Diagnostic limitations of clinical case definitions of pertussis in infants and children with severe lower respiratory tract infection

Rudzani Muloiwa; Mark P. Nicol; Gregory D. Hussey; Heather J. Zar

doi:10.1371/journal.pone.0235703

Peer Review History

Original SubmissionFebruary 9, 2020
24 Apr 2020 Decision Letter - Daniela Flavia Hozbor, Editor PONE-D-20-03797 Diagnostic limitations of clinical case definitions of pertussis in infants and children with severe lower respiratory tract infection PLOS ONE Dear Dr Rudzani Muloiwa, 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. We would appreciate receiving your revised manuscript by May 2. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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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: Yes 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript addresses a topic that has been widely covered but with no final conclusions. I am referring to the difficulties encountered with the clinical diagnosis of pertussis. Even without providing a solution to these difficulties, it brings an interesting analysis of them. The manuscript is correctly written, it is easy to read, methods are clearly described and the results are easily visualized. The conclusions are correctly based on the results and I especially highlight the good analysis of the limitations of the paper. Reviewer #2: The main aim of the manuscript is to propose an improvement to the GPI (Global Pertussis Initiative) experts pertussis case definition to increase the sensitivity and specificity and though enhancing pertussis surveillance and diagnosis in low and middle-income countries which lack resources for laboratory confirmation of pertussis cases. Clinical case definitions with higher sensibilities are specially useful and important to change for countries other than developed ones. Comparison with WHO clinical case definition is also included. This prospective study analyzes clinical symptoms along with pertussis specific PCR confirmatory results in two groups of children under 9 years of age (0 - 3 months and 4 months to 9 years) diagnosed with severe lower tract respiratory infection or apnea. Since GPI clinical case definition does not include for these age groups a duration of coughing, the authors demonstrate a the better accuracy in pertussis diagnosis using GPI clinical case definition that incorporates a duration from 5 to 7 days of cough. To my opinion the authors conclusions and proposal should strictly be mentioned to be used for children admitted to hospital facilities with severe low respiratory tract infections or apnea. This should be reflected along the conclusion section e.g. modify lines 268-72. Although clarified in lines 313-15 it should be highlighted before. It would be nice to include WHO definition for severe lower tract infections for readers who are not clinicians or pediatricians (does it includes pneumonia and bronchitis?). Specially in the context of classical pertussis clinical presentation I wonder the impact of the proposal in regions where pertussis cases present with upper respiratory tract infection. Is this a situation possibly being observed in low and middle-income countries? Line 81: direct fluorescent antigen testing is no longer recommended for laboratory confirmation Line 101: was the time of patients enrollment an outbreak year? please clarify - Was there an exclusion criteria for patients enrollment used? please clarify Lines 118-21: english should be improved. Line 123: reference 12 refers to the use of cotton swabs for Bordetella pertussis culture. Since B. pertussis growth is inhibited by long chain fatty acids present in cotton, it may be possible that positivity by culture is low because of this reason. What kind of swabs do you use? Lines 252-60: I suggest to add a connection sentence with the idea behind this evidence supporting the importance of your results. Line 262: duration is referred to cough duration please clarify Lines 274-84: What is the idea behind incorporating references 17,18 and 19? Is it to include other age groups with higher specificities and sensibilities? is that used for comparison purposes? 282-84: why do authors suggest that? please clarify ****** 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. If you choose “no”, your identity will remain anonymous but your review may still be made public. 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Revision 1
