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10.1371/journal.pone.0308069
PONE-D-24-03848
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Associations between corticosteroid dosage and clinical outcomes in patients with hypoxemic COVID-19 pneumonia: A retrospective cohort study
Corticosteroid intensity and COVID-19 patients
https://orcid.org/0009-0007-2068-8315
Teeratakulpisarn Napassorn Data curation Formal analysis Investigation Methodology Writing – original draft Writing – review & editing
Chiewroongroj Supattra Data curation Investigation
Naorungroj Thummaporn Formal analysis Methodology Writing – review & editing
https://orcid.org/0000-0001-7137-5537
Ratanarat Ranistha Conceptualization Methodology Project administration Supervision Writing – review & editing *
Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Deng Jiawen Editor
University of Toronto, CANADA
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: ranittha@hotmail.com
6 9 2024
2024
19 9 e030806921 3 2024
16 7 2024
© 2024 Teeratakulpisarn et al
2024
Teeratakulpisarn et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background

Corticosteroids are commonly used to treat COVID-19 patients with hypoxemia, and clinicians have adjusted the corticosteroid intensity on the basis of clinical needs. However, neither the optimal dose nor the duration of treatment has been recommended.

Objective

To investigate whether cumulative doses of corticosteroids, measured as dexamethasone-equivalent doses over the first 14 days, impact outcomes in patients with COVID-19 pneumonia.

Methods

We conducted a retrospective cohort study of COVID-19 pneumonia patients admitted between April 1st, 2020, and September 30th, 2021. The study focused on the type and dose of corticosteroid administered during the initial 14 days, clinical outcomes, and complications. The primary outcome was in-hospital mortality.

Results

Among 271 patients, the mean cumulative dexamethasone-equivalent dose was 158 (119.9–197.25) mg in survivors and 185 (131.7–222.0) mg in nonsurvivors. Univariate analysis revealed that the cumulative dexamethasone-equivalent dose was a risk factor for in-hospital mortality. However, this association did not hold true in the multivariate analysis. After the cumulative dexamethasone-equivalent dose was categorized into quartiles, the moderate dosage (126.01–165.00 mg) in the second quartile was found to be associated with the lowest in-hospital mortality (16.2%). Higher cumulative dexamethasone-equivalent doses were associated with longer hospital and ICU stays and fewer ventilator-free days (p < 0.001). Doses exceeding 165 mg were associated with an increased risk of hospital-acquired infections (p < 0.001).

Conclusions

The cumulative dexamethasone-equivalent dose during the first 14 days is not associated with in-hospital mortality in hypoxemic COVID-19 patients. However, higher cumulative doses exceeding 165 mg are associated with an increased risk of in-hospital mortality and secondary hospital-acquired infections.

The author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.
OutbreaksCOVID-19
Data Availability

All relevant data are within the manuscript and its Supporting Information files.
==== Body
pmcIntroduction

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in late 2019 and was declared a pandemic by the World Health Organization (WHO) in March 2020 [1]. The severity of the disease ranges from asymptomatic to severe pneumonia with acute respiratory distress syndrome and fatal outcomes, particularly in patients with comorbidities, who have a greater potential risk of severe COVID-19 [2]. The pathogenesis of COVID-19 involves two main processes: an early phase driven by SARS-CoV-2 replication and a later phase characterized by immune dysregulation and an inflammatory response, leading to tissue damage. Early-phase treatment primarily involves antiviral therapy, whereas immunosuppressive and anti-inflammatory therapies are more beneficial in the later stage [3].

