Blood Transfusion Reactions—A Comprehensive Review of the Literature including a Swiss Perspective

Round 1

Reviewer 1 Report

The manuscript entitled "Blood transfusion reactions – The situation in Switzerland: a Review" by Theresa Ackfeld et al. provides an literature review of potential transfusion reactions to blood components and medical treatment options.  The review lays out a comprehensive overview of complications also nicely displayed in a diagram.

Major comments:

1. Upon reading the title, it was anticipated to see a more Switzerland-specific twist in the review article; however, it turned out to be a more comprehensive review as stated above linked to incident numbers in Switzerland and selected other European countries. Please reword the title as it is somewhat misleading.
2. In the first half of the review, there are several items which need clarifiction, see detailed comments below.

 

Detailed comments:

1. As to the first major comment, the abstract needs to be revised to reflect the content of the review.
2. The intro refers only to RBC transfusions (l. 35), so in order to satisfy "blood transfusion reactions" other blood component transfusions should be mentioned or it needs to be stated why they are omitted.
3. The number of RBC transfusions mentioned (l. 36) is for 2020 but provides only a snapshot and needs some context of years before - especially pre-COVID .
4. 0.7% of 'possible' TRs (l. 36) is very wage and needs some clarification.
5. Comparison to other European countries (l. 49 onward) need to be justified in terms of transfusions executed compared to CH.
6. The last sentence in chapter 2 (l. 66 onward) is confusing as to which topics are excluded, please revise! Additionally, as viral infections seems to be excluded (l. 68) "COVID RBC transfusions" should not be in the list of the search criteria (l. 59).
7. The sentence running l. 65/66 is confusing as somehow incomplete. Please revise.
8. In chapter 3, it states that "275,345 blood products" were transfused, however, this is exactly the same number mentioned in l. 35 for RBC transfusions alone, please correct.
9. The mentioning of epidemiological numbers in chapter 3 is an overwhelming amount of information and comparisons and would benefit from a table for 'easier' display. Please make sure all total numbers have the associated % value (l. 83).
10. Please define 'differs considerably' (l. 93).
11. Abbreviations, such as CH, D, F and UK (l. 95) should be 'introduced' once when mentioned the first time.
12.  Please reword 'figures' (l. 99) as this word in this context is expecting an actual figure.
13. The heading of 'definition' (l. 109) is too unspecific and needs further clarification for the chapter that follows.
14. There are many incidences where the word used is not very clear or not specific enough to understand the sense of the sentence, such as 'nonspecific' (l. 111) and 'suspicious' (l. 112). Please reword or edit.
15. The entire paragraph (l. 108 - 116) somehow is unclear and needs revision in terms of consensus of this topic despite the message is not structured.
16. The notion of '0.09 per 1000 transfusions' (l. 118) is tough to understand; would it be possible to rather write 1 per X?
17. Again, to comment #6, are immuno-mediated AHTRs included as immuno-mediated infections seem to be excluded (l. 69). Please clarify.
18. The reference to small volume of TF products (l. 131) is not clear, are the authors referring to pediatric TFs?
19. Incompatibility is only one of the potential causes of AHTR, what is the frequency?
20. In the paragraph spanning l. 137-140 it is not clear whether this is CH-specific or general, please reword.
21. The entire section spanning l. 141-172 is a nice summary of AHTR, but - maybe this reviewer missed something - does not refer to any incidences in CH, or elsewhere. Please revise to state the purpose of this section.
22. Additional to the comment above, it might be helpful to comment in general on the contribution of the donor (factors) and TF component quality such as storage lesion development vs. recipient factors.
23. The chapters on AHTR (l. 200) and following have less incidence data and especially other than CH data, please comment whether not available or other reasons.
24. The chapters on TRALI and TACO are nicely written!
25. The chapter on MTPs (l. 306) might benefit from a figure outlining the concept.
26. In the chapter on 'septic transfusion reaction' (l. 368), it might be helpful to compare incidence rates across different European countries. As mentioned in this chapter, it would be nice to list bacterial isolate results to put these findings into perspective.
27. Regarding treatment (l. 393), please provide some consensus on the antibiotic regime.
28. Please define 'indications' (l. 446).
29. Nice summery overview of the hemovigilance programs in different countries!
30. Please consider printing figure 1 in landscape as the font size is quite small.
31. Please consider commenting in conclusion section on the aspect mentioned in comment #22. Are any quality control programs for TF products in place in Europe?

