The Effectiveness of No or Low-Dose versus High-Dose Aspirin in Treating Acute Kawasaki Disease: A Systematic Review and Meta-Analysis

Response to Reviewer 1 Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted file

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Must be improved

Is the research design appropriate?

Yes

Are the methods adequately described?

Can be improved

Are the results clearly presented?

Can be improved

Are the conclusions supported by the results?

Can be improved

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1      Abstract

1.1    The first sentence seems poorly worded. I recommend : The systematic review and meta-analysis assess the effectiveness of no or low dose versus high-dose aspirin on the incidence of coronary artery aneurysms (CAAs), intravenous immunoglobulin (IVIG) resistance, hospital stay length, and fever duration during the acute phase of Kawasaki disease. (Lines 21 to 24)

Response: We Agree. Therefore, we have, accordingly, changed the text to emphasize this point.

Revised text: This systematic review and meta-analysis assess the effectiveness of no or low dose versus high-dose aspirin on the incidence of coronary artery aneurysms (CAAs), intravenous immunoglobulin (IVIG) resistance, hospital stay length, and fever duration during the acute phase of Kawasaki disease.

Comments 1.2 To ensure a clear understanding of the methodology, I would change “The risk of bias was assessed using the Newcastle–Ottawa scale for cohort studies and Cochrane’s Risk of Bias Tool for RCTs, and the data were analyzed using the Review Manager software.” to “The risk of bias was assessed using the Newcastle–Ottawa scale for cohort studies and Cochrane’s Risk of Bias Tool for RCTs. The data were analyzed using the Review Manager software.” (Lines 28 to 30)

Response: We agree. Therefore, we have, accordingly changed the sentence.

Comments 1.3 I think it needs to be clearer in the abstract that reported results are for no or low-dose vs. high-dose aspirin. On lines 33, 35 and 37, it is mentioned “between no, low-dose, and high-dose” and “were similar in all groups” suggesting that there are three groups which were compared to each other.

Response: Thank you for pointing this out. We agree. Therefore, we have, accordingly, updated the text.

Revised text: Moreover, fever duration (mean difference [MD] = 3.55 hours, 95% CI = −7.99–15.10) and hospital stay length (MD = −0.54 days, 95% CI = −2.50–1.41) were similar in no and low-dose aspirin compared to high-dose aspirin group. Our review indicates no significant differences in the incidences of CAA and IVIG resistance, fever durations, and hospital stay lengths between no or low-dose versus high-dose aspirin in treating the acute phase of KD.

Comment 1.4 Presenting the p-value on top of the 95%CI does not add any information and is therefore not necessary.

Response: We agree with this comment. Therefore, we removed the p-value.

Comment 1.5 Remove the last sentence “However, more RCTs are needed.” See below for some comments on the need for an RCT (line 38)

Response: We agree with this comment. Therefore, we removed this sentence.

Comment 2     Introduction

2.1   The introduction is long. I recommend only including information necessary to our understanding of the disease and the problematic in the introduction. For example, I do not believe it is necessary to keep the following sentences : “It was first reported by Tomisaku Kawasaki, a Japanese pediatrician.” (Lines 44-45), “The cardiac manifestations were first documented in 1970.” (Line 64). The authors should only include a summary of the description of the disease, its pathophysiology, its complications, its treatment, and the side effects of high-dose aspirin.

Response: Agree. We have, accordingly, modified the introduction to emphasize this point.

Revised text: Kawasaki disease (KD) is an acute, medium vessel vasculitis affecting the coronary arteries and commonly presents in children younger than five years of age [1]. KD is described as a mucocutaneous lymph node syndrome that presents with a fever lasting five days and at least four of the five following clinical manifestations: bilateral bulbar conjunctival injection without exudate, oral mucus membrane changes, peripheral extremity changes, polymorphous rash, and cervical lymphadenopathy [2].

