Ignite Creation Date:
2024-10-26 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06646237
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-11
Brief Title:
Diagnostic Utility of Mycobacterium Tuberculosis Cell-free DNA in Hong Kong
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Liquid Biopsy by Measuring Pleural Fluid Mycobacterium Tuberculosis Cell-free DNA MTB CfDNA Level to Diagnose Tuberculous Pleuritis in a Real-world Setting
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MYDNITE-HK
Brief Summary:
Tuberculosis TB is an endemic infectious disease in Hong Kong and a global health threat Tuberculous pleuritis TBP is the most common form of extrapulmonary tuberculosis in China Its presentation is frequently non-specific and the diagnosis is challenging due to its paucibacillary nature Various studies have shown that there are limitations for conventional diagnostic modalities including low sensitivity for pleural fluid microbiological tests acid-fast bacilli AFB stain Mycobacterium tuberculosis MTB culture and MTB polymerase chain reaction PCR lack of specificity for pleural fluid biomarkers adenosine deaminase especially in low TB prevalence regions invasiveness for pleural biopsy AFB stain MTB culture and MTB PCR by bedside or pleuroscopy biopsy The diagnostic journey can be lengthy due to the long turnaround time for microbiological tests and the need for multiple invasive diagnostic procedures Therefore the diagnosis of TBP is frequently based on a composite of clinical radiological and laboratory endpoints to maximise the diagnostic yield and limit the invasiveness
The application of pleural fluid MTB cell-free DNA cfDNA as a liquid biopsy to diagnose tuberculous pleuritis has been explored Previous study groups focused on TB-specific single gene fragments revealed diagnostic sensitivity between 414 and 795 Due to the suboptimal sensitivity the clinical utility based on the previous technique was limited Our study group has developed a novel MTB cfDNA assay based on different cfDNA processing techniques and interpretation algorithms with sensitivity and specificity greater than 95 in diagnosing TBP Since the performance of this novel MTB cfDNA assay was developed based on a limited number of selected cases its clinical utility should be examined in a non-selective cohort of new-onset unilateral pleural effusion Successful validation of MTB cfDNA in pleural fluid as a liquid biopsy obtained through thoracentesis can obviate the need to perform a pleural biopsy
The application of pleural fluid MTB cell-free DNA cfDNA as a liquid biopsy to diagnose tuberculous pleuritis has been explored Previous study groups focused on TB-specific single gene fragments revealed diagnostic sensitivity between 414 and 795 Due to the suboptimal sensitivity the clinical utility based on the previous technique was limited Our study group has developed a novel MTB cfDNA assay based on different cfDNA processing techniques and interpretation algorithms with sensitivity and specificity greater than 95 in diagnosing TBP Since the performance of this novel MTB cfDNA assay was developed based on a limited number of selected cases its clinical utility should be examined in a non-selective cohort of new-onset unilateral pleural effusion Successful validation of MTB cfDNA in pleural fluid as a liquid biopsy obtained through thoracentesis can obviate the need to perform a pleural biopsy
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 Over seven million people were infected with TB in 2022 and 13 million died from the disease China is among the top three countries with the highest TB burden while Hong Kong has an intermediate burden of TB with an average of 4000 new cases per year
TB infection can cause disease of various manifestations outside the lung parenchyma in about 25 of patients extrapulmonary TB EPTB and is associated with worse treatment outcomes than pulmonary TB Tuberculous pleuritis TBP is its most prevalent form in Hong Kong and China 41 to 50 of all EPTB Although TBP can present with acute to subacute occurrence of unilateral pleural effusion breathlessness and fever its presentation is frequently non-specific Due to its clinical and epidemiological importance accurately discriminating TBP from other types of pleural effusion is crucial to shorten the diagnostic process and optimise the outcomes for these patients