Immunomodulatory therapy for COVID-19 mainly relies on corticosteroids, particularly dexamethasone. However, dexamethasone has inconsistent outcomes depending on oxygen dependence. Landmark studies, such as the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial and the COVID-19 Dexamethasone (CODEX) trial, demonstrated that the use of dexamethasone showed benefits of mitigating disease severity and death in COVID-19 patients receiving oxygen therapy [4, 5]. Conversely, a systematic review and meta-analysis revealed that the use of dexamethasone in patients not requiring oxygen was linked to increased disease severity and mortality risk [6]. Moreover, studies using alternative corticosteroids (e.g., methylprednisolone and hydrocortisone) in COVID-19 patients reported no improvement in clinical outcomes or mortality rates [7–10]. Consequently, the current National Institute’s COVID-19 treatment guidelines recommend the use of dexamethasone only in patients requiring oxygen therapy [3]. Although one study did compare high- vs. low-dose corticosteroids, it did not report statistically significant outcomes [11]. A consensus on the optimal dose and duration of dexamethasone treatment is still needed.

Therefore, we investigated whether corticosteroid intensity, measured by the cumulative dexamethasone-equivalent dose over the first 14 days, affects in-hospital mortality in patients with COVID-19 pneumonia.

Materials and methods

Study design

This single-center retrospective observational study was conducted at Siriraj Hospital, a tertiary hospital affiliated with Mahidol University, Thailand, from April 1st, 2020, to September 30th, 2021. The study protocol was authorized by the Siriraj Institution Review Board (approval no. Si-355/2020).

Participant selection

We included all COVID-19 patients over 18 years of age with pneumonia who required oxygen therapy and were admitted to Siriraj Hospital. The COVID-19 diagnoses were confirmed by real-time reverse transcription–polymerase chain reaction. Patients who had “do not resuscitate” requests or declined endotracheal intubation were excluded from the study.

Outcomes

The primary outcome of this study was in-hospital mortality. The secondary outcomes were ICU mortality and 28-day and 90-day mortality.

Study procedure

We retrospectively reviewed the patients’ data, including demographic information, underlying diseases, duration of symptoms, hemodynamic parameters, Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. We also collected data from laboratory investigations (arterial blood gas analysis, C-reactive protein, interleukin-6, complete blood count, blood chemistry, and liver function tests). Written informed consent was waived due to the retrospective study design, and approval was obtained from the Siriraj Institution Review Board (approval no. Si-355/2020). Data were accessed for research purposes from January 24, 2023, to April 15, 2023.

We recorded treatment interventions administered during hospitalization, such as antiviral drugs, corticosteroids, other anti-inflammatory agents (e.g., tocilizumab and baricitinib), hemoperfusion therapy, oxygen therapy, prone positioning, renal replacement therapy, and extracorporeal membrane oxygenation (ECMO) therapy provided by nurses, according to the physician’s order. The type and daily dose of corticosteroids given to each patient were recorded for the first 14 days and expressed as the dexamethasone-equivalent dose. The cumulative dexamethasone-equivalent dose during the initial 14 days was used to determine the intensity of corticosteroid treatment. We documented concurrent oxygen therapies administered during the same period. The table for calculating the dexamethasone-equivalent dose is shown in S1 Table. In addition, we reviewed potential complications associated with corticosteroid therapy, including hospital-acquired infections including hospital-acquired pneumonia, urinary tract infection, bacteremia, catheter-related bloodstream infection, skin and soft tissue infection, and gastrointestinal bleeding.

Statistical analyses

Normality tests were conducted for qualitative data. Normally distributed data are expressed herein as means and standard deviations, whereas nonnormally distributed data are presented as medians and interquartile ranges (IQRs). Categorical data are reported as frequencies and percentages. To identify risk factors significantly correlated with mortality outcome, comparisons between survivors and nonsurvivors were made via the chi-square test, Fisher’s exact test, Student’s t test, and the Mann–Whitney U test when appropriate. Variables with p < 0.05 in the univariate analysis were included in a multivariate analysis via a multiple logistic regression model. The cumulative dose of dexamethasone received by each patient in the first 14 days was calculated and divided into quartiles (Q1-Q4). Mortality outcomes and complications were compared via the chi-square test. Kruskal‒Wallis tests were used to analyze other clinical outcomes. Data analyses were performed via IBM SPSS Statistics, version 29 (IBM Corp, Armonk, NY, USA). Two-sided p values < 0.05 were considered statistically significant.

