Parainfluenza virus infections in patients with hematological malignancies or stem cell transplantation: Analysis of clinical characteristics, nosocomial transmission and viral shedding

Julia Tabatabai; Paul Schnitzler; Christiane Prifert; Martin Schiller; Benedikt Weissbrich; Marie von Lilienfeld-Toal; Daniel Teschner; Karin Jordan; Carsten Müller-Tidow; Gerlinde Egerer; Nicola Giesen

doi:10.1371/journal.pone.0271756

Peer Review History

Original SubmissionSeptember 20, 2021
13 Apr 2022 Decision Letter - Ahmed S. Abdel-Moneim, Editor PONE-D-21-30394Parainfluenza Virus Infections in Patients with Hematological Malignancies or Stem Cell Transplantation: Analysis of Clinical Characteristics, Nosocomial Transmission and Viral SheddingPLOS ONE Dear Dr. Tabatabai, 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 May 28 2022 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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If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. 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: 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. 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: This is an interesting and well written manuscript that throws light on an important virus that caused outbreaks and high mortality among the immunocompromised patients. My recommendations to authors Please include the epidemiological case definition used to assign patients to an outbreak or cluster. Please include any detected risk factors that increased transmission, and if these risk factors were addressed. Reviewer #2: The authors analyzed PIV infections in a hematology and stem cell transplantation (SCT) unit over the course of three years. Isolated PIV strains were characterized by sequence analysis and nosocomial transmission was assessed including phylogenetic analysis of viral strains. This is a complete and important study, which needs some improvement in the phylogenetic analysis and some edition for publication. Major comments: 1. Page 3, lines 65-66: it is stated that phylogeny is based on the F gene but in this study the authors sequenced the HN gene for phylogenetic analysis, as would be expected. Page 3, lines 61-66: This paragraph is important to sustain part of one the aim of this manuscript and is described somehow very superficially. It should be edited for style improvement. In addition, reference is (are) missing. 2. The length of the amplicon used for phylogenetic analysis is not mentioned in any part of the manuscript. 3. I assume that the typing of PIV according to time and presented in Figure 1 is based on the same sequences used for phylogenetic analysis. Why were some samples untypable? Were they included in the phylogenetic tree? Could the size of the sequence be responsible for a lack of discrimination for these untypable samples? 4. The size of the sequence deposited in GenBank is of 438 bp. Is this size sufficient for a good phylogenetic analysis and to propose nosocomial transmission? In one of the references cited (Abiko et al., 2013), the size of the sequence analyzed is quite larger (1599 bp). 5. Putative nosocomial transmission is presented with colors in the phylogenetic tree. However, other samples exhibit an identical sequence but are not associated with the cluster of putative nosocomial transmission. The authors could perform a blast analysis with their samples to see if there are other samples deposited, with identical sequences in the 438 nt analyzed for the phylogenetic analysis. Thus, in page 9, line 215, the authors should suggest nosocomial transmission, instead of affirming it, unless the previous issues responded. 6. Is a previous study (Lefeuvre C et al., JMV 2021), LRTI was associated with HPIV-3. No mention is done in this study is ther was an association of LRTI with HPIV type. In the fatal cases, two types were detected, in addition to untypable samples. The authors should analyze these findings. 7. No mention is given to the Ct values. Was there any difference in Ct values between URTI and LRTI or during the sheding? Minor comments 8. Page 5, line 119: the number 75 at the beginning of the sentence should be written in letters. 9. Page 6, line 127: Abbreviation URTI is not defined. *******[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: Comment.DOCX* https://doi.org/10.1371/journal.pone.0271756.r001
Revision 1
10 Jun 2022 Author Response Letter of rebuttal / comments on changes in the manuscript Ms. Ref. No.: PONE-D-21-30394 Title: Parainfluenza Virus Infections in Patients with Hematological Malignancies or Stem Cell Transplantation: Analysis of Clinical Characteristics, Nosocomial Transmission and Viral Shedding Plos One Questions and answers to the reviewers: Reviewer#1: This is an interesting and well written manuscript that throws light on an important virus that caused outbreaks and high mortality among the immunocompromised patients. My recommendations to authors: Please include the epidemiological case definition used to assign patients to an outbreak or cluster. Please include any detected risk factors that increased transmission, and if these risk factors were addressed. Response: We thank Reviewer #1 for finding our manuscript interesting and well written. The reviewer raises a very important point in asking to include a clear epidemiological case definition which we added to the methods section of the revised manuscript. Similarly, the question of risk factors for increased transmission is very interesting. Circle threshold values in real time PCR as proxy for viral load did not show any association with LRTI nor severe LRTI in our cohort. However, it is quite conceivable that prolonged viral shedding, such as found in allogeneic transplant patients in our cohort, increases the risk for transmission. In the revised manuscript, we added a paragraph on possible risk factors for transmission to the discussion section. ___________________________________________________________________________ Reviewer#2: The authors analyzed PIV infections in a hematology and stem cell transplantation (SCT) unit over the course of three years. Isolated PIV strains were characterized by sequence analysis and nosocomial transmission was assessed including phylogenetic analysis of viral strains. This is a complete and important study, which needs some improvement in the phylogenetic analysis and some edition for publication. Major comments: 1. Page 3, lines 65-66: it is stated that phylogeny is based on the F