The exact cause of KD remains uncertain. However, it is suspected that some type of infectious agent is responsible for this disease, as it shows seasonal variation [3]. The immunological response to KD is complicated, involving innate and adaptive immune cells activating and infiltrating the coronary artery wall. KD vascular pathology has been categorized into three sequentially connected pathological processes based on observations of post-mortem tissue from patients with KD. During the first two weeks, necrotizing arteritis develops and is accompanied by neutrophilic infiltrations that gradually damage the coronary artery intima, media, and some adventitia. Necrotizing arteritis may lead to the development of coronary artery aneurysms (CAAs) and is followed by two additional processes: luminal myofibroblast proliferation and subacute or chronic vasculitis. These processes happen concurrently and may be noticed months to years after the onset of KD [4].

It has been reported that 9% of patients with KD will experience acute-phase cardiac complications, while about 3% will experience cardiac sequelae. It has also been documented that about 50%–70% of patients in the acute phase of KD will experience myocardial inflammation. Additionally, cases of aortic and mitral regurgitation have been documented. Moreover, data shows that about 15%–25% of untreated children will develop a CAA [1]. There is no specific diagnostic test for KD; it is mainly diagnosed by the presence of four of the five clinical criteria mentioned above. Interestingly, about 15%–20% of KD cases are considered atypical, which is diagnosed by the echocardiographic identification of a coronary artery lesion without fulfilling the criteria [5].

Comment 2.2 What is lacking in the introduction is the details of what is known on ASA efficacy, and what justifies the current meta-analysis.

Response: Agree. We have, accordingly, revised the introduction and added information to emphasize this point.

Revised text: Combining intravenous immunoglobulin (IVIG) and aspirin at a high dose (>30 mg/kg/day) is recommended in the initial phase of the disease as it might result in stronger anti-inflammatory effect. Additionally, the use of low-dose aspirin is recommended after the fever subsides for its anti-platelets effect. However, previous literature has not found clear evidence that high dose aspirin provides greater anti-inflammatory benefits than the IVIG therapy alone and high-dose aspirin has some side effects. Its most common adverse effects are gastrointestinal disturbances, which can range from gastritis to gastrointestinal hemorrhage. Hypersensitivity is also common, affecting 1%–2% of those taking aspirin. The symptoms range from a simple rash to angioedema and anaphylaxis. Moreover, the prevalence of allergic symptoms may be 26% higher among patients with asthma and chronic rhinosinusitis. Lastly, a rare but fatal condition, Reye syndrome, is characterized by a viral upper respiratory tract infection and fever in children treated concurrently with aspirin [8,9].

Comment 2.3 The objectives of the study need to be clearly defined in the last paragraph of the introduction. The authors stated that “our study aimed to assess the effectiveness […]”, but a meta-analysis does not assess effectiveness, especially if it pools results from observational studies. The objectives should also clearly state the primary and secondary outcomes) (lines 97-98).

Response: Agree. We have, accordingly, changed this statement.

Revised text: Therefore, based on the previous literature, our study aimed to assess the association of high-dose aspirin vs. low-dose or no aspirin during the acute phase of KD. The primary outcome was the incidence of CAAs. The secondary outcomes were hospital stay length, fever duration, and IVIG resistance.

Comment 3 methods

3.1   I assume the search strategy included synonyms and probably MeSH terms for Pubmed. The complete search strategy should be available (table in supplements).

Response: We thank the reviewer for his comment. We agree with the need to include the search strategy in details; therefore, we have included the search strategy as a supplementary file.

 Supplementary file can be found in appendix A.

Comment 3.2   I would group the sections Search Strategies and Study Design and Criteria and title it Search strategy and Inclusion/Exclusion criteria. The study design is not mentioned in the paragraph as it has already been mentioned in the beginning (“This systematic review and meta-analysis …” (Line 101). There is also only one search strategy.

Response: We agree with this comment, we have grouped both sections.

Comment 3.3   The exclusion criteria should not be simply the opposite of the inclusion criteria, but rather a list of characteristics that requires exclusion. A study that meets the inclusion criteria could possess additional characteristics that can interfere with the outcome of the study (which would be the exclusion criteria).

Response: We appreciate the reviewer’s insightful comment regarding the exclusion criteria. We agree that the exclusion criteria should focus on specific characteristics that could interfere with the study outcomes. We have revised the exclusion criteria accordingly in the manuscript to address this point.