Author Response

Dear Reviewer,

Thank you for your pertinent comments.

Please see the attachment

Best regards, 

Christophe le Terrier

 

Reviewer #1: The manuscript entitled "Blood transfusion reactions – The situation in Switzerland: a Review" by Theresa Ackfeld et al. provides an literature review of potential transfusion reactions to blood components and medical treatment options. The review lays out a comprehensive overview of complications also nicely displayed in a diagram.

Major comments:

1. Upon reading the title, it was anticipated to see a more Switzerland-specific twist in the review article; however, it turned out to be a more comprehensive review as stated above linked to incident numbers in Switzerland and selected other European countries. Please reword the title as it is somewhat

Response:

We warmly thank the reviewer for the appreciation of our work and the thoroughly lecture of our article. The pertinent comments helped us to strengthen our work. We agree with the reviewer that our title and abstract were misleading. With this review article we aim to give a structured overview of the pathophysiology, clinical presentation, diagnostic approach and the management of acute transfusion reactions. The epidemiologic numbers from Switzerland and selected European countries aim to give the reader a background idea of hemovigilance and should highlight the importance of reporting incidences. We have now revised the title and the introduction to focus on the content of the review. Please see the new title: “Blood transfusion reactions –a comprehensive review of the literature including a Swiss perspective.” We have revised our manuscript as much as possible according to your comments in order to strengthen and clarify the key messages. We hope that our answers will respond to your concerns.

 

 

2. In the first half of the review, there are several items which need clarification, see detailed comments

 

 

Response:

We thank the reviewer for pointing out these errors and we apologize for not having paid closer attention to these issues before submission. As requested, we have now thoroughly revised the manuscript according to your suggestion and have answered the detailed comments below.

 

 

Detailed comments:

1. As to the first major comment, the abstract needs to be revised to reflect the content of the

Response: We would like to thank the reviewer for this comment and apologize for the misleading abstract. We adapted the abstract in order to correspond to the content of our work. Please see abstract, page 1.

2. The intro refers only to RBC transfusions (l. 35), so in order to satisfy "blood transfusion reactions" other blood component transfusions should be mentioned or it needs to be stated why they are

Response: We agree with the reviewer, that the designation of blood products in the introduction was misleading and we adapted the wording accordingly and provided additional information about other blood components. Please see lines 40-78, page 1-2

3. The number of RBC transfusions mentioned (l. 36) is for 2020 but provides only a snapshot and needs some context of years before - especially pre-COVID.

Response: We thank the reviewer for this comment. We agree that providing pre-COVID numbers puts the evolution of transfusion reactions, as well as the sensibilization of the medical staff into spotlight and we therefore adapted this chapter. Please see lines 85-89, page 2.

4. 7% of 'possible' TRs (l. 36) is very wage and needs some clarification.

Response: We apologize if the designation was not sufficiently clear. In 2020 in Switzerland of 275,343 blood products 2 032 transfusion reactions were reported, of which 122 were imputed as improbable (imputability 1: improbable) and were therefore not considered. The 0.7% therefore referred to all transfusion reactions that were considered at least as possible, including imputability 2-4 (2: possible, 3: probable, 4: certain). We agree that this number is not clear and in order to let the reader interpret the numbers we rephrased this paragraph. Please see lines 42-78, page 1-2.

5. Comparison to other European countries (l. 49 onward) need to be justified in terms of transfusions executed compared to CH.