Laboratory challenges for diagnosing TBP Diagnosing TBP is challenging as the disease is caused by a small number of bacteria paucibacillary nature in the pleural space which limits the diagnostic performance of various conventional diagnostic modalities These limitations include low sensitivity for pleural fluid microbiological tests acid-fast bacilli AFB stain Mycobacterium tuberculosis MTB culture and MTB polymerase chain reaction PCR and lack of specificity for pleural fluid biomarkers adenosine deaminase ADA especially in low TB prevalence regions Although the yields of MTB culture and PCR on pleural tissue are higher pleural biopsy by bedside procedure or pleuroscopy carries invasiveness and requires an additional procedure Currently no ideal test can achieve multiple diagnostic goals simultaneously including high detection sensitivity high specificity to exclude other diseases short turnaround time low invasiveness and detection of drug resistance The diagnosis of TBP is practically based on a composite of clinical radiological and laboratory endpoints The diagnosis may occasionally be established clinically without any microbiological or histological proof probable TBP
Consequences of delayed TBP diagnosis The key clinical drawbacks of difficulty in diagnosing TBP include unnecessary invasive pleural interventions and delayed initiation of curative treatment Our internal audit recently revealed that the initiation of treatment was delayed while waiting for confirmatory test results and patients required a median of one additional procedure to establish the diagnosis which included pleural biopsy with a more invasive nature These patients had long hospital stays for workups and trials of multiple antibiotics for unresolved fever Some patients may instead receive empirical anti-TB treatment based on compatible clinical presentations without confirmatory diagnostic investigation results However this is not without risk eg hepatotoxicity particularly in the elderly who are more susceptible to TBP A better diagnostic tool for TBP would mitigate these clinical challenges
Liquid biopsy in pleural effusion latest development from our group Liquid biopsy by detecting the cell-free DNA cfDNA in body fluids is a potential solution When TB bacteria die or break down the DNA fragments shed into the pleural space forming Mycobacterium tuberculosis cfDNA MTB cfDNA Detecting the MTB cfDNA in the pleural fluid can directly prove the presence of TB bacilli or their subunits in the pleural space which is an appealing option Previous studies had employed MTB cfDNA to diagnose TBP but the performance was variable Che et al first measured MTB cfDNA by detecting the IS6110 insertion sequence The sensitivity of diagnosing TBP was 750 95 confidence intervals CI 637-863 with specificity at 1000 95 CI 1000-1000 and pleural fluid MTB culture-negative cases was included in the TBP group The diagnostic sensitivity of MTB cfDNA was better than pleural fluid ADA MTB culture and MTB PCR by Xpert MTBRIF Yang et al employed the same laboratory technique and found a high diagnostic sensitivity at 966 95 CI 920-1000 in TBP cases defined by pleural fluid MTB or PCR positive status However the diagnostic sensitivity dropped to 795 95 CI 724-867 if pleural fluid MTB culture or PCR-negative cases were included in the TBP group Similar findings were also reported by Sharma et al All these study results reflected the heterogeneous diagnostic performance of MTB cfDNA A negative pleural fluid MTB culture or PCR status signifying a low bacterial load can impair the clinical utility of MTB cfDNA
Our group has recently developed a new laboratory assay measuring the MTB cfDNA levels involving targeted sequencing through a capture-probe system and novel bioinformatics algorithm The diagnostic performance remained robust even though pleural fluid MTB culture-negative cases were included which can potentially obviate another invasive diagnostic procedure
Need for a validation cohort before introducing to clinical practice Since the development cohort only contains a limited number of pleural fluid samples with definitive diagnoses the true diagnostic accuracy of the novel MTB cfDNA assay can only be determined in a prospective non-selective cohort reflecting the real-world situation which will give a realistic diagnostic performance This will confirm the clinical utility of MTB cfDNA assay before being introduced in clinical practice We hypothesise that the novel MTB cfDNA assay remains robust in a prospective cohort and outperforms previously reported methods in discriminating pleural effusions due to TBP from non-TBP
TB infection can cause disease of various manifestations outside the lung parenchyma in about 25 of patients extrapulmonary TB EPTB and is associated with worse treatment outcomes than pulmonary TB Tuberculous pleuritis TBP is its most prevalent form in Hong Kong and China 41 to 50 of all EPTB Although TBP can present with acute to subacute occurrence of unilateral pleural effusion breathlessness and fever its presentation is frequently non-specific Due to its clinical and epidemiological importance accurately discriminating TBP from other types of pleural effusion is crucial to shorten the diagnostic process and optimise the outcomes for these patients