Revised text: The exclusion criteria were as follows:  (1) case-control studies or case series, as these study designs are more prone to bias in assessing treatment effects, (2) studies including patients with other vasculitis or autoimmune conditions that could confound the KD treatment response, (3) studies were patients received additional anti-inflammatory treatments beyond standard IVIG and aspirin, (4) studies with incomplete or unclear reporting of aspirin dosing regimens, (5) studies with follow-up periods shorter than 4 weeks, as this may be insufficient to assess CAA outcomes, (6) studies focusing solely on recurrent or refractory KD cases, (7) non-English language publications due to translation limitations, and (8) duplicate reports of the same patient cohort. 

Comment 3.4   In line 111, the authors mention no restriction for language, but an inclusion criterion is studies published in English (line 119).

Response: Thank you for your comment. In the primary search there was no restriction of language (searches were not limited by language and no filters were applied), however, during the study screening phase non-English studies were excluded due to translation limitations. We agree that it appears contraindicating and needs to be clearer to the reader, therefore, the text was revised and corrected accordingly.

Revised text: Two authors (author 3 and author 9) conducted a comprehensive systematic search of the PubMed and Google Scholar databases using the keywords [Kawasaki disease] AND [Aspirin OR Acetylsalicylic acid] to identify relevant studies published from their inception to November 2023.  No language or time restrictions were applied during the primary search and no filters were added. 

Comment 3.5   The primary outcome should be clearly defined. Was there a Z-score cut-off? Was a mild dilatation considered a CAA (Z between 2.0 and 2.5)? The authors should cite the references used to define their primary outcome.

Comment 3.6   The authors should comment of the decision not to include medium CAA and giant CAA in their secondary outcomes.

Response: We appreciate your thoughtful comment. We agree to the need of adding the CAL criteria definitions, therefore, the text was adjusted accordingly. Regarding the medium and giant CAA, all CAA were included in our study, we did not categorize the CAA based on the size in our study and all were included as primary outcome.

Revised text: Outcomes

The primary outcome was the incidence of CAAs, which was assessed using echocardiography according to either the Japanese Ministry of Health criteria which classify coronary arteries as abnormal if the internal lumen diameter is >3 mm in children <5 years old, or >4 mm in children≥ 5 years old; if the internal diameter of a segment measures ≥ 1.5 times that of an adjacent segment; or if the coronary lumen is clearly irregular [7, 11] or the AHA coronary artery Z-score system in which in which the Z-score of coronary artery diameter is calculated using special formulas and a Z-score of ≥2.5 for any coronary artery is considered CAA [12, 13].The secondary outcomes were hospital stay length, reported as the number of days from admission to discharge; fever duration, reported as the number of hours spent in a febrile state after therapy initiation; and IVIG resistance, reported as the number of patients requiring further treatment after receiving the first IVIG dose.

Comment 3.7   Line 138 : Change the term “included” to “selected”. Included studies will be those meeting the inclusion criteria.

Response: Agree. We have changed the term in the manuscript to meet this point.

Comment 3.8   Line 171 : It is not necessary to mention the p-value as well as the CI or the I². Since CI and I² provide more information, p values should not be reported.

Response: Agree. We have, accordingly, revised the text and the p-value was removed.

Comment 3.9   In the results, the test for an overall effect is mentioned and z-score are reported, but this test is not described in the Statistical Analysis section.

Response: We appreciate the reviewer’s comment. We agree on the importance of describing the z-score in the statistical analysis section. The text was revised and changes were made accordingly.

Revised text:  In addition to the previously described analyses, we conducted tests for overall effect in our meta-analysis. The overall effect was assessed using a z-test, which evaluates whether the pooled effect size is significantly different from zero. The z-score, which represents the number of standard deviations the pooled effect is from zero, was calculated and reported for each meta-analysis. A two-tailed p-value associated with the z-score was used to determine the statistical significance of the overall effect, with p-value <0.05 considered statistically significant.

Comment 4 results

4.1   Figure 1 : Change the title. The figure does not show the search strategy. It shows the results of the documentary search and study selection. Also, the figure looks stretched, and the layout needs improvement (blue rectangle around identification too small). In the first box, the authors should only present the number in each database. I would also the terms "studies" instead of "reports" or "records". In the last box, "Studies included in the review" is sufficient. Those are not new.