3 Jun 2020 Author Response Reviewer's comments NB. Due to a well-known Microsoft Word glitch, some line numbers are ‘lost’, skipped at the start of new pages in the tracked document. This has led to different numbering between the tracked and untracked documents. The line numbers referring to the changes made are those of the untracked document. Reviewer #1: Reviewer #1 comment 1: The manuscript addresses a topic that has been widely covered but with no final conclusions. I am referring to the difficulties encountered with the clinical diagnosis of pertussis. Even without providing a solution to these difficulties, it brings an interesting analysis of them. The manuscript is correctly written, it is easy to read, methods are clearly described, and the results are easily visualized. The conclusions are correctly based on the results and I especially highlight the good analysis of the limitations of the paper. Response to reviewer #1 comment 1 Thank you for your encouraging comment. We really appreciate it. Reviewer #2: Reviewer #2 comment 1: The main aim of the manuscript is to propose an improvement to the GPI (Global Pertussis Initiative) experts pertussis case definition to increase the sensitivity and specificity and though enhancing pertussis surveillance and diagnosis in low and middle-income countries which lack resources for laboratory confirmation of pertussis cases. Clinical case definitions with higher sensibilities are especially useful and important to change for countries other than developed ones. Comparison with WHO clinical case definition is also included. This prospective study analyzes clinical symptoms along with pertussis specific PCR confirmatory results in two groups of children under 9 years of age (0 - 3 months and 4 months to 9 years) diagnosed with severe lower tract respiratory infection or apnea. Since GPI clinical case definition does not include for these age groups a duration of coughing, the authors demonstrate a the better accuracy in pertussis diagnosis using GPI clinical case definition that incorporates a duration from 5 to 7 days of cough. To my opinion the authors conclusions and proposal should strictly be mentioned to be used for children admitted to hospital facilities with severe low respiratory tract infections or apnea. This should be reflected along the conclusion section e.g. modify lines 268-72. Although clarified in lines 313-15 it should be highlighted before. Response to reviewer #2 comment 1: Thank you for this comment. We appreciate it and are greatly encouraged. To address the specific issue of highlighting the current population, an amendment has been made on lines xx to xx. The section now reads, “This suggests that suspected cases of pertussis, in children hospitalized with LRTI or apnea, are more likely to be correctly classified as positive or negative in children with this symptom duration.” Line 273 Reviewer #2 comment 2: It would be nice to include WHO definition for severe lower tract infections for readers who are not clinicians or pediatricians (does it includes pneumonia and bronchitis?). Response to reviewer #2 comment 2: We have included the WHO definition we used and added a reference. The modified section in Material and Methods now reads, “Children were included if they presented with WHO defined severe LRTI (cough or difficulty breathing and age specific tachypnoea plus chest indrawing and/or presence of any danger sign necessitating hospital admission) or apnea after written informed consent was received from the parent or legal guardian” [12] Lines 103 – 104 A reference [Lines 399 – 400] has also been added: 12. Handbook: integrated management of childhood illnesses. Geneva: World Health Organization; 2005. Please note that these criteria for classifying severity have since undergone further modification. Reviewer #2 comment 3: Specially in the context of classical pertussis clinical presentation I wonder the impact of the proposal in regions where pertussis cases present with upper respiratory tract infection. Is this a situation possibly being observed in low and middle-income countries? Response to reviewer #2 comment 3: Thank you for the comment. Mild cases have indeed been observed, for example as seen in surveillance data from acute influenza-like illnesses. For this study we wanted to see how diagnostic criteria hold in the case of severe cases – the sort of cases that lead to more resources being required and in which deaths are a potential outcome. We have noted this as a limitation of our study by stating, “In addition, as our study population consisted of children with severe disease requiring hospitalization, these findings may not be generalizable to children with less severe disease.” Lines 317 – 319 Reviewer #2 comment 4: Line 81: direct fluorescent antigen testing is no longer recommended for laboratory confirmation Response to reviewer #2 comment 4: Thank you for pointing this out. The reference to direct fluorescent antigen has been removed. The sentence now reads, “Although culture and ELISA can be used to confirm pertussis, polymerase chain reaction (PCR) has gained favor as the most practical confirmatory method with an acceptable level of sensitivity and specificity.