PONE-D-24-41837Global Prevalence of Elevated Estimated Pulmonary Artery Systolic Pressure in Clinically Stable Pediatrics and Adults with Sickle Cell Disease: A Systematic Review and Meta-analysisPLOS ONE

Dear Dr. Ghazaiean,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers found merit in your study but also identified several areas that need more clarification.  For example, the sickle cell disease genotype and definitions of severity that you have used are not consistent with the literature and should be revised accordingly.  Further discussion is also needed to better understand changes before 2014 and after 2015, particularly since hydroxyurea was not recommended until after this time period.

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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?

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: Thank you for your efforts to clarify an unclear topic of real significance to the morbidity and mortality of sickle cell disease. Overall, your analysis is well-done, but the groupings do not fully make sense. Specifically sickle cell disease is the overarching diagnosis that includes severe genotypes (HbSS and HbS/beta-zero thalassemia) and these severe genotypes are referred to as "sickle cell anemia." These patients make up the majority of patients with the disease. I have stated this further and with additional comments below.

Abstract

Background: Suggest rephrasing "stable pediatric and adult" as "stable children and adults"

Results/methods: pediatric patients and patients under 18 years old are usually considered to be the same. I don't see this explained in the methods or presented in the results in the text with this same duplicative description

Introduction:

- Both sentences mentioning homozygous vs compound heterozygous sickle cell disease are redundant

- Regarding the statement about the importance of screening and early detection on page 3, the sickle cell guidelines are mixed regarding the utility of screening ECHOs. The American Society of Hematology does not recommend screening ECHO's for asymptomatic patients. Because of this, even though you include "stable patients" it is not possible to know from your analysis if they are asymptomatic. Screening symptomatic patients would yield higher rates of ePASP, and this difference in testing may explain some of the heterogeneity. If the authors are unable to clarify how many patients were symptomatic, please add this as a limitation

Methods

- Why did you include "sickle cell trait" in your search? I would think this should be excluded

- There may be a typo in the description of the study dichotomy by dates "before 2015 and after 2014"?

- The two different groups of "type of disease (SCA and SCD)" vs "genotype severity of SCD" does not make sense to me. Sickle cell anemia typically is used to describe the severe SCD genotypes (HbSS and HbS/beta zero thalassemia). These seem redundant.

- Additionally, patients with SCA (aka with more severe genotypes) are also patients with SCD (which includes all genotypes)

- I would suggest the authors revisit their analysis and either redefine their groups appropriately or remove the attempt to stratify studies based on genotype/disease severity, since patients with severe genotype SCD (aka with SCA) represent the majority of patients with sickle cell disease

Results

- "western" and "non-western" countries does not provide much meaning to readers. Consider stating the countries or continents.

- 3.3 "prevalence of elevated ePASP in adults and pediatrics." Pediatric is an adjective. Consider changing pediatrics to children or adding the word patients to the end

Reviewer #2: Summary:

This manuscript by Ghazaiean et al is a thorough and extensive systematic review and meta-analysis evaluating the prevalence of elevated estimated pulmonary artery systolic pressure (ePASP) in pediatrics and adults with sickle cell disease (SCD) worldwide. The authors included 79 primary studies comprising 6,256 pediatric and 6,582 adult patients with SCD from 22 countries. They found that the prevalence of elevated ePASP was 21.8% in the pediatric population and 30.6% in adults. There were differences in the prevalence of elevated ePASP in subgroup analyses with age, sex, severity of SCD genotype, and year (before 2015 and after 2014). Those with elevated ePASP had significant differences in clinical characteristics and laboratory values compared to those without elevated ePASP. The authors concluded that there is a high prevalence of elevated ePASP in patients with SCD.

Elevated ePASP on a TTE is an important approach to early detection/screening of pulmonary hypertension, a major risk factor for morbidity and mortality in SCD. There was a systematic review on this in 2015 (Caughey et al, BJH), and this updated version 9 years later features the addition of 34 more studies (2,925 more adults & 3,804 more pediatric patients). This is a much needed updated review given there have been various improvements in the management of SCD including in treatment and technology. Given that there is no consensus on optimal screening practices for PH, it is important to first establish the scope of elevated ePASP in the SCD population. Thus, it is critical in the field of SCD to publish this data given the implications for health policy and updated guidelines. The strengths of this paper are its thoroughness, great tables and figures, and interesting subgroup analyses. In the discussion section, there was also a comprehensive review on the pathophysiology of pulmonary hypertension. However, there are some areas where this manuscript could be strengthened, to further enhance and convey the importance of elevated ePASP screening.