Results

Baseline characteristics

Data were collected from 271 patients with COVID-19 pneumonia who required oxygen therapy at Siriraj Hospital between April 1st, 2020, and September 30th, 2021. Among these, 202 (74.5%) were in the survivor group, and 69 (25.5%) were in the nonsurvivor group (Fig 1). The characteristics of the study patients and treatment according to in-hospital mortality are summarized in Table 1. In the overall cohort, the median age of the patients was 62 years (IQR: 51, 69). Most patients were male, accounting for 66% of the study population. The baseline APACHE II and SOFA scores were 10 (IQR: 7, 13) and 3 (IQR: 2, 4), respectively. All patients had hypoxemia, with a median PaO2/FiO2 (PF) ratio of 151.4 (IQR: 104.8, 224.0). The median cumulative dexamethasone-equivalent dose administered in the first 14 days was 165 mg (IQR: 126, 203). In-hospital mortality occurred in 69 patients (25.5%). Survivors were younger, had a lower proportion of chronic kidney disease, and had lower severity scores (SOFA and APACHE II scores). In contrast, nonsurvivors had lower lymphocyte counts and PF ratios. Compared with survivors, nonsurvivors had a more significant dose of cumulative dexamethasone equivalence, received ECMO and mechanical ventilation more frequently, and had a longer duration of total ventilator days (Table 1).

10.1371/journal.pone.0308069.g001 Fig 1 CONSORT flow chart.

10.1371/journal.pone.0308069.t001 Table 1 Baseline characteristics of the patients and treatment-related data according to in-hospital mortality.

variables	Survivors	Nonsurvivors	p value	
(n = 202)	(n = 69)	
Male, no. (%)	130 (64%)	50 (73%)	0.22	
Age, years	57.82 ± 15.79	67.04 ± 12.28	< .001	
Body mass index, kg/m2	27.45 ± 6.63	27.37 ± 6.04	0.93	
Underlying diseases, no. (%)	
• Obesity (BMI > 30)	56 (27.7%)	22 (31.9%)	0.51	
• Diabetes mellitus	90 (44.6%)	35 (50.7%)	0.38	
• Hypertension	110 (54.4%)	49 (71%)	0.02	
• COPD	5 (2.5%)	4 (5.8%)	0.18	
• Coronary artery disease	19 (9.4%)	11 (15.9%)	0.14	
• Chronic kidney disease	31 (15.3%)	22 (31.9%)	0.003	
• Immunosuppression	10 (5%)	5 (7.4%)	0.46	
APACHE II	9.5 ± 4.8	12.2 ± 4.9	0.001	
SOFA	2.5 (2–4)	3 (2–5)	< 0.001	
Laboratory investigations at baseline	
• C-reactive protein level, mg/L	73.2 ± 64	80.6 ± 79	0.44	
• Lymphocyte count, cell/mm3	521.8 (303.7–960.2)	406.1 (287.3–660.5)	0.03	
• Serum interleukin-6 level, pg/ml	20.8 (10.5–77.9)	21.0 (12.3–120.6)	0.1	
• Serum procalcitonin level, ng/ml	0.2 (0.1–0.9)	0.2 (0.1–1.0)	0.10	
• PaO2/FiO2 ratio	143.3 (112.6–178.6)	141 (99.3–185.4)	< .001	
Treatment	
Cumulative dexamethasone-equivalent dose during D1-D14, mg	158 (119.9–197.25)	185 (131.7–222.0)	0.02	
DOS before steroid treatment, day	5 (3–8)	4 (3–5.5)	0.43	
Remdesivir, no. (%)	57 (28.2%)	28 (40.6%)	0.06	
Tocilizumab, no. (%)	32 (15.8%)	16 (23.2%)	0.17	
Baricitinib, no. (%)	7 (3.5%)	3 (4.3%)	0.74	
Cytokine adsorptive therapy, no. (%)	29 (14.4%)	15 (21.7%)	0.15	
ECMO, no. (%)	1 (0.5%)	6 (8.7%)	< 0.001	
Ventilator requirement, no. (%)	78 (38.6%)	67 (97.1%)	< 0.001	
Total ventilator days, days	5.5 (0–11.5)	8.5 (8–33.5)	< 0.001	
Normally distributed variables are presented as the mean ± standard variation; nonnormally distributed variables are presented as the median (interquartile range).

