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Brazilian medicinal plants to treat upper respiratory tract and bronchial illness: systematic review and meta-analyses—study protocol

Introduction Respiratory illness, often associated with cough and sputum, is frequent. In Brazil, herbal medicines are often recommended as a first-line treatment for respiratory illness. There exists uncertainty regarding the effectiveness of these treatments. No systematic review has evaluated Brazilian medicinal plants (BMP) to treat upper respiratory tract and bronchial illness (URTI). Methods and analysis We will conduct a systematic review and, if appropriate, a series of meta-analyses evaluating the safety and effectiveness of BMP for URTI. Eligible randomised controlled trials and observational studies will enrol adult or paediatric patients presenting with URTI treated by BMP approved by the Brazilian Health Surveillance Agency compared with placebo, no treatment or an alternative therapy. Our search will include the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Illness Group's Specialized Register; MEDLINE; EMBASE; CINAHL (Cumulative Index to Nursing and Allied Health Literature); Web of Science; AMED; LILACS; CAB abstracts; clinical trial.gov; the WHO Trial Register and the Brazilian thesis database (CAPES) without any language restrictions. Outcomes of interest are time to resolution of clinical symptoms and/or signs (cough, sputum production or activity limitations), severity of symptoms prior to resolution and major/minor adverse events. Teams of reviewers will, independently and in duplicate, screen titles and abstracts and the complete full text to determine eligibility. For eligible studies, reviewers will perform data abstraction and assess risk of bias of eligible trials. When appropriate, we will conduct meta-analyses. We will also assess the quality of body of evidence (confidence in estimates of effect) for each of the outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Ethics and dissemination The systematic review will be published in a peer-reviewed journal. Brief reports of review findings will be disseminated directly to appropriate audiences via email and other modes of communication. The review will guide healthcare practice and policy in Brazil. Trial registration number Prospero CRD42014007057.


GENERAL COMMENTS
This paper is essentially a description of a methodology to review "all" plants used in Brazil for respiratory diseases. The methodology does however have some serious shortfalls: -the methodology is not new. There are an increasing number of studies, especially in Brazil, that provide revisions of plant use, often with a much broader scope. A revision of clinical studies is interesting, but, again, much too narrow in scope -the plant material selected is very problematic for a variety of reasons: 1. many clinical studies do not contain voucher specimens, so the correct identification of much of the material is doubtful, and as such a review makes little sense, because the correct id of the "same plant" is not guaranteed across studies. It makes e.g. no sense to compare "Mikania" or "Mentha", even with some species given, if it is not cleat that these are really the same in various studies. Mentha "piperita" and "villosa" are actually both hybrids, and certainly not the only species that are being used.
-the species selection in general seems to be strange, because many more species are used for respiratory infections, and a review should not only look at clinical studies, but also report on the general use.

GENERAL COMMENTS
The manuscript of this proposed systematic review comprises an interesting and relevant research question. However, there are inconsistencies in the methodological plan described by the authors. Moreover, the manuscript needs an extensive text review in order to correct several grammar problems and improve the logical organisation of the text. My main comments are as follow: -The abstract differ from the full manuscript and needs revision.
-There several section included before the Introduction section that are an unusual scientific style to this reviewer. Moreover, the title of the sections does not reflect its contents. For instance, the section entitled as "Key Messages" presents the summary of the research methods. The section "Strengths and Limitations" should be part of the Discussion Section.
-It is confusing from text the exactly problem at which the intervention under investigated is directed. The title cites the respiratory diseases as a whole, but later the authors define that they are interested specifically on common cold and upper respiratory tract infection associated with cold. But in several parts of the text the author also state that they are investigating the medicinal plants in the treatment of common cold, lower and upper respiratory tract infection associated with cold.
-The Introduction is unnecessary extensive, confusing and of difficult comprehension. Moreover, it lacks an overview of the accumulated knowledge regarding the intervention under investigation.
-The methods section needs in order to improve comprehension.
-The authors state that they will consider randomised controlled trials and observational studies. However, they define only superficially the outcomes of interest. In other to achieve the goal of assess the efficacy and safety of the intervention under investigation, how data from cross-sectional and case-control studies will be handled? -The search methods need revision.
(1) Databases are cited in duplicate and it is included an electronic library that does not constitutes a formal electronic database. However, LILACS, the most important and comprehensive index of scientific and technical literature of Latin America and the Caribbean, is not considered. (2) The search strategy needs improvement. In its present format, it does not appear sensitive enough for a systematic review.
-Risk relative is not an appropriate risk measure of some observational studies. Again, it is not clear which specific data will be extracted and how different studies will contribute for the estimates summarised in the systematic review. We are not clear on the scope that the reviewer would like us to take. If the reviewer could clarify his desired scope that would be helpful. As of the present moment, our impression is that the scope is adequate to inform a relevant research and policy community.

