PONE-D-20-02362

Predictors of Acute Respiratory Distress Syndrome (ARDS) in adults with imported severe Plasmodium falciparum malaria: a 10 years study in a Portuguese tertiary care hospital

PLOS ONE

Dear Dr Santos,

Thank you for submitting your manuscript to PLoS ONE. After careful consideration, we felt that your manuscript requires revision, following which it can possibly be reconsidered. Although your manuscript was of interest to the three reviewers, major concerns were related to study design and data interpretation.  A methodological concern raised by the reviewers was related to   sample size as it may have compromised the conclusion.    Also, the authors should revise some distorted definitions; for example, the definition of semi-immunity.   Given the study limitations, it has been suggested that the purpose of the study should be adjusted from a “predictive” to a “descriptive” of ARDS among patients with severe imported malaria. Therefore, it seems to be a consensus that the word "predictors" should be removed from the title. For your guidance, a copy of the   reviewers' comments was included below

We would appreciate receiving your revised manuscript by March 30. 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Luzia Helena Carvalho, Ph.D.

Academic Editor

PLOS ONE

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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: Partly

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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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: No

Reviewer #2: No

Reviewer #3: Yes

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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: No

Reviewer #3: Yes

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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 manuscript entitled “Predictors of Acute Respiratory Distress Syndrome (ARDS) in adults with imported severe Plasmodium falciparum malaria: a 10 years study in a Portuguese tertiary care hospital” presents an interesting set of data from malaria-associated ARDS patients, which contributes a great deal and are, in fact, very scarce in literature in this area. The work shows clinical, laboratory, hypoxemia and parasitemia data, comorbidities, treatments, among others. On the other hand, no substantial early predictive marker of ARDS has been identified, because PaO2/ FiO2 ratio <300 mmHg (already well established and known for ARDS) and SAP <90 mmHg, as the authors themselves reported in their conclusion “the absence of early predictors”. Therefore, I believe the word "predictors" should be removed from the title, as being overinterpretation, suggests a false idea of research presented to the reader.

I suggest MINOR REVISION.

Main points:

1- Flow diagram of cohort study detailing ARDS, no ARDS and exclusion criteria and also some data forest plot of the odds ratios should be used as it would be more interesting and attractive.

2- The authors should describe the results more clearly, following the format x% (y/z), as similar to data presented in the tables.

3- The authors could discuss a little about C-reactive protein, albumin, and platelets once these laboratory parameters as they appear differently between ARDS and non-ARDS patients.

4- Considering the fact that a greater number of ARDS-developing patients are semi-immune, it is interesting that the results be better discussed.

5- It is known the reported mortality in literature is very high concerning ARDS cases, but it is not shown in this manuscript. The authors could suggest (hypothesize) the reason why there was no difference in ARDS and non-ARDS cases, as well regarding SAP.

Minor points

1- “10 years study” must be written “10-year study”

2- What do “NIV” and “NIV trial” mean? The meaning of this acronym must appear when quoted for the first time, not in the end.

3- The acronym ECMO must be described in full when it appears first in the text.

4- What does UTI mean? Is it ICU?

5- Antibiotic treatment lasted 7 days in all groups. How do you explain p-value of 0.006 (table 3)?

6- “Nosocomial infections” and “Any infection” are shown in table 4. It is not clear if “any infection” means any nosocomial infection. Do the cases of community-acquired infections (<48h after admission) not appear in this table?

7- The tables should contain the type of statistical test used in each row or in legend.

Reviewer #2: Graca and coworkers examining retrospectively 98 patients with severe P. falciparum malaria admitted to their ID-ICU in Portugal between 2008-2018, aimed to identify “predictors” of ARDS development. However, their final conclusion is “ARDS is a hard to predict late complication of severe malaria”. I think that this study is flawed by two main issues: 1) the retrospective enrolment of patients; 2) the limited number of patients. Both contributed to their negative findings.

In their multivariate model only two variables were independently associated with development of ARDS: 1) PaO2/FIO2 < 300 mmHg); 2)SAP < 90 mmHg. However, the first one is now part of the ARDS Berlin definition (previous ALI , now mild ARDS) therefore should not be considered a risk factor for development of ARDS, and the second is, more properly, an indicator of severe malaria.

Given the above mentioned limitations I will suggest to change the purpose of the study from a “predictive” to a “descriptive” of ARDS among patients with severe imported malaria.

Results:

Subheadings

-(Patient demographic and clinical and laboratory characteristics):nationality of patients should be indicated and the area of acquisition of malaria specified. Former Portuguese colonies (either in results and table 1) is ambiguous and the reader is not required to know what they were.