Response: We would like to apologize for not giving an adequate overview of the aims of this article. We adapted the paragraph accordingly. Please see lines 90-97, page 2.

6. The last sentence in chapter 2 (l. 66 onward) is confusing as to which topics are excluded, please revise! Additionally, as viral infections seems to be excluded (l. 68) "COVID RBC transfusions" should not be in the list of the search criteria (l. 59).

Response: We agree with the reviewer that the description of exclusion criteria is confusing. We excluded viral infections in order to provide a clear, structured and focused article. In our opinion transfusion associated viral infections would deserve their own review article. We considered however to address adverse transfusion reaction in COVID-19, not only because of the important impact that the COVID-19 pandemic has on the healthcare system and the numbers of transfusions, but also because of the frequently raised concern of transmission of COVID and transfusion management in COVID positive patients.

We also adapted the chapter on “Adverse transfusion reaction and COVID-19” in regard to the comments of reviewer 2. We also adapted the last sentence in chapter 2 as requested in order to clarify exclusion criteria.

7. The sentence running 65/66 is confusing as somehow incomplete. Please revise.

Response: We thank the reviewer for pointing out this grammatical error and we apologize for not having paid closer attention to the language issues before submission. We erased the sentence since it does not give any supplementary information on the inclusion criteria, and tables are considered part of the original articles, already mentioned above.

8. In chapter 3, it states that "275,345 blood products" were transfused, however, this is exactly the same number mentioned in 35 for RBC transfusions alone, please correct.

Response: We would like to thank reviewer 1 for pointing out this wrong designation in the introduction. According to our literature in Switzerland 275,343 blood products were transfused in 2020, thereof 212,947 red blood cells (RBC). We adapted the designation in the manuscript. Please see l. 39.

9. The mentioning of epidemiological numbers in chapter 3 is an overwhelming amount of information and comparisons and would benefit from a table for 'easier' display. Please make sure all total numbers have the associated % value (l. 83).

Response: We would like to thank the reviewer for this pertinent comment. We absolutely agree that the data is overwhelming and we now included a table in our manuscript, as suggested. We further adapted the percentages in the text. Please see Table 1, page 13 and chapter 3.

10. Please define 'differs considerably' (l. 93).

Response: We thank the reviewer for this comment. The wording was adapted. Please see l. 105.

11. Abbreviations, such as CH, D, F and UK (l. 95) should be 'introduced' once when mentioned the first

Response: We apologise for this oversight and we thank the reviewer for pointing out this missing introduction of abbreviations. We revised the paragraph accordingly.

12. Please reword 'figures' (l. 99) as this word in this context is expecting an actual

Response: We thank the reviewer for this comment. We replaced the word figure with number. Please see l. 389.

13. The heading of 'definition' (l. 109) is too unspecific and needs further clarification for the chapter that

Response: We would like to thank reviewer 1 for pointing out the missing clarity of this headline. We adapted as requested. Please see l. 127.

14. There are many incidences where the word used is not very clear or not specific enough to understand the sense of the sentence, such as 'nonspecific' (l. 111) and 'suspicious' (l. 112). Please reword or

Response: We thank the reviewer for this comment and we apologize for not having paid closer attention the clarity of this paragraph. We now adapted l. 132-134 accordingly.

15. The entire paragraph (l. 108 - 116) somehow is unclear and needs revision in terms of consensus of this topic despite the message is not

Response: We apologize that the section was not sufficiently clear. We revised the paragraph as requested. Please see l127-140.

16. The notion of '0.09 per 1000 transfusions' (l. 118) is tough to understand; would it be possible to rather write 1 per X?

Response: Thank you for this comment, we agree that 1 per 10000 would be easier to understand for the reader. We adapted the number accordingly. Please see l. 142.