Response: We appreciate your comment. Therefore, we updated Figure 1 based on the above comments.

Comment 4.2   Table 1 :  Gender should be changed to biological sex. What are CAL criteria? What do the N:, L:, M: and H: mean (no, low, moderate and high dose?) I would change the column with the NOS score/RoB2 to Possible bias since the total score for the NOS is presented in the following table. Under the Table, describe all the abbreviations (RoB2 has never been defined).

Response: Thank you for your comment. We replaced gender with biological sex, NOS score/RoB2 with possible bias, and added abbreviations (N: no aspirin, L: low dose aspirin, M: moderate dose aspirin, H: high dose aspirin, CAL criteria: coronary artery lesion criteria.)

The was no need to add an abbreviation for RoB2 in this section as it was removed.

Comment 4.3   Add percentage in Risk of bias assessment section.

Response: We appreciate the comment. We added percentages to this section.

Revised text: Risk of bias assessment 

The NOS [15] quality assessments of the 11 included RCS are summarized in Table 2. Three had NOS scores >6 % and were judged as high quality, and eight had NOS scores of 4–6 % and were judged as moderate quality. The Cochrane risk of bias [16] assessment of the only included RCT indicated a low risk of bias in all domains.

Comment 4.4 Table 2 : Change the title to avoid repetition and mention it is the quality assessment of the included studies. No need to repeat how to interpret the results under the Table (line 213) (already mentioned in the Methods section).

Response: The title was changed, and line 231 was removed since it was already mentioned in the Methods section.

The new title: Table 2: Quality Assesment of Included Studies

Comment 4.5   For all the results section, I recommend presenting only facts and avoiding the interpretation of the results. Therefore, all the sentences mentioning, “indicating …“ or “suggesting …” should be erased. (lines 217-218, 231-232, 235-236, 239-240, 247-248, 252-253, 258, 266-267, 276-277)

Response: Thank you for pointing this out. Any sentences used for results interpretation were deleted.

Comment 4.6   Line 219, 233, 237, 249, 257, 277: The heterogeneity was high (the cut-off of 50% has already been presented and there was no mention of extremely high). It is better to interpret heterogeneity has recommended (> 50% = high).

Response: We agree with the reviewer’s comment. As such, extremely high was replaced with only high.

Comment 4.7   The authors could mention that combining all studies means comparing no or low-dose to high-dose aspirin (lines 223, 238, 255, 275).

Response: We agree that for better clarification it should be added. Therefore, we added it accordingly in the text.

Comment 4.8   Figure 2 : The title needs to describe what is presented in the Figure. Here is a recommendation: “Forest plot of the relative risk of CAA in no or low-dose versus high-dose aspirin groups.”

Response: The following title of Figure 2 was changed from “A forest plot showing the relative risk of CAA identified in the meta-analysis of the 12 included studies. “to “Forest plot of the relative risk of CAA in no or low-dose versus high-dose aspirin groups.”

Comment 4.9   Figure 3, 4, 5 : see previous comments on figure titles.

Response: The titles of the mentioned figures were updated based on the suggestions.

The revised version:

Figure 3:  Forest plot of the relative risk of IVIG resistance in no or low-dose versus high-dose aspirin groups.

Figure 4: Forest plot of the MD in fever duration in no or low-dose versus high-dose aspirin groups.

Figure 5: Forest plot of the MD in hospital stay in no or low-dose versus high-dose aspirin groups.

Comment 4.10     I wonder if it is necessary to mention “Heterogeneity could not be assessed since this analysis included only one study” (lines 253-254 and 268-269), because heterogeneity is the variation between studies and therefore can obviously not be measured with only one study.

Response: We agree with the reviewer’s comment. We removed any sentences mentioning the heterogeneity of the only included RCT.

Comment 4.11        I would remove the expression “highly significant” and rather mention that the p-value was small.

Response: We agree with the reviewer’s comment. As such, the highly significant part was removed, and a mention of a small p-value was added.

Comment 4.12          I also think it would be interesting to discuss what is clinically significant, which is different than what is statistically significant, but I believe this should be done in the discussion.