gene but in this study the authors sequenced the HN gene for phylogenetic analysis, as would be expected. Response: We thank Reviewer#2 for carefully reading this manuscript as indeed we have sequenced the HN gene and there was a typing error we have corrected accordingly in the revised manuscript. Reviewer#2: Page 3, lines 61-66: This paragraph is important to sustain part of one the aim of this manuscript and is described somehow very superficially. It should be edited for style improvement. In addition, reference is (are) missing. Response: We appreciate the reviewers wish for more detail on the genetic and molecular epidemiology of PIV. We have therefore edited this paragraph extensively and added further references. Reviewer#2: 2. The length of the amplicon used for phylogenetic analysis is not mentioned in any part of the manuscript. Response: The length of the amplicon varied depending on the PIV type between 430 and 500 nt, we have added this information to the methods section. Reviewer#2: 3. I assume that the typing of PIV according to time and presented in Figure 1 is based on the same sequences used for phylogenetic analysis. Why were some samples untypable? Were they included in the phylogenetic tree? Could the size of the sequence be responsible for a lack of discrimination for these untypable samples? Response: The reviewer is raising an important issue. Due to low viral load (accordingly high ct-values), some samples could not be sequenced and typed, so we had only information from the monoplex PCR (altona diagnostics) stated whether samples were PIV positive or negative. We have added this information to the legend of Figure 1 in the manuscript. Reviewer#2: 4. The size of the sequence deposited in GenBank is of 438 bp. Is this size sufficient for a good phylogenetic analysis and to propose nosocomial transmission? In one of the references cited (Abiko et al., 2013), the size of the sequence analyzed is quite larger (1599 bp). Response: We thank the reviewer for this important question. As we have primarily defined nosocomial infection based on clinical criteria and used phylogenetic data in order to support clusters of nosocomial infection, we believe that the sequence length we have used is suitable for that purpose. In contrast, for extensive molecular epidemiological studies complete sequencing of the HN gene might be ideal. Therefore, we believe that the sequence length used in this study is sufficient for our study design. We have added additional information on the definition of nosocomial infection in the methods section. Reviewer#2: 5. Putative nosocomial transmission is presented with colors in the phylogenetic tree. However, other samples exhibit an identical sequence but are not associated with the cluster of putative nosocomial transmission. The authors could perform a blast analysis with their samples to see if there are other samples deposited, with identical sequences in the 438 nt analyzed for the phylogenetic analysis. Thus, in page 9, line 215, the authors should suggest nosocomial transmission, instead of affirming it, unless the previous issues responded. Response: The reviewer is mentioning the presentation of suspected nosocomial infection as marked in the phylogenetic tree. As stated in the Figure legend “clinically suspected nosocomial infections matching identical sequence clusters (cl. 1-7) are highlighted in color”, meaning that we have defined nosocomial infection solely based on clinical criteria and marked it in the phylogenetic tree to see if this was supported by identical sequences. We believe that this information is indeed supporting the clinical suspicion of nosocomial infection, but of course sequence analysis as done here does not finally prove nosocomial infection. We have therefore edited our statement in the discussion section accordingly. Reviewer#2: 6. Is a previous study (Lefeuvre C et al., JMV 2021), LRTI was associated with HPIV-3. No mention is done in this study is there was an association of LRTI with HPIV type. In the fatal cases, two types were detected, in addition to untypable samples. The authors should analyze these findings. Response: We thank Reviewer #2 for raising the important issue of PIV subtype and outcome. We did not observe a significant association between PIV type and LRTI incidence and added this statement more prominently to the results section. While no association between PIV type and LRTI was detected, PIV type 3 accounted for nearly 4 in 5 infections overall. Furthermore, as the reviewer mentions, the occurrence of fatal non-PIV3 infections is noticeable. We added a paragraph to discuss these findings, also including the suggested study by Lefeuvre et al, to the discussion section of the revised manuscript. Reviewer#2: 7. No mention is given to the Ct values. Was there any difference in Ct values between URTI and LRTI or during the shedding? Response: We thank the reviewer for this interesting question. Circle threshold values in real time PCR as proxy for viral load did not show any association with LRTI nor severe LRTI in our cohort. We have added this information to the manuscript. Reviewer#2: Minor comments 8. Page 5, line 119: the number 75 at the beginning of the sentence should be written in letters. 9. Page 6, line 127: Abbreviation URTI is not defined. Response: We thank for the reviewers careful reading of the manuscript and have edited the manuscript accordingly. Attachments Attachment Submitted filename: Rebuttal_letter_Parainfluenza.docx https://doi.org/10.1371/journal.pone.0271756.r002
7 Jul 2022 Decision Letter - Ahmed S. Abdel-Moneim, Editor Parainfluenza Virus Infections in Patients with Hematological Malignancies or Stem Cell Transplantation: Analysis of Clinical Characteristics, Nosocomial Transmission and Viral Shedding PONE-D-21-30394R1 Dear Dr. Tabatabai, 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, Ahmed S. Abdel-Moneim, Ph.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0271756.r003
Formally Accepted
12 Jul 2022 Acceptance Letter - Ahmed S. Abdel-Moneim, Editor PONE-D-21-30394R1 Parainfluenza virus infections in patients with hematological malignancies or stem cell transplantation: analysis of clinical characteristics, nosocomial transmission and viral shedding Dear Dr. Tabatabai: 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 Prof. Ahmed S. Abdel-Moneim Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0271756.r004

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