17. Again, to comment #6, are immuno-mediated AHTRs included as immuno-mediated infections seem to be excluded (l. 69). Please

Response: We agree with the reviewer that the description of exclusion criteria is confusing. We would like to apologize for not paying attention to this before submitting. In this article we address immuno-mediated transfusion reactions, such as AHTR, FNHTR and TRALI as we judged them as especially important and frequent in the clinical setting. We deleted the exclusion of “transfusion-related immuno- modulation” as this paragraph is confusing. Please see chapter 2 on page 2. Review design and methods.

18. The reference to small volume of TF products (l. 131) is not clear, are the authors referring to pediatric TFs?

Response: We agree with reviewer 1 that this sentence is not clear. The small transfusion volume does refer to pediatric transfusions and we modified the paragraph to make this information clearer. Please see l. 155-157

19. Incompatibility is only one of the potential causes of AHTR, what is the frequency?

Response: We would like to thank reviewer 1 for this pertinent comment. Immune mediated AHTR is the most frequent type of AHTR. No numbers on the general incidence are found in the current literature and especially numbers from Europe are missing. Nevertheless, the FDA reported 48% of all transfusion associated fatalities from 1976-1985 that were caused by acute immunological hemolysis and only 2% that were due to non-immunological hemolysis (1). Yet the rate of reported fatalities from ABO-incompatible has significantly decreased in the past decade (2). Incompatibility as a potential cause of AHTR however is most common cause of clinically significant hemolytic transfusion reactions. Unfortunately, no numbers on the overall incidence were found. Several authors referred to immunological incompatibility as the most frequent reason, without mentioning concrete numbers (3,4). We believe that going further into detail on the incidences in this paragraph will be an overwhelming amount of information. We adapted the phrase however in order to highlight the fact that immunological incompatibility is the most frequent cause of hemolytic transfusion reactions. Please see l. 158-161.

1. Sazama, , 1990. Reports of 355 transfusion-associated deaths: 1976 through 1985. Transfusion 30, 583–590. https://doi.org/10.1046/j.1537-2995.1990.30790385515.x
2. Storch, E.K., Rogerson, B., Eder, A.F., 2020. Trend in ABO-incompatible RBC transfusion- related fatalities reported to the FDA, 2000-2019. Transfusion 60, 2867–2875. https://doi.org/10.1111/trf.16121
3. Panch, S.R., Montemayor-Garcia, C., Klein, H.G., 2019. Hemolytic Transfusion Reactions. N Engl J Med 381, 150–162. https://doi.org/10.1056/NEJMra1802338
4. Goel, R., Tobian, A.A.R., Shaz, B.H., 2019. Noninfectious transfusion-associated adverse events and their mitigation strategies. Blood 133, 1831–1839. https://doi.org/10.1182/blood- 2018-10-833988

 

20. In the paragraph spanning 137-140 it is not clear whether this is CH-specific or general, please reword.

Response: We apologize if the paragraph is not clear. The emergency transfusion of non- compatible blood products is practiced in trauma centers worldwide. We adapted the paragraph accordingly. Please see l. 163-164.

21. The entire section spanning l. 141-172 is a nice summary of AHTR, but - maybe this reviewer missed something - does not refer to any incidences in CH, or elsewhere. Please revise to state the purpose of this section.

Response: Thank you for this comment. We agree with the reviewer that little epidemiologic data is given in the chapters focusing on each transfusion reaction. Especially in regard to the initial title and abstract, the reader would expect a more detailed discussion of the incidences in Switzerland. We adapted the title and abstract accordingly. We here aim to provide a structured overview of the pathophysiology, clinical presentation, diagnostic approach and the management of acute transfusion reactions. Providing further epidemiologic data in this chapter would therefore beyond the scope of our article. Supplemental data from Switzerland, France and Germany is provided in Appendix B. The numbers and form of presentation from the UK however were not comparable and are not shown. Full data is available in reference 1,4,5,6.

22. Additional to the comment above, it might be helpful to comment in general on the contribution of the donor (factors) and TF component quality such as storage lesion development recipient factors.