Major issues:

• Please cite the previous meta-analysis on ePASP and sickle cell disease (Caughey MC, Poole C, Ataga KI, Hinderliter AL. Estimated pulmonary artery systolic pressure and sickle cell disease: a meta-analysis and systematic review. Br J Haematol. 2015 Aug;170(3):416-24. doi: 10.1111/bjh.13447. Epub 2015 Apr 9. PMID: 25854714.) The authors mention this paper in the introduction and it is a crucial cutoff point in the analysis (before 2015, after 2014), so it should be acknowledged. This paper can also be referenced to highlight in the discussion any new findings from the analysis, and possible explanations. It is great that this work builds on work done previously.

• The definitions for sickle cell anemia (SCA) versus sickle cell disease (SCD) and mild/moderate/severe TRV, should be clearly defined as it is not entirely apparent who is included in these groups, which makes the paper confusing to read. Does SCA just include HbSS or did it also include HbSbeta-0-thalassemia? For severity of ePASP, what were the cutoffs? These definitions are important as the authors later make recommendations on screening practices.

• The authors have many interesting findings such as the decrease in prevalence of ePASP in pediatrics after 2014 compared to before 2015, lab correlations, sex differences, and non-Western countries versus Western countries – the manuscript could be enhanced with further discussion of at least a few of these findings if not all of them. TTE may be more accessible in non-Western countries, which may be an important factor as to why this is an important screening tool.

Minor issues:

• In the introduction paragraph, the following sentence is ambiguous to me as it makes right heart catheterizations seem like the initial and sole method of diagnosing pulmonary hypertension for some cases, but it is typically done after a screening TTE: “This underscores the importance of screening and early detection of PASP elevations through non-invasive methods, such as trans-thoracic echocardiography, rather than relying solely on invasive right heart catheterization (RHC) for diagnosis.”

• In the introduction, when mentioning the compound heterozygous state, you should clarify that HbSC is an example of a compound heterozygous state, as the way it is written know suggests it is the only heterozygous state.

• In the introduction, would clarify that a RHC is required for diagnosis of PH. TRV > 2.5 is a great screening tool but is not always indicative of pulmonary hypertension (sensitivity increases with higher TRV), however, given that elevated TRV is associated with increased mortality, it is still an important clinical feature to assess, particularly since it is noninvasive.

• It feels as though the author of sections 3.3.1-3.3.2 was different from the author of 3.3.3- 3.3.7. The use of the phrase, “meticulously assessed” in the latter sections do not appear consistent with the writing style of previous sections. Would recommend being more consistent and possibly removing a few of the “meticulously” phrases as it is repetitive.

• In section 3.4, please highlight some important takeaways from table 3.

• In the discussion, you mention, “Thankfully, there has been a slightly meaningful decrease in the prevalence of elevated ePASP in children since 2015, as compared to the previous rate.” Why is this 2015 date important? The meta-analysis had been published at that time, but those results would not change clinical practice. What do you think could explain this finding?

• In the discussion, you write “The prevalence of elevated ePASP is notably higher in pediatric males compared to females. However, this trend reverses in adults, where females exhibit a greater prevalence than males.” Please discuss why this is important or what could explain this.

• In the discussion, you write, “Clinical and laboratory analyses of pediatric and adult patients with SCD revealed significant mean differences in various characteristics, including age, oxygen saturation, Hb, HbF, WBC count, and reticulocyte levels between those with elevated ePASP and those without.” Please discuss why this is important.