Laboratory challenges for diagnosing TBP Diagnosing TBP is challenging as the disease is caused by a small number of bacteria paucibacillary nature in the pleural space which limits the diagnostic performance of various conventional diagnostic modalities These limitations include low sensitivity for pleural fluid microbiological tests acid-fast bacilli AFB stain Mycobacterium tuberculosis MTB culture and MTB polymerase chain reaction PCR and lack of specificity for pleural fluid biomarkers adenosine deaminase ADA especially in low TB prevalence regions Although the yields of MTB culture and PCR on pleural tissue are higher pleural biopsy by bedside procedure or pleuroscopy carries invasiveness and requires an additional procedure Currently no ideal test can achieve multiple diagnostic goals simultaneously including high detection sensitivity high specificity to exclude other diseases short turnaround time low invasiveness and detection of drug resistance The diagnosis of TBP is practically based on a composite of clinical radiological and laboratory endpoints The diagnosis may occasionally be established clinically without any microbiological or histological proof probable TBP
Consequences of delayed TBP diagnosis The key clinical drawbacks of difficulty in diagnosing TBP include unnecessary invasive pleural interventions and delayed initiation of curative treatment Our internal audit recently revealed that the initiation of treatment was delayed while waiting for confirmatory test results and patients required a median of one additional procedure to establish the diagnosis which included pleural biopsy with a more invasive nature These patients had long hospital stays for workups and trials of multiple antibiotics for unresolved fever Some patients may instead receive empirical anti-TB treatment based on compatible clinical presentations without confirmatory diagnostic investigation results However this is not without risk eg hepatotoxicity particularly in the elderly who are more susceptible to TBP A better diagnostic tool for TBP would mitigate these clinical challenges
Liquid biopsy in pleural effusion latest development from our group Liquid biopsy by detecting the cell-free DNA cfDNA in body fluids is a potential solution When TB bacteria die or break down the DNA fragments shed into the pleural space forming Mycobacterium tuberculosis cfDNA MTB cfDNA Detecting the MTB cfDNA in the pleural fluid can directly prove the presence of TB bacilli or their subunits in the pleural space which is an appealing option Previous studies had employed MTB cfDNA to diagnose TBP but the performance was variable Che et al first measured MTB cfDNA by detecting the IS6110 insertion sequence The sensitivity of diagnosing TBP was 750 95 confidence intervals CI 637-863 with specificity at 1000 95 CI 1000-1000 and pleural fluid MTB culture-negative cases was included in the TBP group The diagnostic sensitivity of MTB cfDNA was better than pleural fluid ADA MTB culture and MTB PCR by Xpert MTBRIF Yang et al employed the same laboratory technique and found a high diagnostic sensitivity at 966 95 CI 920-1000 in TBP cases defined by pleural fluid MTB or PCR positive status However the diagnostic sensitivity dropped to 795 95 CI 724-867 if pleural fluid MTB culture or PCR-negative cases were included in the TBP group Similar findings were also reported by Sharma et al All these study results reflected the heterogeneous diagnostic performance of MTB cfDNA A negative pleural fluid MTB culture or PCR status signifying a low bacterial load can impair the clinical utility of MTB cfDNA
Our group has recently developed a new laboratory assay measuring the MTB cfDNA levels involving targeted sequencing through a capture-probe system and novel bioinformatics algorithm The diagnostic performance remained robust even though pleural fluid MTB culture-negative cases were included which can potentially obviate another invasive diagnostic procedure
Need for a validation cohort before introducing to clinical practice Since the development cohort only contains a limited number of pleural fluid samples with definitive diagnoses the true diagnostic accuracy of the novel MTB cfDNA assay can only be determined in a prospective non-selective cohort reflecting the real-world situation which will give a realistic diagnostic performance This will confirm the clinical utility of MTB cfDNA assay before being introduced in clinical practice We hypothesise that the novel MTB cfDNA assay remains robust in a prospective cohort and outperforms previously reported methods in discriminating pleural effusions due to TBP from non-TBP
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None