A case of pleural Mycobacterium tuberculosis infection with reversion of Quantiferon Gold Plus results from positive to negative
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Introduction. Mycobacterium tuberculosis (MTB) infections continue to have a high mortality and morbidity burden globally. Interferon-gamma release assays such as Quantiferon Gold Plus (QFG-Plus) aid in diagnosis of latent TB but diagnosis of pleural TB remains challenging. We present a case of active pleural MTB infection with reversion from positive to negative of IGRA result as well as negative Xpert MTB/RIF Ultra PCR result from tissues obtained from pleural biopsy.
Case summary. A 52-year-old otherwise healthy male presented in August 2022 with a 2 week history of pleuritic chest pain associated with modest elevation in inflammatory markers. The patient had had a positive QFG-Plus result in 2018, however QFG-Plus during this admission was negative. Computed-tomography pulmonary angiogram and needle thoracocentesis showed an exudative left pleural effusion with predominant lymphocytes. The patient’s symptoms failed to resolve with empiric antimicrobial therapy for community-acquired pneumonia. Broncho-alveolar lavage as well as biopsies of pleural tissues via video-assisted thoracoscopic surgery from the left lower lobe yielded negative results on routine microbiological culture as well as Xpert Ultra PCR. Growth of acid-fast bacilli was noted from mycobacterial cultures of pleural tissues which was identified as MTB.
Conclusion. Despite significant technological advances, microbiological diagnosis of MTB infections remains challenging. We document QFG-Plus reversion during development from latent to active pleural TB. Decline in the ability of CD4 + and CD8 + T cells to produce interferon gamma in response to TB antigens (ESAT-6 and CFP-10) was likely associated with loss of host control of latent MTB. This case serves as a reminder that despite exhaustive testing with state-of-art diagnostic platforms, MTB infections can still elude discovery.
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I am pleased to tell you that your article has now been accepted for publication in Access Microbiology. The work presented is clear and the arguments well formed. The manuscript is well written and contributes to the literature. Thank you for addressing all reviewers comments satisfactorily and in a timely manner.
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Thank you for submitting your manuscript for publication in Access Microbiology. It has been examined by expert reviewers who have concluded that the work is of potential interest to the readership of Access Microbiology. However, based on the comments received, it is clear that a major revision of this manuscript will be required before a decision can be made on its publication. I will be pleased to consider a revised manuscript along with a document including a point by point response to each of the reviewers comments. Your revised manuscript may be returned to one or more of the original reviewers, along with your itemised response to the reviewers’ comments.
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Comments to Author
The case studies presented examine a single subject of analysis, but there is a lack of a comparative investigation to elucidate relationships between two or more subjects. The manuscript does not address the use of the Quantiferon Gold test for latent TB diagnosis. In 2018, the test yielded positive results but was seemingly disregarded. Was there consideration for initiating LTBI treatment regimens, such as once-weekly isoniazid plus rifapentine for 3 months, daily rifampin for 4 months, daily isoniazid plus rifampin for 3-4 months, or daily isoniazid for 6-9 months? Given the findings on parietal pleura, the patient was initiated on standard first-line anti-mycobacterial treatment, indicating a clinical diagnosis. Further clarification regarding this diagnostic process is needed. There is an …
Comments to Author
The case studies presented examine a single subject of analysis, but there is a lack of a comparative investigation to elucidate relationships between two or more subjects. The manuscript does not address the use of the Quantiferon Gold test for latent TB diagnosis. In 2018, the test yielded positive results but was seemingly disregarded. Was there consideration for initiating LTBI treatment regimens, such as once-weekly isoniazid plus rifapentine for 3 months, daily rifampin for 4 months, daily isoniazid plus rifampin for 3-4 months, or daily isoniazid for 6-9 months? Given the findings on parietal pleura, the patient was initiated on standard first-line anti-mycobacterial treatment, indicating a clinical diagnosis. Further clarification regarding this diagnostic process is needed. There is an inconsistency regarding MTB detection. While Line 129 reports negative MTB detection by BAL and pleural tissue on Xpert Ultra, subsequent paragraphs (Line 135) indicate a positive result with Xpert Ultra on pleural tissue and positive MTB culture. This discrepancy raises questions about the reliability of TB culture versus PCR-based diagnosis. If Xpert ultra also came positive in such case why it would be recommended to wait for TB culture results. Stool-based diagnosis for pleural TB has demonstrated positive results on GeneXpert and Xpert Ultra. WHO recommends Xpert testing of stool specimens as a primary diagnostic test for children with symptoms of TB, but such non-invasive specimen can be tested along with clinical findings.
