Parenteral Iron Therapy for Pediatric Patients
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a well written and highly relevant review of parenteral iron therapy for pediatric patients. This article will be important to a range of pediatric physicians, including hematologists, gastroenterologists, general pediatric hospital physicians, critical care and emergency physicians. It was a pleasure to read and I have no major concerns. Below are some minor comments.
Table 2 – in addition to the title of the table, I think the authors should add a heading for each column for oral iron and intravenous iron.
Line 64 and 67 – “In 1964 Marchasin and Wallerstein were the first to publish results…The first prospective study on the use of intravenous iron was published in 1980…”. Can the authors clarify why they refer to the 1980 study as the first prospective study? Was the design different from the 1964 study? Perhaps the 1964 study was retrospective?
Line 121 – “…but the highest single doses…” Perhaps add the word ‘recommended’: “…but the recommended highest single doses …”
Line 125 – “…forbidding the administration…” Perhaps ‘prohibiting’ rather than ‘forbidding’.
Line 125 - “…of large doses of iron in a single setting” Perhaps ‘sitting’ or ‘visit’ rather than ‘setting’.
Line 126 – “…maximum approved daily dose of ferric gluconate is only 125 mg.” Is this maximum regardless of age or weight?
Line 127 – “Avni et al performed an exhaustive systematic review and meta-analysis…” Could the authors indicate the age of participants in the RCTs? Specifically, did any of the RCTs include children?
Line 139 – “metanalysis”. Please revise to ‘meta-analysis’
Line 174 – “…program described a total of 274 anaphylaxis…”. Were the participants in this study adults, children or both?
Lines 111-216 – 4. Safety of intravenous iron – for this section, can the authors indicate which studies include children? In addition, can they make a summary statement regarding current knowledge of safety in the pediatric age group?
Line 351 – “A Cochrane Library systematic review of interventions for treating IDA in IBD…”. Did this systematic review include pediatric studies?
Line 365 – “The efficacy and safety of IIM in routine care of IBD patients with IDA…”. Can the authors note that this study included only adults.
Author Response
We would like to thank Reviewer 1 of our manuscript 2749549 titled “Parenteral iron therapy for pediatric patients” for her/his useful comments. A point-by-point response follows in the next few sentences. The comments of the reviewer appear first in italicized text followed by our response in plain text. Please, note that all changes made in the revised manuscript (2749549.R1) appear highlighted with a yellow text-marker so that you can track them easily.
Reviewer 1
Comment: Table 2 – in addition to the title of the table, I think the authors should add a heading for each column for oral iron and intravenous iron.
Response: There is already a side heading for each line on Table II. In other words, the headings appear before each line.
Comment: Line 64 and 67 – “In 1964 Marchasin and Wallerstein were the first to publish results…The first prospective study on the use of intravenous iron was published in 1980…”. Can the authors clarify why they refer to the 1980 study as the first prospective study? Was the design different from the 1964 study? Perhaps the 1964 study was retrospective?
Response: It is unclear if the study by Sidney Marchasin and Ralph Wallerstein was retrospective or prospective (not clarified by the authors), although my impression by carefully studying the manuscript is that it was likely retrospective.
Comment: Line 121 – “…but the highest single doses…” Perhaps add the word ‘recommended’: “…but the recommended highest single doses …”
Response: We have now added the word recommended as per the reviewer's suggestion.
Comment: Line 125 – “…forbidding the administration…” Perhaps ‘prohibiting’ rather than ‘forbidding’.
Response: We have changed the wording to prohibiting as per the reviewer’s recommendation.
Comment: Line 125 - “…of large doses of iron in a single setting” Perhaps ‘sitting’ or ‘visit’ rather than ‘setting’.
Response: We have changed the wording to visit as per the reviewer’s recommendation.
Comment: Line 126 – “…maximum approved daily dose of ferric gluconate is only 125 mg.” Is this maximum regardless of age or weight?
Response: The maximum recommended dose of sodium ferric gluconate complex (FerrlecitÒ) for intravenous administration is 125mg of elemental iron for adults and 1.5 mg/kg of elemental iron up to a maximum of 125mg for children. This has been clarified in the revised manuscript.
Comment: Line 127 – “Avni et al performed an exhaustive systematic review and meta-analysis…” Could the authors indicate the age of participants in the RCTs? Specifically, did any of the RCTs include children?
Response: The meta-analysis of Avni et al included only adult studies. This has been clarified in the revised manuscript.
Comment: Line 139 – “metanalysis”. Please revise to ‘meta-analysis’
Response: We thank the reviewer for catching this typo. The correction to meta-analysis has been made in the revised manuscript.
Comment: Line 174 – “…program described a total of 274 anaphylaxis…”. Were the participants in this study adults, children or both?
Response: The study: Wang C, et al. Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA. 2015;314(19):2062 included only adults. This has been clarified in the revised manuscript.
Comment: Lines 111-216 – 4. Safety of intravenous iron – for this section, can the authors indicate which studies include children? In addition, can they make a summary statement regarding current knowledge of safety in the pediatric age group?
Response: All studies on the safety of intravenous iron in the relevant section deal with adults, i.e., are derived from adult studies. The limited pediatric data on the safety of LMWID, iron sucrose, and ferric carboxymaltose are mentioned in the relevant sections of these parenteral iron products.