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; IQR, interquartile range; PaO2/FiO2 ratio: the ratio of arterial oxygen partial pressure to fractional inspired oxygen; SD: standard difference; SOFA: sequential organ failure assessment score; D1-D14, days since steroid therapy was initiated; DOS, day of symptom onset; ECMO, extracorporeal membrane oxygenation therapy; IQR, interquartile range.

Outcomes

In univariate analyses, risk factors, including age, chronic kidney disease, baseline SOFA score, lymphocyte count, baseline PF ratio, cumulative dexamethasone dose in the first 14 days, and ventilator requirement, were significantly associated with in-hospital mortality (Table 1). When these factors were included in the multivariable analysis, the risk factors that remained independently associated with in-hospital mortality were age, chronic kidney disease, baseline PF ratio, and ventilator requirement but not the cumulative dexamethasone dose (S2 Table). Although the cumulative dexamethasone equivalent dose was not statistically significant in the multivariable analysis, it remained a potentially modifiable risk factor during treatment. Therefore, patients were divided into quartiles on the basis of the cumulative dexamethasone dose in the first 14 days (8–126.00, 126.01–165.00, 165.01–203.00, and 203.01–481.40 mg) (S3 Table). The second quartile group (126.01–165.00 mg/14 days) had the lowest in-hospital mortality rate at 16.2%, followed by the first, third, and fourth quartile groups at 22.1%, 25.0%, and 38.8%, respectively (Fig 2). The ICU mortality, 28-day mortality, and 90-day mortality rates showed similar patterns with statistical significance. Details of mortality and other clinical outcomes are presented in Table 2.

10.1371/journal.pone.0308069.g002 Fig 2 Hospital mortality based on the cumulative dose of dexamethasone.

[a] statistically significant with p < 0.005.

10.1371/journal.pone.0308069.t002 Table 2 Clinical outcomes stratified into quartiles according to the cumulative dexamethasone-equivalent dose in the first 14 days.

Clinical outcomes	Cumulative dexamethasone-equivalent dose (mg)	
8–126.00	126.01–165.00	165.01–203.00	203.01–481.4	p—value	
[Q1]	[Q2]	[Q3]	[Q4]	
ICU mortality, no. (%)	10 (14.7%)	6 (8.8%)	12 (17.6%)	18 (26.9%)	0.01	
In-hospital mortality, no. (%)	15 (22.1%)	11 (16.2%)	17 (25.0%)	26 (38.8%)	0.004	
28-day mortality, no. (%)	14 (24.1%)	7 (11.5%)	10 (16.4%)	15 (23.4%)	0.29	
90-day mortality, no. (%)	16 (29.1%)	12 (21.1%)	18 (32.1%)	26 (42.6%)	0.02	
ICU LOS, days	8.5 (6–12)	10 (6.25–15.75)	11.50 (7–16.75)	16 (8–24)	< 0.001 a,b	
Hospital LOS, days	13 (9–17)	15 (11.25–24)	20 (14–31.75)	26 (17–40)	< 0.001 a,b,c	
Total ventilator days, days	7.5 (3.25–12.75)	10.5 (7–19.25)	9 (5.5–17.75)	20 (8–34)	0.003 a	
Ventilator-free days at day 28, days	28 (20.75–28)	27 (17.5–28)	23 (1.25–28)	2 (0–28)	< 0.001 a,b,c,d	
Hospital acquired infection, no. (%)	27 (39.7%)	38 (55.9%)	45 (66.2%)	52 (77.6%)	< 0.001	
GI bleeding, no. (%)	7 (10.3%)	8 (11.8%)	7 (10.3%)	16 (23.9%)	0.06	
Abbreviations: ICU, intensive care unit; IQR, interquartile range; LOS, length of stay; GI, gastrointestinal; Q, quartile

[a] Pairwise comparison revealed significant data with asymptotic significance (2-sided tests), with p < 0.05 between Q1 and Q4.