• On the last sentence of page 26: “Our study proposes a noninvasive screening protocol for PH in children with SCD, which may facilitate the identification of a specific subgroup of patients who would benefit from further evaluation via catheterization. Implementing a strategy to recognize children at risk for hemolysis-associated vasculopathy through a straightforward biomarker, such as elevated TRV, followed by preventive interventions like hydroxycarbamide, transfusions, or other methods to mitigate hemolysis, could significantly enhance survival outcomes in SCD.” – what is your screening protocol? Screen every pediatric patient with TTE? What age? How often? Is there a TRV cutoff? Should we follow the ATS guidelines or ASH guidelines? It would be important to acknowledge there is no consensus. TRV is not a straightforward biomarker, as you mention later in the limitation section – TTEs are highly tech and reader dependent. It would also be important to mention the next steps if the TRV is elevated, including obtaining a pro-NT-BNP, assessing 6 minute walk distance, and a RHC. It would be interesting to discuss any differences in the approach of non-Western versus Western countries given the amount of resources in each setting. It was thoughtful to include potential treatment strategies.

• In the limitations section, I would not recommend listing each limitation with “firstly,” “secondly,” “thirdly,” … “twelfthly” as this makes the paragraph choppy and less interesting to read.

• Section 2.7 Risk of bias assessment – please write in past tense, as you did for the other paragraphs in this section.

• Table 3 is great. Why is “No of studies/total listed” twice?

• I am surprised that there were no differences observed between patients from Western and non-Western countries? Why do you think that is?

Reviewer #3: Abstract

1. In the results section, can the authors clarify the definition of SCA and severe genotype? SCA and severe genotype both typically refer to HbSS and HbSbeta zero thalassemia but both have different prevalence rates and confidence intervals. The statement below is from the paper…

“When stratified by disease type, the prevalence rates for patients with sickle cell anemia (SCA) were 16.55% (95% CI: 12.49 to 20.61) in pediatric patients and 36.06% (95% CI: 31.53 to 40.6) in adults. The prevalence of elevated ePASP among studies with severe SCD genotype was found to be 19.45% (95% CI: 14.95 to 23.95) in pediatric patients and 29.55% (95% CI: 24.21 to 34.89) in adults.”

Introduction

1. Can the authors elaborate more on the importance of elevated PASP in the SCD population in the introduction? For example, multiple studies exist linking elevated TRV with increased morbidity in children and mortality in adults. This was more clearly explained in the discussion but would have been helpful in the introduction to carry the reader along.

2. Sickle cell anemia (SCA) conventionally refers to HbSS and HbSbeta zero thalassemia. Also referred to as “severe genotype.” However, the authors report different values for SCA and “severe genotype.” Please clarify definition.

Results

1. Since the study involved such robust statistical analysis, was a biostatistician involved in this study? I do not see a biostatistician listed among the authors.

2. Were there any echo complications seen in those patients with elevated PASP like diastolic dysfunction? Or were studies with these complications completely excluded during the review process?

- Were other parameters such as normal ejection fraction, left ventricular wall thickness, etc evaluated?

3. Did any cohort have right heart catheterization data? It will be helpful to include this data to demonstrate a correlation between elevated PASP confirmed by right heart catheterization.

4. I found it interesting that there was no statistically significant difference in the prevalence rates of elevated PASP across Western and non-Western countries. Can the authors provide a possible reason for this?

5. Why were the date ranges selected for analysis? “Studies published prior to 2014” and “prior to 2015” were specifically selected as the cut-off year in the selection.

Discussion

1. Can the authors put forward a hypothesis why there has been a “slightly meaningful decrease” in the prevalence of elevated PASP in children since 2015? It is interesting because hydroxyurea did not become very widely adopted until FDA approved hydroxyurea for use in children in 2017. Other factors may be in play.

2. The paper ostensibly sought to estimate the global prevalence of elevated estimated pulmonary artery systolic pressure in children and adults with SCD, but the discussion devotes large sections to tricuspid regurgitation velocity (TRV). Is the argument that PASP may be superior to TRV in estimating pulmonary hypertension or are they equally acceptable alternatives? Does one measurement parameter have any advantage over the other specifically for estimating PH in SCD?

4. Instead of using Firstly to twelfthly to highlight limitations, perhaps the authors can combine some limitations and use other introductory words such as “Furthermore” to introduce the other limitations.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-24-41837R1Global Prevalence of Elevated Estimated Pulmonary Artery Systolic Pressure in Clinically Stable Children and Adults with Sickle Cell Disease: A Systematic Review and Meta-analysisPLOS ONE

Dear Dr. Ghazaiean,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

There are still some minor issues that the reviewer has indicated that should be addressed to improve the clarity of the manuscript.  