Comment: Line 351 – “A Cochrane Library systematic review of interventions for treating IDA in IBD…”. Did this systematic review include pediatric studies?
Response: The answer is yes. The Cochrane Library systematic review of interventions for treating IDA in IBD: Gordon M, et al. Interventions for treating iron deficiency anaemia in inflammatory bowel disease. Cochrane Database Syst Rev. 2021;2021(1), included both adults and children. This has been clarified in the revised manuscript.
Comment: Line 365 – “The efficacy and safety of IIM in routine care of IBD patients with IDA…”. Can the authors note that this study included only adults.
Response: The reviewer’s comment is correct. The study by Stein et al: Stein J, Bager P, Befrits R, Gasche C, Gudehus M, Lerebours E, et al. Anaemia management in patients with inflammatory bowel disease: routine practice across nine European countries. Eur J Gastroenterol Hepatol. 2013;25(12):1456–63, included only adults. This has been clarified in the revised manuscript.
We are confident that the above revisions and clarifications solve all the issues raised by Reviewer 1 and that our revised manuscript should now be acceptable for publication to Hemato.
Sincerely,
Elpis Mantadakis
Reviewer 2 Report
Comments and Suggestions for AuthorsThe paper reports all the evidence available and offers a complete and exhaustive review.
Minor points for further improvement are:
1) the authors describe the current therapeutic scenario and refer to oral iron supplementation as the standard therapy and parenteral iron administration as a underutilized therapy that should not be feared anymore, given the safety and convenience offered by newer products. To further express such message, they can also refer to the fact that even oral iron supplementation still offers many unsolved issues, such as recommended dose, type of formulation; they can include in their reference list this recent paper, a real-life observation on oral iron therapy: Ann Hematol. 2020 Mar;99(3):413-420. doi: 10.1007/s00277-020-03906-w.on
2) page 4, after the previous description of drugs according to different generation, it is mentioned "Type-one complexes..... type-two complexes....."; two distinct classifications, one according to generation, first-generation, second generation.....and the other according to structure may generate some confusion; the Authors should clarify
3) I would like to read a very brief comment of the pros and cons of each formulation; after reading the paper, a non-expert reader understands that parenteral iron therapy is a valuable option, but may be not well oriented on choosing the right formulation, the dose and the necessary precautions. I suggest to prepare a summarizing table.
Author Response
We would like to thank Reviewer 2 of our manuscript “Parenteral iron therapy for pediatric patients” for her/his useful comments. A point-by-point response follows in the next few sentences. The comments of the reviewer appear first in italicized text followed by our response in plain text. Please, note that all changes made in the revised manuscript (2749549.R1) appear highlighted with a yellow text-marker so that you can track them easily.
Comment: 1) the authors describe the current therapeutic scenario and refer to oral iron supplementation as the standard therapy and parenteral iron administration as a underutilized therapy that should not be feared anymore, given the safety and convenience offered by newer products. To further express such message, they can also refer to the fact that even oral iron supplementation still offers many unsolved issues, such as recommended dose, type of formulation; they can include in their reference list this recent paper, a real-life observation on oral iron therapy: Ann Hematol. 2020 Mar;99(3):413-420. doi: 10.1007/s00277-020-03906-w.on
Response: We totally agree with reviewer 2. There are several unresolved issues with oral iron therapy including what formulation to choose, what dose to use, the number of daily doses, etc. The recommended reference by Russo et al has been added to the revised manuscript 2749549.R1 (reference No.68).
Comment: 2) page 4, after the previous description of drugs according to different generation, it is mentioned "Type-one complexes..... type-two complexes....."; two distinct classifications, one according to generation, first-generation, second generation.....and the other according to structure may generate some confusion; the Authors should clarify
Response: We believe that there is no area for confusion. The term type is used to describe parenteral iron products by their structure and ability to generate labile-free iron after intravenous administration. The term generation refers to the years a product is on the market, with the 1st generation products being the oldest ones, and the 3rd generation products (ferric carboxymaltose and iron isomaltoside) being the newest ones.
Comment: 3) I would like to read a very brief comment of the pros and cons of each formulation; after reading the paper, a non-expert reader understands that parenteral iron therapy is a valuable option, but may be not well oriented on choosing the right formulation, the dose and the necessary precautions. I suggest to prepare a summarizing table.
Response: A summarizing table (Table V) has been created, as per the reviewer’s recommendation. All products are safe and effective, but LMWID and ferric carboxymaltose have the additional advantage of total dose infusion, as indicated in Table V, which allows correction of the total body iron deficit at a single or very few visits. The inclusion of preparation (dilution) and administration guidelines in Table V will help the interested non-expert physician to administer intravenous iron safely into a patient with IDA.
We are confident that the above revisions and clarifications solve all the issues raised by reviewer 2 and that our revised manuscript should now be acceptable for publication.
Sincerely,
Elpis Mantadakis
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThank you for addressing all of my comments. The manuscript looks excellent and I have no further comments.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors improved their manuscript according to the reviewers' suggestions.
I am totally satisfied with the revised version