[7, 8]” Lines 81 – 83 Reviewer #2 comment 5: Line 101: was the time of patients enrollment an outbreak year? please clarify Response to reviewer #2 comment 5: The year was not an outbreak year. We have added a section to clarify this. Line xx now reads, “Here we investigate the sensitivity and specificity, in a non-outbreak setting, of clinical criteria recommended by WHO and GPI to diagnose pertussis with PCR as the diagnostic reference standard, in a LMIC.” Lines 92 – 94 Reviewer #2 comment 6: Was there an exclusion criteria for patients enrollment used? please clarify Response to reviewer #2 comment 6: Thank you for pointing this out. We have amended the section to make explicit our exclusion criteria by stating, “Participants were excluded if they had been admitted in a health care facility in the preceding two weeks, or if a legal guardian was not available to sign consent.” Lines 106 – 107 Reviewer #2 comment 7: Lines 118-21: English should be improved. Response to reviewer #2 comment 7: After rereading the section, we can see the ambiguity created by our use of language. The sentence has been broken into two to improve clarity. The section now reads, “PCR targeting the IS481 common Bordetella insertion site and IS1001 for Bordetella parapertussis was done. Specimens testing positive for IS481were further tested with PCR for hIS1001 to exclude Bordetella holmesii which shares the same IS481 insertion site.” Lines 121 – 123 Reviewer #2 comment 8: Line 123: reference 12 refers to the use of cotton swabs for Bordetella pertussis culture. Since B. pertussis growth is inhibited by long chain fatty acids present in cotton, it may be possible that positivity by culture is low because of this reason. What kind of swabs do you use? Response to reviewer #2 comment 8: We use rayon and Dacron swabs in our setting, this study used the latter. Although we agree that the type of swab could impact on culture yield, we think that the quality of the swabs would not have increased the detection rate to exceed that of PCR, hence our adoption of PCR as the reference standard. Reviewer #2 comment 9: Lines 252-60: I suggest to add a connection sentence with the idea behind this evidence supporting the importance of your results. Response to reviewer #2 comment 9: Thank you for this advice. In order to relate our study to the previous section, we have added the following sentence, “Our study with its best likelihood ratios of four and five for WHO and GPI criteria, respectively, still fell short of ratios of at least 10, that would be required for a useful clinical diagnostic tool.[15]” Lines 261 – 263 The reference at the end of the sentence has already been used previously in the text: 15. Cornia PB, Lipsky BA. Symptoms Associated With Pertussis Are Insufficient to Rule In or Rule Out the Diagnosis. Chest. 2019;155(2):449-50. Epub 2019/02/09. doi: 10.1016/j.chest.2018.10.028. PubMed PMID: 30732694. Lines 409 – 411 Reviewer #2 comment 10: Line 262: duration is referred to cough duration please clarify Response to reviewer #2 comment 10: Thank you for pointing this omission out. We have clarified this by adding the word ‘cough’. The sentence now reads, “In our study, when duration of cough was added to the other clinical features, …” Line 265 Reviewer #2 comment 11: What is the idea behind incorporating references 17,18 and 19? Is it to include other age groups with higher specificities and sensibilities? is that used for comparison purposes? 282-84: why do authors suggest that? please clarify Response to reviewer #2 comment 11: The three references were included to demonstrate the difficulty consistently encountered of having to make very ‘expensive’ trade-offs between sensitivity and specificity, a pattern that we also observed in our study. The following line has been added to clarify this, “For each clinical feature evaluated, there was an inverse relationship between sensitivity and specificity; a pattern we observed throughout the current study.” Lines 284 – 285 With the lines highlighted above (282-284) we wanted to show that when cases are preselected to undergo a laboratory confirmatory test using clinical features that are in keeping with pertussis when the same laboratory test is used also as gold standard to test ‘sensitivity’ of the same features, it should not be surprising to have an observation of higher sensitivity than in studies such as ours, in which cases are not similarly preselected on clinical suspicion of pertussis. We have amended the sentence to clarify this, “Unlike in our study, the three studies mentioned here seem to have selected participants on the bases of pertussis clinical criteria some of which were later tested for their sensitivity, which may explain the high sensitivity reported in some of them.” Lines 285 – 288 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0235703.r002
22 Jun 2020 Decision Letter - Daniela Flavia Hozbor, Editor Diagnostic limitations of clinical case definitions of pertussis in infants and children with severe lower respiratory tract infection PONE-D-20-03797R1 Dear Dr. Rudzani Muloiwa, 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, Daniela Flavia Hozbor Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0235703.r003
Formally Accepted
6 Jul 2020 Acceptance Letter - Daniela Flavia Hozbor, Editor PONE-D-20-03797R1 Diagnostic limitations of clinical case definitions of pertussis in infants and children with severe lower respiratory tract infection Dear Dr. Muloiwa: 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. Daniela Flavia Hozbor Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0235703.r004

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