most importantly a direct confirmation of MTB in the pleural space However previous PCR-based methods reported suboptimal sensitivity for diagnosing TBP of about 40-80 The sensitivity may be limited by the low level of MTB cfDNA and the single-gene target IS6110 or devR in the detection With the advancement of next-generation sequencing NGS technology the detection of microbial cfDNA by metagenomic NGS mNGS has been applied in infectious disease diagnostics Chang et al have previously evaluated the use of mNGS in blood and urine samples for tuberculosis diagnostics They revealed that such methodology is limited by the low MTB concentration and the background of contaminating non-tuberculous mycobacterial NTM DNA which shares similar sequences to the pathogenic MTB
Our group has recently developed a new laboratory assay measuring the MTB cfDNA levels We hypothesise that the new MTB cfDNA assay has better diagnostic performance than conventional microbiological methods in discriminating pleural effusions due to TBP from non-TBP Since the development cohort only contains a limited number of pleural fluid samples a large-scale confirmatory study containing pleural effusions with a wide spectrum of causes is required to confirm its clinical utility before being introduced in clinical practice This study has three major aims First the diagnostic accuracy of the new MTB cfDNA assay in diagnosing TBP will be determined using a large cohort containing pleural fluid samples of various causes from countries with different TB burdens Second the clinical and laboratory factors determining the pleural fluid MTB cfDNA level will be identified Third the ability of the assay to capture different anti-TB drug-resistance genes will be explored on pleural fluid from DR-TB endemic areas
The paucibacillary nature of TBP leads to its diagnostic challenge Despite being a gold standard diagnostic test the diagnostic sensitivity of pleural fluid Mycobacterium tuberculosis MTB culture is suboptimal It varies between 70 and 750 depending on the culture medium and HIV status Its long turnaround time of around 4 to 8 weeks also impairs its clinical practicality Commercial PCR techniques such as Xpert MTBRIF or Xpert Ultra are rapid and specific tests with positive results However their utilities are limited by suboptimal sensitivity Pleural biopsy for histology and combined histology culture might raise the sensitivity to 66 and 79 but this procedure is more invasive than thoracentesis Pleural fluid adenosine deaminase ADA is the most commonly studied biomarker with diagnostic sensitivity and specificity of 093 and 090 at a cutoff of 40 UL Its cutoff range may vary with patient characteristics age comorbid illness The difficulty in diagnosing TBP therefore leads to delayed initiation of anti-TB treatment Empirical anti-TB treatment may be initiated based on compatible clinical presentations without confirmatory diagnostic microbiological results bearing the risk of treatment toxicities eg hepatotoxicity This suggests an unmet clinical need for a better diagnostic tool for TBP
Detecting MTB cell-free DNA cfDNA in the pleural fluid may solve the above problems It is a potential diagnostic tool with minimal invasiveness and most importantly a direct confirmation of MTB in the pleural space However previous PCR-based methods reported suboptimal sensitivity for diagnosing TBP of about 40-80 The sensitivity may be limited by the low level of MTB cfDNA and the single-gene target IS6110 or devR in the detection With the advancement of next-generation sequencing NGS technology the detection of microbial cfDNA by metagenomic NGS mNGS has been applied in infectious disease diagnostics Chang et al have previously evaluated the use of mNGS in blood and urine samples for tuberculosis diagnostics They revealed that such methodology is limited by the low MTB concentration and the background of contaminating non-tuberculous mycobacterial NTM DNA which shares similar sequences to the pathogenic MTB
Our group has recently developed a new laboratory assay measuring the MTB cfDNA levels We hypothesise that the new MTB cfDNA assay has better diagnostic performance than conventional microbiological methods in discriminating pleural effusions due to TBP from non-TBP Since the development cohort only contains a limited number of pleural fluid samples a large-scale confirmatory study containing pleural effusions with a wide spectrum of causes is required to confirm its clinical utility before being introduced in clinical practice This study has three major aims First the diagnostic accuracy of the new MTB cfDNA assay in diagnosing TBP will be determined using a large cohort containing pleural fluid samples of various causes from countries with different TB burdens Second the clinical and laboratory factors determining the pleural fluid MTB cfDNA level will be identified Third the ability of the assay to capture different anti-TB drug-resistance genes will be explored on pleural fluid from DR-TB endemic areas
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None