VERSION 1 -AUTHOR RESPONSE
Q3.The plant material selected is very problematic for a variety of reasons: Many clinical studies do not contain voucher specimens, so the correct identification of much of the material is doubtful, and as such a review makes little sense, because the correct id of the "same plant" is not guaranteed across studies. It makes e.g. no sense to compare "Mikania" or "Mentha", even with some species given, if it is not cleat that these are really the same in various studies. Mentha "piperita" and "villosa" are actually both hybrids, and certainly not the only species that are being used. R3: The implications of the authors" view are that one can say nothing about any of these studies because one does not know what plants are being studied. We believe that this is an excessively extreme position. The uncertainty is undoubtedly a limitation, and should be acknowledged, but to us this does not mean that the exercise is hopeless from the start. Q4. -The species selection in general seems to be strange, because many more species are used for respiratory infections, and a review should not only look at clinical studies, but also report on the general use. In case of clinical studies there should be an emphasis of studies done on the same species in other countries, in particular because almost all of of the species in question are introduced to Brazil. From this perspective, there is very little new information to be gained from the current species selection. R4: The reviewer is interested in a particular scope of the review. We have chosen a narrower scope.
We have chosen species that are approved by the Brazil Health surveillance Agency (ANVISA) to use in respiratory disease. We believe this is a reasonable choice and would be informative for Brazilian practitioners and regulatory agencies. If the reviewer, or anyone else, wishes to undertake a broader review, that would be his or her prerogative. It does not follow that a review with narrower scope would not be informative. Q5. The plant list is simply unacceptable. Most species names are not complete (no authors), no family names are given. R5 As far as we can tell, the comment is inaccurate. We"ve checked again and we have listed authors for each. All scientific names are botanically accepted according to the databases: www.tropicos.org and www.theplantlist.org. Q6. The English of the paper is almost impossible to understand. This looks like a rough translation from Portuguese, and cannot be published as such, it should in fact not even be sent for review in its current state. R6. Although we consider the comment excessively harsh and somewhat offensive in tone, we have revised to improve the English. The reviewer provides no specific examples. We note that a coauthor, a native English speaker, has published over 900 articles in the English language peer-reviewed literature. These include over 70 systematic reviews and the language in the methods section of the submitted manuscript is completely consistent with the language used in these published systematic reviews. Nevertheless, this author has, in the light of the comments re-reviewed the manuscript for English usage. Q7. See above. This methodology, as it stands, will provide little new scientific insights, nor a good review of the topic Papers like this should be rejected by the editor! R7: Based on our previous responses, we respectfully disagree.
Reviewer: 3 Reviewer Name Daniela RG Junqueira Institution and Country Universidade de Sorocaba -Uniso Please state any competing interests or state "None declared": None declared.
Q1. The manuscript of this proposed systematic review comprises an interesting and relevant research question. R1: OK! Q2. However, there are inconsistencies in the methodological plan described by the authors. R2: Ok. Q3. Moreover, the manuscript needs an extensive text review in order to correct several grammar problems and improve the logical organization of the text.
R3: We have reviewed the manuscript and endeavored to correct the grammar and improve the organization. In the absence of specific comments, it is difficult to know whether we have addressed all the reviewer"s concerns. Q4. The abstract differ from the full manuscript and needs revision. R4: We"ve checked to be consistent. Q5. -There several section included before the Introduction section that are an unusual scientific style to this reviewer. Moreover, the title of the sections does not reflect its contents. For instance, the section entitled as "Key Messages" presents the summary of the research methods. The section "Strengths and Limitations" should be part of the Discussion Section. R5: The reviewer does not seem to be familiar with the specifications of the journal, and our organization adheres to those specifications. Q6. -It is confusing from text the exactly problem at which the intervention under investigated is directed. The title cites the respiratory diseases as a whole, but later the authors define that they are interested specifically on common cold and upper respiratory tract infection associated with cold. But in several parts of the text the author also state that they are investigating the medicinal plants in the treatment of common cold, lower and upper respiratory tract infection associated with cold. R6: We have revised the title to be more specific. We have revised the manuscript to ensure consistency: we are interested in the upper respiratory tract and bronchial illness.
Q7. The Introduction is unnecessary extensive, confusing and of difficult comprehension. Moreover, it lacks an overview of the accumulated knowledge regarding the intervention under investigation. R7: We have revised the introduction. The purpose of the review is to provide a summary of the accumulated knowledge. If the reviewer has particular papers the reviewer would like cited and discussed in the introduction we would be happy to do so. Q8. The methods section needs in order to improve comprehension. R8. If the reviewer could be more specific as to the problems the reviewer perceives in the methods section (beyond what the reviewer has noted below) we would be pleased to deal with them. Q9. The authors state that they will consider randomized controlled trials and observational studies. However, they define only superficially the outcomes of interest. In other to achieve the goal of assess the efficacy and safety of the intervention under investigation, how data from cross-sectional and case-control studies will be handled? R9. In the cross-sectional and case-control studies we will document the proportion of patients in the intervention and control groups who experience each of the outcomes of interest. Q10. The search methods need revision.
(1) Databases are cited in duplicate and it is included an electronic library that does not constitutes a formal electronic database. However, LILACS, the most important and comprehensive index of scientific and technical literature of Latin America and the Caribbean, is not considered. We have removed duplicates and included LILACS. Q11.
(2) The search strategy needs improvement. In its present format, it does not appear sensitive enough for a systematic review. R11: We update the strategy using specifications in the Cochrane Handbook. Q12.Risk relative is not an appropriate risk measure of some observational studies. Again, it is not clear which specific data will be extracted and how different studies will contribute for the estimates summarized in the systematic review.
We have specified that we will use odds ratios for case-control studies. We have dealt with what we will extract in response to a previous criticism.