Please submit your revised manuscript by Feb 22 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're 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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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Santosh L. Saraf

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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 #2: (No Response)

Reviewer #3: All comments have been addressed

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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 #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

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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 #2: Yes

Reviewer #3: Yes

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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 #2: Yes

Reviewer #3: Yes

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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 #2: The revised manuscript is greatly improved although there are a few small points that should be addressed prior to being published. Here are my comments below.

1. In the abstract, lines 39-41 and the second conclusion (“There has been a slightly meaningful reduction in the prevalence of elevated ePASP among children since 2014) is an overstatement, so I would recommend removing these, particularly since it was not explained in the discussion.

2. In the abstract, lines 37-38, “Age specific analysis… in adults” does not add to the results section and can be removed.

3. In the introduction, lines 64-72, the authors wrote: “The TRV cutoff of >=2.5m/s seems inappropriate… (It is important to note that NT-pro-BNP levels can be deceptive in a condition of renal insufficiency)” should not be in the introduction. Discussing the ambiguity of TRV measurements and cutoffs in the introduction weakens the premise of this meta-analysis (that people use TRV measurements to estimate ePASP), and should instead be in the limitations section.

4. In the introduction and the rest of the manuscript, please be consistent with “TRV” and “TRJV” – are these the same? Only TRJV was defined in line 64 as tricuspid regurgitant jet velocity. Also please define the abbreviation ePASP in the introduction as well – PASP was defined in line 62, but ePASP appears in 87 and the reader may not know what the “e” stands for.

5. In the definition section, line 167, what is SPAP? Please define.

6. For tables 1 and 2, they would be strengthened by including the number of patients used to calculate the prevalence rate. You mention using thousands of patients in the meta-analysis, so it would strengthen the validity of the table to show these numbers here as well.

7. For the results section, I am a little perplexed by the sex-specific analysis. Are the authors saying that among male children, the rate of elevated ePASP is 60.35% (because that is quite alarming) or are the authors saying that among children with elevated ePASP, the percentage of males is 60.35%? Similarly, for the adults, is the prevalence of elevated ePASP among male adults with SCD 45.6%? - because that is what is implied by the table. The discussion on sex (lines 452-461) may have to be adjusted if the prevalence rates change upon further re-analysis.

8. Please be consistent in what is statistically significant. If your cutoff is p<=0.05, please do not write that p=0.06 is marginally significant, as this can be misleading. Instead, for the analyses where p=0.06 (variation in heterogeneity indices, children’s ePASP prevalence before and after 2015), you can say that numerically there was a trend towards some specific direction, but it was not statistically significant.

9. In table 3, why are the P-values of the mean difference and standardized mean difference columns separated by the columns “heterogeneity/ I-square and p-value”? If the model is the same for all of the studies, this column can be removed.

10. In the discussion, lines 422-424, the authors note that 22-46% of patients with elevated PASP actually had PH. This should be highlighted as a limitation of using ePASP from TTEs – that TTEs are a good screening tool but do not necessarily equate to pulmonary hypertension. However, there are studies, as the author mentioned that elevated TRVs do portend worse outcomes, so this can be highlighted as well.

11. In the discussion, lines 474-488: this paragraph is confusing and hard to follow. The first sentence states that the prevalence of elevated ePASP in children decreased after 2015, so I was expecting a paragraph about why the authors thought this finding could be valid and true. However, it is unclear how HbF and other factors that affect disease severity in SCD relate to a lower prevalence of ePASP in children, specifically.

12. The discussion should also highlight the interesting findings from the subgroup analyses and how these factors could confound the TTE findings (severe anemia, low O2, etc) or how these could potentially help figure out who to screen (elevated WBC, low Hgb, low HbF, etc). These markers are all indicators of severe disease, and given that the authors consolidated multiple studies, the fact that these all are associated with elevated ePASP is validating.

Reviewer #3: (No Response)

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Reviewer #2: No

Reviewer #3: Yes:  Chibuzo Ilonze

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<p>Global Prevalence of Elevated Estimated Pulmonary Artery Systolic Pressure in Clinically Stable Children and Adults with Sickle Cell Disease: A Systematic Review and Meta-analysis

PONE-D-24-41837R2

Dear Dr. Ghazaiean,

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