[b] Pairwise comparison revealed significant data with asymptotic significance (2-sided tests), with p < 0.05 between Q2 and Q4.

[c] Pairwise comparison revealed significant data with asymptotic significance (2-sided tests), with p < 0.05 between Q1 and Q3.

[d] Pairwise comparison revealed significant data with asymptotic significance (2-sided tests), with p < 0.05 between Q3 and QQ.

Complications

The complications related to corticosteroids are shown in Table 2. Higher cumulative dexamethasone doses were significantly associated with an increased incidence of hospital-acquired infections (p < 0.001) and tended to increase the occurrence of gastrointestinal bleeding (p = 0.06).

Discussion

In this retrospective cohort study of COVID-19 pneumonia patients, multivariate analysis revealed that the cumulative dexamethasone-equivalent dose was not a risk factor associated with increased in-hospital mortality. However, in the subgroup analysis, when we divided the cumulative dexamethasone-equivalent doses into quartiles, the second quartile (P25–P50; 126.01–165.00 mg/14 days) was significantly associated with the lowest mortality. Moreover, a greater cumulative dexamethasone-equivalent dose was associated with increased ICU LOS, hospital LOS and ventilator-free days at day 28.

The recommended dose and regimen of corticosteroids in COVID-19 pneumonia patients with hypoxemia remain inconclusive. Studies such as the COVID STEROID2 study and those conducted by Maskin LP et al. have shown trends favoring higher doses of dexamethasone, with benefits in days alive without life support and time required for cessation of mechanical ventilation [11, 12].

However, conflicting results have been reported, such as those of the randomized controlled trial by Toroghi et al., who found no clinical benefit of high-dose dexamethasone over conventional low-dose dexamethasone [13]. Similarly, the COVIDICUS trial did not demonstrate improved 60-day survival with a higher cumulative dexamethasone dose [14]. These discrepancies may be attributed to differences in corticosteroid intensity and disease severity across the various studies, as shown in S4 Table.

Our findings demonstrated the relationship between increased intensity of corticosteroids administered daccording to the hypoxemia severity and improved in-hospital mortality. This association was shown between the lowest intensity (dexamethasone equivalent < 126 mg) in patients with a median PF ratio of 290 (190–439) and a moderate intensity (126.01–165.00 mg) with a median PF ratio of 175 (129–268) (Table 2 and Fig 2). However, this association disappeared in patients with a greater degree of hypoxemia. Increasing the cumulative dexamethasone-equivalent dose beyond 165 mg was associated with increased in-hospital mortality.

This phenomenon could be explained by the fact that higher doses of steroids (> 165 mg) lead to an increased risk of hospital-acquired infections, as shown in Table 2. The incidence of secondary infections increased proportionally with an increasing cumulative dexamethasone dose, with statistical significance observed.

This “J-shaped” pattern aligns with the results of a retrospective study conducted by Maia et al. [15], which showed a strong correlation between the cumulative corticosteroid dose (expressed as a methylprednisolone equivalent) and the duration of mechanical ventilation. The shortest ventilation time was associated with a cumulative dose of 560 mg of methylprednisolone (which corresponds to 105 mg of dexamethasone). However, Maia et al. did not report other important clinical outcomes, particularly mortality.