Response: Thank you for this proposition. We agree that addressing the concern of blood product quality as well as storage lesions need to be addressed. We therefore added the chapter “Blood transfusion quality”. Please see l. 560- 602. We believe however that discussing donor and recipient factors would be beyond the scope of our article.

23. The chapters on AHTR (l. 200) and following have less incidence data and especially other than CH data, please comment whether not available or other

Response: We would like to thank Reviewer 1 for this remark and apologize that the scope of this article was unclear. In the chapters considering each transfusion reaction we decided to not compare or provide data from other European countries in order to give a structured overview of the etiology, clinical presentation, diagnostic measures and management. We here provide a comprehensive review of the literature from a Swiss perspective. Discussing epidemiologic data from each country in each section would therefore be beyond the scope of our article.

24. The chapters on TRALI and TACO are nicely written!

Response: We would like to warmly thank reviewer 1 for the appreciation of our work.

25. The chapter on MTPs (l. 306) might benefit from a figure outlining the concept.

Response: We would like to thank the reviewer for this proposition. We agree that a figure would nicely display the algorithm used when considering PTPs. We included the suggested figure. Please see figure 1 page 13.

26. In the chapter on 'septic transfusion reaction' (l. 368), it might be helpful to compare incidence rates across different European countries. As mentioned in this chapter, it would be nice to list bacterial isolate results to put these findings into perspective.

Response: Thank you for this suggestion. We have completed our chapter with incidence rates across European countries and included the most important microorganisms detected. Please see l. 397-407.

27. Regarding treatment (l. 393), please provide some consensus on the antibiotic

Response: We have revised our manuscript according to your comment. Please see l. 429-435.

28. Please define 'indications' (l. 446).

Response: We would like to apologize that the section was not sufficiently clear. We adapted the paragraph as requested. Please see l. 505-507.

29. Nice summery overview of the hemovigilance programs in different countries!

Response: We would like to warmly thank you for this comment.

30. Please consider printing figure 1 in landscape as the font size is quite

Response: We agree with this comment and would like to thank the reviewer for this proposition. We adapted the figure accordingly. Please see figure 2 page 14.

31. Please consider commenting in conclusion section on the aspect mentioned in comment #22. Are any quality control programs for TF products in place in Europe?

Response: We would like to thank the reviewer for this pertinent comment. We added a short chapter under “blood transfusion quality” resuming the quality control program in Europe. Detailed information can be found on the website of the European Directorate for the Quality of Medicines & HealthCare (EDQM). The link is provided in the chapter. Please see l. 593-602.

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Ackfeld et al have done an excellent job of reviewing the literature, providing an overview of transfusion complications and discussing the management of each transfusion reaction.

My major concern is that platelets can contain SARS-CoV-2 as shown by several recent studies, which makes platelet transfusion crucial and questionable. Please discuss the following works:

PMID: 32938299
PMID: 32887634
PMID: 34293929

Author Response

Dear Reviewer,

Thank you for your pertinent comments.

Please see the attachment

Best regards,

Christophe le Terrier

Reviewer 2

Comments and Suggestions for Authors Ackfeld et al have done an excellent job of reviewing the literature, providing an overview of transfusion complications and discussing the management of each transfusion reaction. My major concern is that platelets can contain SARS-CoV-2 as shown by several recent studies, which makes platelet transfusion crucial and questionable. Please discuss the following works: PMID: 32938299: PMID: 32887634 PMID: 34293929

Response: We warmly thank the reviewer 2 for the appreciation of our work. Furthermore, we would like to thank Reviewer 2 for this very interesting proposition of literature. We agree that COVID-19 and blood safety is a major concern and especially the risk of SARS-CoV-2 transmission via platelets was not sufficiently addressed in our article. We have now discussed the mentioned articles and believe that this will help to strengthen our manuscript. Please see l. 449-469.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The revised version addressed all comments for this reviewer.