Please rate the quality of the presentation and structure of the manuscript
Satisfactory
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
This study is informative but it needed to improve the grammatical abbreviation mistakes in the whole manuscript, especially the abstract, introduction, discussion part. Add 5-6 latest references in the present study, which are correlated with the present data. Comment 1: Line 67-68: Write the keywords (3-5 words) most commonly used in manuscript and alphabetically order as: IGRA; Quantiferon Gold; Mycobacterium tuberculosis; PCR; Pleural TB; Reversion. Author response: Comment 2: The title of manuscript does not provide accurate information and it will be modified as: "Pleural tuberculosis diagnosis by IGRA: A case report" Or "Quantiferon Gold Plus assay detect Mycobacterium tuberculosis in Pleural-TB: A case report" Or "A case report of Pleural tuberculosis diagnosis by Quantiferon Gold Plus …
Comments to Author
This study is informative but it needed to improve the grammatical abbreviation mistakes in the whole manuscript, especially the abstract, introduction, discussion part. Add 5-6 latest references in the present study, which are correlated with the present data. Comment 1: Line 67-68: Write the keywords (3-5 words) most commonly used in manuscript and alphabetically order as: IGRA; Quantiferon Gold; Mycobacterium tuberculosis; PCR; Pleural TB; Reversion. Author response: Comment 2: The title of manuscript does not provide accurate information and it will be modified as: "Pleural tuberculosis diagnosis by IGRA: A case report" Or "Quantiferon Gold Plus assay detect Mycobacterium tuberculosis in Pleural-TB: A case report" Or "A case report of Pleural tuberculosis diagnosis by Quantiferon Gold Plus assay" Author response: Comment 3: Line 46: Interferon-Gamma Release Assay is abbreviated IGRA instead of Interferon-Gamma Release Assays. Author response: Comment 4: Line 53: Quantiferon Gold Plus is abbreviated as QFT-Plus but you abbreviate QFG-Plus in line 53. Author response: Comment 5: Line 63-64: Decline in the ability of CD4 and CD8 T cells to produce interferon gamma in response to TB antigens (mentioned antigens name) was associated with loss of host control of latent MTB. For your accuracy of data, which antigens play a major role in the IGRA test?. Author response: Comment 6: What are the limitations of your present study? Author response: Comment 7: Line 78: Purified Protein Derivative is abbreviated as PDD instead of Purified Protein Derivatives. Author response: Comment 8: Line 79-80: Correct the Quantiferon-Gold and Quantferon-Gold Plus abbreviation as QFG-Gold and QFG-Gold Plus or QFT-Gold and QFT-Gold Plus, respectively. Author response: Comment 9: Line 95-96: Although Australia falls outside of global hotspots or high incidence zones for MTB, an estimated 1500 people are diagnosed with TB each year, with Victoria accounting for about 450 to 500 of these cases (2). You work on pleural tuberculosis as suggested in your title but where are you introduced about Pleural TB? Write a short not on pleural TB? I have attached same pleural TB references as: Insight into diagnosis of pleural tuberculosis with special focus on nucleic acid amplification tests. Expert Review of Respiratory Medicine. https://doi.org/10.1080/17476348.2022.2093189 Diagnosis of pleural tuberculosis by multi-targeted loop-mediated isothermal amplification assay based on SYBR Green I reaction: comparison with GeneXpert® MTB/RIF assay. Expert Review of Respiratory Medicine. https://doi.org/10.1080/17476348.2023.2292738 Author response: Comment 10: Line 132-134: Histopathological analysis of pleural tissue showed granulomatous inflammation, with lesions composed of epithelioid histiocytes, Langhans-type giant cells surrounded by cuffs of lymphocytes arranged within fibrous stroma. Granulomas also exhibited central necrosis (Figure 2). What are the drawbacks of Histopathological examination, in EPTB including Pleural TB? Add some interesting line as: Conversely, histology does not distinguish between EPTB including Pleural TB/OATB and the other granulomatous diseases such as sarcoidosis, systemic lupus erythematosus, etc., except for the presence of acid-fast bacilli (AFB) by Ziehl-Neelsen (ZN) staining. Bacteriological examination by both smear microscopy and culture lack sensitivity for diagnosing EPTB including Pleural TB/OATB, owing to paucibacillary nature of specimens. Moreover, culture identification for Mycobacterium tuberculosis (Mtb) on Lowenstein-Jensen (LJ) medium has a prolonged turnaround time of 4-8 weeks and requires skillful technicians that causes a significant