Response: Thank you for your valuable point of view. We agree, therefore, we added clinical implications section line 280-line 395

Revised text: Clinical implications

Since all patients diagnosed with KD are treated initially with aspirin and IVIG, it was necessary to further investigate the need of administration of high-dose aspirin to patients in acute phase KD. Considering the possible side effects of high dose aspirin and the anti-inflammatory effect of IVIG, the clinical significance of adding high dose aspirin to act as an anti-inflammatory in the acute stage is still in doubt. Our review investigated clinically important parameters including developing CAA, IVIG resistance, fever duration and hospital stay length and their relationship with different doses of aspirin. 

This study found no statistically significant association between different doses of aspirin and the incidence of CAA, IVIG resistance, fever duration, and hospital stay length. Hence, based on our results it is adequate to use low-dose aspirin in the acute phase of KD. Nonetheless, implementing these outcomes in clinical practice requires consideration of various factors, including the study design of included studies, differences in sample size between different aspirin doses groups, and possible confounders effect. Additionally, the overall heterogeneity across the included studies cannot be ignored, which may encourage further analysis of intrinsic differences between included studies. Thus, it is rational to adhere to the present AHA guidelines regarding administration of high-dose aspirin in the acute phase of KD until further well-designed studies are carried.

Comment 5       Discussion

5.1   The last sentence should be reformulated (lines 289 to 291). The meta-analysis did not demonstrate the efficacy of no or low-dose compared to high-dose aspirin, but the lack of difference between both treatments. Overall, it is more appropriate to use the term “association” rather than “efficacy”, as most studies were observational.

Response: Thank you for pointing this out. We agree with this comment. Therefore, we have substituted the term efficacy with the term association.

Comment 5.2   Lines 310-311: I wonder if the study really “potentially indicat[ed] that high-dose aspirin has fewer benefits than low-dose” or if it indicated no difference between both treatments. Do you mean it has fewer benefits, because effectiveness is the same, but high dose has more side effects?

Response: We appreciate your comment. Yes, we meant that since high dose aspirin has some side effects and both low and high dose has same effectiveness, then high dose aspirin would have fewer benefits. However, we can see that this sentence can be confusing to the redear, therefore, we have changed the text accordingly to make it clearer to the reader.

Revised text: Similarly, previous studies showed that low-dose aspirin did not increase CAA risk [31, 33, 34], potentially indicating that high-dose aspirin has the same effect in lowering CAA incidence compared to low-dose aspirin.

Comment 5.3   References for lines 312-313 “Moreover, previous studies indicate no significant difference in IVIG resistance between low-dose and high-dose aspirin.” Is it only reference 29? If so, change to “Moreover, a previous meta-analysis indicated no significant difference in IVIG resistance between low-dose and high-dose aspirin [29].”

Response: we appreciate the reviewer’s comment and for pointing this out. We noticed missed reference and corrected the text and the reference list accordingly.

Revised text: Moreover, previous studies indicate no significant difference in IVIG resistance between low-dose and high-dose aspirin. Similarly, we found that IVIG resistance did not differ significantly between aspirin groups [31, 32, 33, 34].

Comment 5.4   I am confused about the references for the paragraphs on fever duration and hospital stay lengths. Reference [25], [26] and [27] are studies included in the studies and should therefore not be discussed in the paragraph comparing the results to previous literature. Are the references [30] and [31] meta-analyses? I would describe those more and identify differences that could explain why the authors obtained different results.

Response: We thank and appreciate the reviewer’s insightful and informative comment on the discussion section. We agree with this comment and we have reviewed the text. We have noticed that we had referenced wrong studies, therefore, the text and the reference list were corrected accordingly.

Revised text:

While the role of high-dose aspirin in the acute phase of KD has been comprehensively investigated, only a few studies evaluated the effectiveness of low-dose or no aspirin in the acute phase of KD. Our study showed that no or low-dose aspirin did not significantly increase CAA incidence compared to high-dose aspirin. Similarly, previous studies showed that low-dose aspirin did not increase CAA risk [31, 33, 34], potentially indicating that high-dose aspirin has the same effect in lowering CAA incidence compared to low-dose aspirin. Moreover, previous studies indicate no significant difference in IVIG resistance between low-dose and high-dose aspirin. Similarly, we found that IVIG resistance did not differ significantly between aspirin groups [31, 32, 33, 34].

