Diagnostic accuracy of chest ultrasound scan in the diagnosis of childhood tuberculosis

Geoffrey Erem; Caroline Otike; Maxwell Okuja; Faith Ameda; Dorothy Irene Nalyweyiso; Aloysius Gonzaga Mubuuke; Michael Kakinda

doi:10.1371/journal.pone.0287621

Peer Review History

Original SubmissionJune 16, 2023
17 Jul 2023 Decision Letter - Mao-Shui Wang, Editor PONE-D-23-17231Diagnostic accuracy of chest ultrasound scan in the diagnosis of childhood tuberculosisPLOS ONE Dear Dr. Erem, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Aug 31 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors describe the performance of point of care ultrasound for the diagnosis of pulmonary tuberculosis in children in a high burden country. Although not totally new, this data adds to the body of evidence for POCUS showing it is feasible and possibly replacing CXR in resource limited settings. However, neither CXR nor POCUS alone are able to diagnose TB in children as thee major manifestation is lymphadenopathy that is not specific for TB, therefore without bacterial confirmation of M.tb, there are some difficulties in calculating sensitivity of this diagnostic tool. - Line 50: introduce alle introduction, e.g. CXR chest X-ray - Line 67/68: add reference for studies - There already exists a body of evidence for chest ultrasound for paediatric TB also from low-income countries. An overeview can be found: Ruby, L. C., Heuvelings, C. C., Grobusch, M. P., Andronikou, S., & Bélard, S. (2022). Transthoracic mediastinal ultrasound in childhood tuberculosis: A review. Paediatric respiratory reviews, 41, 40–48. https://doi.org/10.1016/j.prrv.2020.11.002: Pediatr Pulmonol - Line 80: does this only refer to pulmonary TB or all TB manifestations? Please specify - Line 101: Sentence is incomplete - Table between line 146/147: insert caption, lowercase all letters - Line 121: Please specify what criteria were used on ultrasound and CXR to classify findings as TB likely or TB unlikely (e.g. consolidation could also be pneumonia) - Line 196-198 please reword sentence - Line 200: a definite TB diagnosis cannot be made by CXR and clinical symptoms, and therefore a sensitivity or specificity for diagnosis of TB not be calculated unless further testing is available. How is the diagnosis of TB supported? Were any immunological tests performed? Was there any other evidence of M. tb from sputum/Stool/nasopharyngeal aspirate….? I suggest to compare pathological findings detected by POCUS versus CXR instead of sensitivities. Reviewer #2: This is a well-constructed manuscript that gives insights into the use of CUS for TB and hopefully moves the field towards its integration into standard clinical care. The study had a clearly defined question, with assessments of the index and reference tests being independent and blinded. Furthermore, the tests were done on an appropriate spectrum of patients with all patients receiving the same reference test. The study used appropriate statistical methods and measures to report the study. The data suggests that CUS is just as useful as CXR. However, my main concern is that they did not confirm the disease in children found to have TB on CUS. Minor comments Line 50: Define CXR at first use. Line 79: pediatric tuberculosis should read pediatric TB to maintain consistence in the use of the abbreviation “TB”. Line 85: 2weeks weeks – repeated word Line 88: Pulmonary Tuberculosis (PTB). This is already defined on line 51. Include a STARD checklist ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. 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Revision 1
11 Aug 2023 Author Response Response to the Editors 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We thank the editor for this comment. We have edited the manuscript to ensure that it meets the PLOS ONE style requirements. 2. Thank you for stating the following financial disclosure: The authors received no specific funding for this work. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. We thank the editor for this reminder. We have deleted the Ethics and approval and consent to participate under Declarations. Which were previously lines 255-262. Response to the Reviewers Response to Reviewer 1 The authors describe the performance of point of care ultrasound for the diagnosis of pulmonary tuberculosis in children in a high burden country. Although not totally new, this data adds to the body of evidence for POCUS showing it is feasible and possibly replacing CXR in resource limited settings. We thank the reviewer for this compliment. However, neither CXR nor POCUS alone are able to diagnose TB in children as thee major manifestation is lymphadenopathy that is not specific for TB, therefore without bacterial confirmation of M.tb, there are some difficulties in calculating sensitivity of this diagnostic tool. We expected the reviewer to raise this comment. Bacterial confirmation for Childhood TB is an exception not the rule. Data from an operational setting has found that only 10% of childhood TB was confirmed using GeneXpert MTB/RIF Ultra and Culture is likely to miss up to half of the TB cases. Because of this there was a consensus agreement on a clinical case definition for classification of Intrathoracic Tuberculosis in Children. https://doi.org/10.1093%2Fcid%2Fciv581 The use of CXR or POCUS falls under Unconfirmed Tuberculosis using symptoms/signs suggestive of TB, and chest radiograph consistent with TB with both required to make a diagnosis of unconfirmed TB. We are trying to extend this to include findings on CUS. To find the diagnostic accuracy we would ideally need to compare the persons presumed to have TB on CUS compared to a Composite Reference Standard (CRS) given that there is no perfect reference standard for Childhood TB. Using other modalities that can diagnose TB like Culture, GeneXpert MTB/RIF Ultra, CXR and probably response to treatment. Using the AND/OR rule, so found with TB on Culture OR GeneXpert OR findings on CXR OR response to treatment. However, our study was not set up to use the CRS. Another possible alternative