- (Prediction of ARDS development): table 2 shows patients admitted to ID-ICU with (=32) and without ARDS (=66); however , as stated in the text “thirteen of these patients already fulfilled ARDS criteria on admission to the ICU”. The majority of pts developed ARDS during ICU stay (as reported in the literature and also in my experience) and therefore table should be changed accordingly.

It would be interesting to know parasitaemia value at the time of ARDS occurrence in comparison with other criteria (see the article by Marks ME et al. BMC Infect Dis 2013; 13:118).

Also in table 2 there is a discrepancy between “acidosis” (5/57, 0/28) and arterial pH < 7.35 (13/57, 2/29); a pH < 7,35 encompass the definition of acidosis (metabolic acidosis= plasma bicarbonate < 15 mmol /litre or pH < 7.35. WHO Guidelines for the treatment of malaria, 2nd Edition).

-(Management of respiratory failure): this is a descriptive paragraph difficult to follow; I suggest to try to summarize main messages in a table.

Discussion: It would be important to discuss the role of albumin level (high risk factor for both severe malaria and ARDS) (see article Bruneel F et al. Intensive Care Med 2016;42:1588-96)and malaria semi-immunity. Moreover, ARDS is (together with shock and acidosis) one of the factor associated with malaria death but in the present experience none of the patients died with/for ARDS. In a previous article from the same group (Malaria J 2012) regarding 59 pts with severe malaria admitted in the ICU from 2000-2011, 8/9 patients who died with malaria had ARDS. Can you comment on?

Although , your experience is about ARDS in P. falciparum malaria, it should be mentioned the role of this complication in P. vivax and P. knowlesi severe malaria.

Minor:

“Immunochromatogenic” change to ” immunochromatographic”

Reference 12 refers to India, actually to be considered an endemic country for malaria.

Table 1: seven patients were immunocompromised: 3 had HIV infection; I do not agree that HIV “per se” should be considered immunocompromission.

Reviewer #3: The paper by Graca et al is a retrospective study of ARDS in malaria patients, indicating that it is difficult to identify predictors for the development of this complication. It is very descriptive, the conclusions are not really novel, and some inaccuracies need to be corrected. Still the topic is important and it is useful to have a study on this complication from a well-equipped center.

Major comments:

1. The authors state that more ARDS is observed in semi-immune patients than in non-semi-immune. This is most likely wrong and based on a fairly misleading definition of semi-immunity in the methods section. What is meant by 'endemic area'? Semi-immunity only occurs in areas of high-exposure. Semi-immunity refers to protection from severe malaria, as a consequence of high exposure. I would suggest to use the terminology of 'semi-immunity' only if significant antimalarial immunity can be shown (e.g. antimalarial antibodies). If this cannot be proven, it is better to indicate that these patients were living for at least 2 years in an endemic area, without using the term semi-immunity. In fact, real semi-immunity might be supposed to protect from malaria ARDS, just like it does for other malaria complications.

2. It is surprising to note that several patients with PaO2/FiO2 < 300 mmHg are classified in the non-ARDS group. A better discussion of these patients is required. Do these patients correspond to those in the same group that have pulmonary edema (see table 2)? What was the cause of this pulmonary edema? Most likely these patients have also pulmonary pathology caused by malaria? It would be preferable to identify these patients as having malaria-associated pulmonary pathology, although they do not correspond perfectly to the Berlin definition of ARDS. I would suggest to discriminate these patients in a separate column in the tables and to discuss whether the Berlin criteria are or are not appropriate for malaria-related ARDS.

3. Result section: please indicate how many patients did develop ARDS before the start of antimalarial treatment.

4. Discussion: the first sentence is not correct. There are several studies in the literature available describing malaria patients developing ARDS. This has also been reviewed, e.g. Taylor et al. Chest 2012, Van den Steen et al. Trends Parasitol 2013, Mohan et al. J Vector Borne Dis 2008.

Minor comments:

Introduction: it is not true to state that severe malaria is almost universally caused by P. falciparum. This is geographically dependent; it is true in Africa but in other parts of the world P. vivax can also be a cause, and in some parts of South-East Asia (e.g. Borneo), P. knowlesi is the most important cause. The latter is particularly relevant for malaria-associated ARDS.

Introduction: it is wrong to state that ARDS has been reported in 5 to 25% of patients with severe Pf malaria. The great majority of severe malaria patients are children, who do not develop ARDS. This statement is only true for adult patients (and this study also includes only adults). This should be better stated.

