Sickle Cell Disease, a Review

Round 1

Reviewer 1 Report

Manuscript Sickle cell disease, A review by Cameron K. Tebbi is a well-written review on SCD covering almost all the aspects of the disease from genetics to pathology and treatment.

Though I have the following suggestions-

Somehow subheadings are breaking the flow of smooth reading. I think the manuscript can be summarized in parts dealing with genetics, pathology, treatment, and conclusions.

• Maybe various paragraphs under 'Genetic background' and 'Genetics and origin' can be combined as there are some repetitive sentences on point mutation under these headings.
• Similarly, ‘Disease manifestations’ can be given as one main heading under which ‘pain, ‘acute chest syndrome, ‘cardiac complications, etc. can be given as subheadings.
• Similarly, under the ‘Treatment’ section, the rest of the treatment-related sections can be given under subheadings.
• To be consistent 1-40 percent can be written as 1-40 % in line 202

Author Response

Response to reviewer 1:

The review and suggestions by reviewer 1 are helpful. The following changes were made:

1. To have a better flow, sub-headings are made as a part of subject paragraph.
2. Multiple corrections are made to comply with the reviewer 1 suggestions to make the article easier to read.
3. The manuscript was revised to improve the subjects discussed.

Reviewer 2 Report

The review about sickle cell disease by Cameron Tebbi is a comprehensive and well written manuscript. Nevertheless, I have a few points of criticism:

Major Points:

1. Table 1 needs a mayor revision. It should change from a list into a table with proper columns for treatment category, target, drug category, drug (or a similar structure). Currently, treatment categories are mixed with treatments and separated from the drugs. In addition, in this section, please refer to the comprehensive review of Salinas Cisneros and Thein (doi.org/10.3389/fphys.2020.00435), especially since it will be impossible to include all details.
2. When it comes to the molecular mechanism in the red blood cells (both, in the Introduction and in the Pathophysiology section), the description requires a bit more structure in terms of causality: external 'stimulation' trough, e.g., inflammation associated substances, oxidative stress or others, activates Ca(2+) conducting ion channels (since the Ca(2+) is the central part of the mechanism, it would be nice to mention at least the associated receptors) and then Ca(2+) activates the Gárdos channel (K(+) loss and dehydration), the scramblase (phospatidylserine exposure), cytoskeleton remodelling, vesiculation etc. (compare introduction in doi.org/10.3390/cells10020456 and references therein).
3. The section 'Psychosocial effects' is very vague and needs a more concrete extension.

Minor points:

1. The author refers (as it is usually called) to the polymerization of the hemoglobin. However, chemically it is not a polymerization but a crystallization! I don't ask the author to replace all 'polymerizations' but to mention that although it is widely referred to as 'polymerisation' it is actually a 'crystallization'.
2. The author mentions SCD the most common monogenic disorder, which is obviously right. However, I would like the author to also mention that in quite a number of countries it is a rare disease, which is also an important aspect.
3. The author uses the terms 'red cells', 'red blood cells' and 'erythrocytes'. I recommend to stick to one of them (no matter which one), except if it refers to different cell populations (e.g., with or without reticulocytes) - but then it would need to be defined.
4. The author speaks about 'significant microRNA expression in the human mature erythrocyte' (line 83). It's true that red blood cells are full of microRNA, but I would not call it expression. I think 'abundance' is more appropriate.
5. K-Cl co-transporter is NOT an ion channel (line 111)!
6. When referring to glycolysis, the author refers to Emden Meyerhof (EMP) (line 264), where to my best knowledge the 'P' stands for 'Parnas', which is missing.
7. Some of the headlines are followed by a colon, some not.
8. The wording 'SCD can be prevented prenatally' (line 523) sounds a bit odd. Although it is explained in the following paragraph, it requires in vitro fertilization, which is rather the exception than the rule.
9. Lines 585-587: Please provide the relation number of deaths per what number of patients and death at what (average) age.
10. Lines 592/593: Hospitalizations out of how many patients?
11. The author states 'These values usually increase during acute events.' (line 642/643) As a cause or a consequence?
12. On page 14 and 15 there are a number of hyperlinks. Unclear why they are there.
13. Line 717: 'ant'? 

Author Response

The comments made by the reviewer 2 is sincerely appreciated and changes were made accordingly.

Major points:

1. (Reviewer state “Table 1” but the subjects mentioned in the comments appear to refer to the “Table 2”). In response to the reviewer, table 2 is revised, additional data is added, and the table is reorganized. A paragraph regarding newer treatments is added to the manuscript. A reference to the work published by Salinas Cisneros and Thein is added (Salinas Cisneros G.; Thein S.L.: Recent Advances in the Treatment of Sickle Cell Disease. Frontiers in Physiology. 2020,11:435. doi10.3389/fphys.2020.00435).  
2. The manuscript is revised and a paragraph describing transport pathway is added to the ”Pathophysiology” section. . A paragraph regarding the events culminating to sickle cell production, as recommended by the reviewer, is added to the pathophysiology section.
3. Section on psychological effect of the disease is expanded

Minor points:

1. In the “Introduction “ section, a sentence is added to indicate polymerization is chemically equivalent to crystallization.
2. A sentence indicating in some countries the disease is rare and a diagnostic and management difficulties is added in the “Epidemiology, distribution, incidence and prevalence section”.
3. The term “red cells” and “red blood cells” are replaced with “erythrocytes”.
4. Regarding “microRNA’, the word expression is replaced with “abundant”.
5. To better explain the role of K-cl co-transporter, a descriptive paragraph is added to the pathophysiology section.
6. The abbreviation of EMP was used for Emden Myerhof Pathway. The word “Pathway” which was left out is added.
7. A colon is uniformly added to all headlines.
8. Prenatal prevention is commonly used in the field and therefore is not changed.
9. The number of deaths is er year and not per total number of patients.
10. The number of hospitalizations mentioned is per year and not based on the number of patients.
11. Additional information is added to indicate as a consequence of the disease
12. No hyperlink in the version sent by the editor were found
13. The word anti was missing “i” and this was added