is the use of a correction method, as suggested by Staquet et al., which was deemed to be the most accurate in the literature. https://doi.org/10.1186/s12874-021-01255-4 Using CXR as a Reference Standard albeit an imperfect one, to get the diagnostic accuracy of CUS. - Line 50: Introduce an alle introduction, for example, CXR chest X-ray We thank the reviewer for pointing this out. We have introduced CXR in full and the sentence now reads as follows...” Hence Chest X-ray (CXR) is often used alongside clinical symptoms to make presumptive diagnosis of Pulmonary Tuberculosis (PTB) in the absence of bacteriological confirmation” ... - Line 67/68: add reference for studies We have added a citation describing a systematic review of the diagnostic accuracy of point-of-care ultrasound for pulmonary tuberculosis. https://doi.org/10.1371/journal.pone.0251236. This includes all studies conducted on the subject for both children and adults. - There already exists a body of evidence for chest ultrasound for paediatric TB also from low-income countries. An overeview can be found: Ruby, L. C., Heuvelings, C. C., Grobusch, M. P., Andronikou, S., & Bélard, S. (2022). Transthoracic mediastinal ultrasound in childhood tuberculosis: A review. Paediatric respiratory reviews, 41, 40–48. https://doi.org/10.1016/j.prrv.2020.11.002: Pediatr Pulmonol We have extensively reviewed the article suggested by the reviewer. Whilst we set out to find the diagnostic accuracy of Chest Ultrasound Scan for Childhood PTB, the suggested article was a review of transthoracic mediastinal ultrasound in childhood Tuberculosis. However, mediastinal lymph nodes could be pathognomonic of Tuberculosis in children. They could also be available in other diseases, and we used the availability of lymph nodes, consolidations, and effusions. - Line 80: does this only refer to pulmonary TB or all TB manifestations? Please specify We have clarified whether it is PTB or both PTB and extra-pulmonary TB. The statement on line 80 now reads as follows “On average, 12 children were diagnosed with TB (both pulmonary TB and extra-pulmonary TB) monthly’... - Line 101: Sentence is incomplete. We thank the reviewer for pointing this out. We have re-edited the sentence to read as follows...” A sample size of 80 participants was considered for this study” ... - Table between line 146/147: insert caption, lowercase all letters We have re-written the letters to all lowercase letters. - Line 121: Please specify what criteria were used on ultrasound and CXR to classify findings as TB likely or TB unlikely (e.g. consolidation could also be pneumonia) On CUS, the radiologists examined for pleural effusions, an increased pleural gap, an interrupted pleural line, greater than 3-B lines, lymph nodes, consolidation, and pericardial effusion. These were all suggestive of PTB but, the location, size and number of features are either suggestive of TB or not. Hence the classification by radiologists as either TB or not While on CXR, the radiologist looked out for consolidations, nodular opacities, hilar or paratracheal nodes and pleural effusions. The size, location and combination of features were used by the radiologist to determine whether TB was likely or unlikely. - Line 196-198 please reword sentence We have re-written line 196-198 to read as follows,” However, there was a disagreement between the two modalities on 24 children. Twenty children were found likely to have TB on CUS but not on CXR. While the reverse was true for four children (CXR found them likely to have TB but not CUS)” .... - Line 200: a definite TB diagnosis cannot be made by CXR and clinical symptoms, and therefore a sensitivity or specificity for diagnosis of TB not be calculated unless further testing is available. How is the diagnosis of TB supported? Were any immunological tests performed? Was there any other evidence of M. tb from sputum/Stool/nasopharyngeal aspirate….? I suggest comparing pathological findings detected by POCUS versus CXR instead of sensitivities. We thank the reviewer for this suggestion. We have a pre-print which compares the findings on https://doi.org/10.21203/rs.3.rs-2994488/v1. However, for this paper we set out to Diagnostic Test Accuracy of CUS for childhood TB. The processes and explanations have been provided above. Reviewer 2 Line 50: Define CXR at first use. We thank the reviewer for pointing out this omission, the same omission was raised by Reviewer 1 and it was fixed. Line 79: pediatric tuberculosis should read pediatric TB to maintain consistence in the use of the abbreviation “TB”. We have made this change as suggested by the reviewer. Line 85: 2weeks weeks – repeated word We thank the reviewer for this observation. We have deleted the repeated word. Line 88: Pulmonary Tuberculosis (PTB). This is already defined on line 51. We have used PTB, to ensure that there is consistency. Include a STARD checklist. We thank the Reviewer for this comment. We have included having used the STARD Checklist in reporting our results. The statement reads as follows:” We report our findings in accordance with ‘The Standards for Reporting of Diagnostic Accuracy Studies” (STARD) statement [20]’’. Attachments Attachment Submitted filename: Response to Editor and Reviewers Comments PLOSOne.pdf https://doi.org/10.1371/journal.pone.0287621.r002
1 Sep 2023 Decision Letter - Mao-Shui Wang, Editor Diagnostic accuracy of chest ultrasound scan in the diagnosis of childhood tuberculosis PONE-D-23-17231R1 Dear Dr. Erem, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Mao-Shui Wang Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: Yes: Dr Humphrey Mulenga ******** https://doi.org/10.1371/journal.pone.0287621.r003
Formally Accepted
11 Sep 2023 Acceptance Letter - Mao-Shui Wang, Editor PONE-D-23-17231R1 Diagnostic accuracy of chest ultrasound scan in the diagnosis of childhood tuberculosis Dear Dr. Erem: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Mao-Shui Wang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0287621.r004

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