Our meta-analysis also showed no significant difference in the average fever duration between no aspirin or low-dose aspirin compared to high-dose aspirin, indicating that high-dose aspirin has no additional benefits in reducing fever duration than low-dose aspirin. However, previous studies showed a shorter fever duration among patients receiving high-dose aspirin [33, 34]. Nonetheless, other studies reached conclusions consistent with our study [31, 32].

Moreover, our study showed that hospital stay lengths did not differ significantly between no/low-dose aspirin versus high-dose aspirin. This is consistent with previous systematic reviews [31, 32, 34].  However, a previous study indicated shorter hospital stays among patients receiving high-dose aspirin [33], which is inconsistent with previous studies and this can be attributed to the high level of heterogeneity of that study.

Comment 5.5   In the Limitations and recommendations section, it would be interesting to develop on how the identified limits could have influenced the results.

Response: Thank you for pointing this out. We agree with this comment. Therefore, we have updated the limitation and recommendation section to emphasize this point.

Revised text: Limitations and recommendations

Our meta-analysis had some limitations. Firstly, most of the included studies were RCS due to the lack of RCTs on this topic, so there was poor control over the exposure factors, covariates, and potential confounders. Secondly, the heterogeneity in the reported results could be attributed to several factors including, study setting, different CAA criteria (Z-score and Japanese criteria), and calculation of fever duration at diverse time points. Thirdly, only one included study compared no aspirin to high dose aspirin in regards to fever duration. In addition, only one included study compared low dose to high dose aspirin regarding hospital stay length. Lastly, the sample size was unequal across aspirin doses. Therefore, it is important to acknowledge that the identified limitations could influence the generalizability of the results.

Comment 6         Conclusion

6.1   As mentioned in the abstract, it needs to be clear that no and low-dose were not compared and it is no or low-dose versus high dose (line 343).

Response: Agree. We have revised the text and changes were made accordingly.

Revised text: This comprehensive meta-analysis assesses the effectiveness of various aspirin doses during the acute phase of KD in pediatric patients. Its findings suggest no significant difference in the incidences of CAA and IVIG resistance, fever duration, and overall hospital stay length between no aspirin or low-dose aspirin versus high-dose aspirin during IVIG treatment for acute phase KD.

Comment 6.2 The authors mention the need for an RCT in the conclusion, in the abstract, and in the section “Limitations and recommendations”. This should be more nuanced. Some will argue that we should not perform RCT to prove that a medication does not work. RTC are to confirm results from observational studies. In my opinion, this metanalysis represents strong evidence that and RTC would be a waste of resources and that there is no equipoise to randomize children to high-dose aspirin.

Response: We agree with your point of view. We have removed the recommendation to do more RCTs from the abstract and limitation section and adjusted the conclusion section accordingly.

Revised text: This comprehensive meta-analysis assesses the effectiveness of various aspirin doses during the acute phase of KD in pediatric patients. Its findings suggest no significant difference in the incidences of CAA and IVIG resistance, fever duration, and overall hospital stay length between no aspirin or low-dose aspirin versus high-dose aspirin during IVIG treatment for acute phase KD. This observation emphasizes that opting for lower aspirin doses might be prudent, given the substantial and potentially serious side effects associated with high-dose aspirin. Nonetheless, it is important to consider that drawing a definitive and robust conclusion is challenging since only one RCT was included in this study. Therefore, this study’s results highlight the need for further well-designed prospective studies with larger samples, better control of covariates, and fewer confounders to further verify the effectiveness of low-dose or no aspirin. By addressing these aspects, researchers can significantly enhance the conclusiveness and reliability of insights into the impact of these aspirin doses in the clinical management of acute phase KD.

Comment 1         General comments

1.1   I noticed the authors use both “efficacy” and “effectiveness”. “Effectiveness” seems more appropriate since mostly observational studies were included. It is appropriate to use “efficacy” with RCTs only (controlled ideal circumstances).