delay in treatment (Khan et al. 2021). Diagnosis of osteoarticular tuberculosis: multi-targeted loop-mediated isothermal amplification assay versus multiplex PCR. Future Microbiology. https://doi.org/10.2217/fmb-2021-0030 Author response: Comment 11: Line 203-205: Our case presented an interesting scenario where the extra-pulmonary (parietal pleura) manifestation of MTB was not detected by PCR on biopsies of the lesions, and yet had a positive histopathology finding and eventually a positive mycobacterial culture. PCR and LAMP are alternative good NAATs to detect EPTB types such pleural TB. Why not use PCR and LAMP assay in the present study? Author response: Comment 12: You could not perform the PCR technique for your study so discus some important drawbacks of PCR in your manuscript and quotes latest reference as: "Diagnosis of osteoarticular tuberculosis: multi-targeted loop-mediated isothermal amplification assay versus multiplex PCR" Future Microbiology (2021). https://doi.org/10.2217/fmb-2021-0030 Author response: Comment 13: Line 137-138: Xpert Ultra was positive for MTB and negative for the rpoB gene mutation. What is the main difference between GeneXpert MTB/RIF and GeneXpert MTB/RIF Ultra assays? Add 1-2 line about GeneXpert MTB/RIF and GeneXpert MTB/RIF Ultra assays as: GeneXpertMTB/RIF assay, an automated cartridge-based seminested real-time PCR employing rpoB (Rv0664), is leading innovation in TB diagnostics, which concomitantly detects Mtb and rifampicin resistance within 2 h but its utility to detect EPTB specimens remains elusive, since variable sensitivities are obtained in different laboratories (Khan et al., 2022). GeneXpert® MTB/RIF Ultra is a fully nested real-time PCR targeting IS6110, IS1081 and rpoB, which is utilized for detecting Mtb and rifampicin resistance within 80 min (Dahiya et al., 2023). Diagnosis of osteoarticular tuberculosis by immuno‐PCR assay based on mycobacterial antigen 85 complex detection. Letters in Applied Microbiology. https://doi.org/10.1111/lam.13567 Diagnosis of extrapulmonary tuberculosis by GeneXpert MTB/RIF Ultra assay. Expert Review of Molecular Diagnostics. https://doi.org/10.1080/14737159.2023.2223980 Author response: Comment 14: Line 148-149: WHO has recommended the Xpert Ultra assay for diagnosis of TB from extra pulmonary TB samples (mentioned the particular TB names), children and HIV infected patients and on pleural fluid or biopsy. Which EPTB samples are diagnosed by Xpert Ultra assay and by and recommended by WHO?. Comment 15: Lines 136-137: Which one mycobacterial culture (i.e. MGIT-960 or 460 in) is used for Mtb detection the present study? Author response: Comment 16: What is the limitation of IGRA assay? Author response: Comment 17: Lines 145-147: Per WHO definitions, pleural TB is considered as extra pulmonary rather than pulmonary TB. Pleural biopsy rather than pleural fluid is the specimen of choice for diagnosis; for pleural fluid, Xpert Ultra has sensitivities under 50%, but high sensitivities approaching 100% for pleural biopsy. Which types of fluids are used for Mtb detection in present study by CBNAAT (i.e. GeneXpert or GeneXpert Ultra)?. Author response: Comment 18: Lines 196-199: Cases of negative IGRA and PCR results with positive culture have previously been reported in the literature, particularly from high prevalence settings. The gold standard remains mycobacterial culture. In addition, higher mortality is noted in MTB patients where IGRA is negative, owing mostly to delayed therapeutic interventions (18). Some previous studies also discuss in your manuscripts, which are more related to pleural TB as: Interferon gamma release assays for diagnosis of pleural tuberculosis: a systematic review and meta-analysis. Journal of Clinical Microbiology. https://doi.org/10.1128/jcm.00823-15 Evaluating pleural ADA, ADA2, IFN-γ and IGRA for diagnosing tuberculous pleurisy. Journal of Infection https://doi.org/10.1016/j.jinf.2013.05.009 The tuberculous pleural effusion. Breathe https://doi.org/10.1183/20734735.0143-2023 To add the latest references in your manuscript for accuracy of your data with the previous report on pleural TB. Author response: Comment 19: How are your results of study different from other already published studies on pleural TB? Author response: Comment 20: Clayton is a suburb located near south-east of Melbourne's Central Business District within the City of Monash local government area at Victoria, Australia. So, what is the prevalence rate of pleural TB at Clayton, Victoria-Australia? Author response:
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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