Materials and methods: how were bacterial coinfections defined? Cultures of blood, bronchoalveolar lavages? Please define the methodology. Were viral co-infections (e.g. influenza, …) excluded or not? This should be mentioned.

Why are 87.8% of the patients males? Why this huge gender imbalance?

Some abbreviations should be defined, e.g. UTI, ECMO, EI

Result section: Eight patients in the no-ARDS required mechanical ventilation for other reasons than respiratory failure. Please define which other reasons.

Table 1: former Portuguese colonies in Africa: the countries should be named, not all biomedical scientists know all the details of Portuguese history.

Table 1. P value of 0.160 for reason to travel: what does this P value refers to? Comparison of which parameters?

Table 1: Previous diagnosis of malaria: indicate within which time frame

Table 1: smokers are classified as ‘respiratory disease’. While it is obvious that smoking contributes to respiratory disease, it might be better to differentiate the smokers from other respiratory diseases in a separate row in this table.

Table 2: How was pulmonary edema defined? Radiologically? Please define.

Table 3: use of vasopressors in the treatment: it would be preferable to indicate the number of patients with low blood pressure, or what were the thresholds or indications to start vasopressor therapy?

Define how volume overload was defined?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[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 to be viewed.]

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Attachments

Attachment

Submitted filename: PONE-D-20-02362.docx

PONE-D-20-02362R1

Descriptive Acute Respiratory Distress Syndrome (ARDS) in adults with imported severe Plasmodium falciparum malaria: a 10 years study in a Portuguese tertiary care hospital

PLOS ONE

Dear  Dr. Santos,

Thank you for resubmitting your manuscript to PLoS ONE. Although the data from this study has potential to be informative, relevant topics raised by the reviewer #3 during the peer review process remain to be addressed by the authors. Unfortunately, the authors did not submit a rebuttal letter that responds to each point raised by the reviewers as required by the publication policy of PLoS journals. More Specifically, the authors should take into account relevant concerns such as  (i) comments on semi-immunity, including criteria to define immune status of their patients; (ii) the unreliable statement about the incidence of ARDS. At this time, we strongly suggest the authors to proper address all topics raised by the reviewers.  For your guidance, a copy of the reviewer’s comments was included below. 

We would appreciate receiving your revised manuscript by  June 10. 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.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Luzia Helena Carvalho, Ph.D.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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 #1: All comments have been addressed

Reviewer #3: (No Response)

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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 #1: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: 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 #1: No

Reviewer #3: 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 #1: Yes

Reviewer #3: 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 #1: The authors have adequately addressed most of the comments by the reviewers and I am satisfied with the quality of the paper in its present form.

Reviewer #3: Major comments:

1. The authors have to provide a decent point-by-point rebuttal to all of the referee comments, thereby copy-pasting each comment of each reviewer, with addition of their reply, including indication of the precise changes that were performed with page and line numbers. The referees are putting time and efforts in providing comments, the authors are requested to take the time and effort to provide a decent reply.

2. The authors have not taken our comment on semi-immunity seriously. Semi-immunity may easily take 5 years to develop, and is supposed to protect against severe malaria (=definition of semi-immunity). They should rephrase and remove this term from their manuscript. Also their new statement on partial immunity in the discussion is not correct. The authors did not provide any measurement on the antimalarial-immune status of these patients.

3. I don’t see any response to my second comment.

4. The erratic statement about the incidence of ARDS in malaria patients (my second minor comment) has not been corrected. See e.g. abstract of reference 7, ARDS is rare in children with malaria, and children are >90% of severe malaria patients. Children with severe malaria may develop respiratory distress due to completely different etiologies, e.g. acidosis, but this is not ARDS.

5. In addition to the problems indicated above, several of the other minor comments were also not addressed at all. This is chiefly unacceptable.

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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 #1: No

Reviewer #3: No

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Descriptive Acute Respiratory Distress Syndrome (ARDS) in adults with imported severe Plasmodium falciparum malaria: a 10 year-study in a Portuguese tertiary care hospital

PONE-D-20-02362R2

Dear Dr.  Santos,

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,

Luzia Helena Carvalho, Ph.D.

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 #1: All comments have been addressed

Reviewer #3: 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 #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #3: 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 #1: No

Reviewer #3: 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 #1: Yes

Reviewer #3: 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 #1: The authors have adequately addressed most of the comments by the reviewers and I am satisfied with the quality of the paper in its present form.

Reviewer #3: (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 #1: No

Reviewer #3: No