Response: We appreciate the reviewer’s insightful comment and pointing this out. We agree that effectiveness is more appropriate to use as our systematic review and meta-analysis mostly included observational studies, therefore, we have accordingly changed the text and used effectiveness instead to emphasize this point. Additionally, the title was changed and efficacy was substituted by effectiveness.  

Comment 1.2   Some sentences could be reformulated to improve the flow of the text. For example, while this following sentence is grammatically correct : “However, it is suspected that a type of infectious agent causes it since it shows seasonal variation” (lines 51-52), it could be better worded (for example, “However, it is suspected that some type of infectious agent is responsible for this disease, as it shows seasonal variations.”).

Response: Agree. We have, accordingly, changed the sentence to improve the flow.

4. Response to Comments on the Quality of English Language

Point 1: ok

Response 1: the manuscript was edited by Cambridge Proofreading LLC for English grammar, punctuation, spelling, and style to improve the quality of English Language.

5. Additional clarifications

changes were applied to the text according to reviewers’ comments.

The title was changed from “efficacy” to “effectiveness”.

The reference list was updated.

Response to Reviewer 2 Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Yes

Is the research design appropriate?

Yes

Are the methods adequately described?

Yes

Are the results clearly presented?

Yes

Are the conclusions supported by the results?

Yes

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1: One minor comment: authors may consider highlighting that only one study compared no Aspirin to high Aspirin dose (lines 250-251) regarding the fever duration as a limitation. Same for line 264 (low dose to high dose Aspirin regarding hospital stay length).

Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have updated the limitation paragraph accordingly.

Revised text:

Limitations and recommendations

Our meta-analysis had some limitations. Firstly, most of the included studies were RCS due to the lack of RCTs on this topic, so there was poor control over the exposure factors, covariates, and potential confounders. Secondly, the heterogeneity in the reported results could be attributed to several factors including, study setting, different CAA criteria (Z-score and Japanese criteria), and calculation of fever duration at diverse time points. Thirdly, only one included study compared no aspirin to high dose aspirin in regards to fever duration. In addition, only one included study compared low dose to high dose aspirin regarding hospital stay length. Lastly, the sample size was unequal across aspirin doses. Therefore, it is important to acknowledge that the identified limitations could influence the generalizability of the results.

4. Response to Comments on the Quality of English Language

Point 1: fine, no issues detected

5. Additional clarifications

Changes were applied to the text according to reviewers’ comments.

Title was changed from “efficacy” to “effectiveness”.

Reference list was updated.

Response to Reviewer 3 Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Can be improved

Is the research design appropriate?

Yes

Are the methods adequately described?

Yes

Are the results clearly presented?

Yes

Are the conclusions supported by the results?

Yes

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1: 1.      The abstract, Introduction, and Methods sections are well-written.

Response: Thank you for taking the time to review this manuscript.

2.      Page 3 line 137: abbreviations i.e., HA, LA, NA, 137, and RA; expansions not given earlier. Similarly line 140: AI and SA terms. Instead of researcher abbreviation can be mentioned as author 2 and 3 like that.

Response: Thank you for pointing this out. We agree with this comment. Therefore, we have substituted authors abbreviations with their number.

3.      Figure 1-5: Text information must be made readable font size.

Response: Thank you for pointing this out. We agree with this comment. Therefore, we have modified the figures layout to address this issue.

4.      Page 12: between paragraphs line space and indent need to be verified and throughout the manuscript as well.

Response: Agree. We have, accordingly, changed and modified the text alignment.

5.       References are limited and recent references are covered only 16%. Need to update with recent relevant references.

Response: We Agree. We have, accordingly, revised and updated the reference list with references where applicable.

Minor comments

1.      A text alignment needs to improve.

Response: Agree. We have, accordingly, changed and modified the text alignment.

2.      References are not recent. Need to update.

Response: Thank you for your valuable comment. We have, accordingly, revised and updated the reference list with references where applicable. Line 316 page 12 to line 389 page 13.

4. Response to Comments on the Quality of English Language

Point 1: fine, no issues detected

5. Additional clarifications

Changes were applied to the text according to reviewers’ comments.

Title was changed from “efficacy” to “effectiveness”.

Reference list was updated.