The beneficial effects of higher corticosteroid doses on clinical outcomes have been demonstrated in studies with cumulative dexamethasone doses ranging from approximately 120 to 130 mg [11, 12]. These findings are consistent with our study, which showed that there was lower mortality when the cumulative dose of dexamethasone equivalence increased from low (< 126 mg) to moderate (126.01–165.00 mg) doses. Additionally, a study by Toroghi et al. revealed a trend of increasing 60-day mortality from 17% to 30% and 41% with cumulative dexamethasone doses of 80 mg, 160 mg, and 240 mg, respectively [13]. Similarly, in our investigation, cumulative doses of dexamethasone equivalent exceeding 165 mg were associated with increased in-hospital mortality.

The strength of our study lies in the consideration of both the cumulative dose and the timing of corticosteroid therapy. We followed clinical guidelines for personalized steroid modulation on the basis of patient severity and risk factors, adjusting the daily dose in response to parameters such as the degree of hypoxemia, chest radiography progression, and C-reactive protein levels [16]. Furthermore, the complications from corticosteroid therapy [17] were carefully monitored and recorded due to concerns about potential harm.

However, our study has several limitations. First, it was a retrospective, observational investigation with a limited number of patients and several unmeasured confounders. Thus, a larger trial is needed to confirm or refute these findings. Second, since the data were collected during the pandemic, therapeutic agents such as remdesivir, tocilizumab, and baricitinib were limited in availability, potentially influencing the clinical outcomes observed in this study. Third, we used the cumulative dexamethasone equivalent dose during the treatment period, which probably did not represent the daily dose of corticosteroids in COVID-19 patients with pneumonia in real-world practice. Fourth, our population varied in terms of age, comorbidities, days since symptom onset, and severity of disease, which may have resulted in heterogeneity in the clinical outcomes. Fifth, most of the patients in this study were recruited during the delta variant pandemic of SARS-CoV-2, which is not the current strain. Therefore, the results might not apply to the current variant. Sixth, our study reported hospital mortality as the primary outcome and mortality at different time points as secondary outcomes. We did not report the actual cause of death for each patient, which could have obscured a mechanism of death that might not be related to COVID-19. Seventh, we recruited only hypoxemic patients requiring corticosteroids, and thus, we could not compare the outcomes of these patients with those of patients not receiving corticosteroids.

Conclusions

The intensity of corticosteroid therapy, measured as the cumulative dexamethasone-equivalent dose during the first 14 days, is not a risk factor for in-hospital mortality in hypoxemic COVID-19 patients. However, cumulative doses exceeding 165 mg are associated with higher in-hospital mortality and secondary hospital-acquired infection.

Supporting information

S1 Checklist TREND statement checklist.

(PDF)

S1 Table Dexamethasone equivalent dose.

(DOCX)

S2 Table Univariable and multivariable analyses.

(DOCX)

S3 Table Demographic data, treatment and clinical outcomes stratified into quartiles according to the cumulative dexamethasone equivalent dose.

(DOCX)

S4 Table Previous study.

(DOCX)

S1 Data (XLSX)

We would like to express our deep gratitude to Suthipol Udompunthurak for statistical analysis consultation and correction.

10.1371/journal.pone.0308069.r001
Decision Letter 0
Deng Jiawen Academic Editor
© 2024 Jiawen Deng
2024
Jiawen Deng
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
22 Apr 2024

PONE-D-24-03848Effects of Corticosteroid Intensity on Clinical Outcomes in Hypoxic COVID-19 PatientsPLOS ONE

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Reviewer #1: Thank you for the opportunity to review the manuscript "Effects of Corticosteroid Intensity on Clinical Outcomes in Hypoxic COVID-19 Patients". The authors seek to address the knowledge gap in optimal dose and duration of steroid dosing in COVID-19 pneumonia patients using a retrospective cohort study, categorizing cumulative dexamethasone dosing over 14 days into quartiles.

Major questions to address:

- why did the authors choose to study an intervention duration of 14 days? (most of the cited studies included 10 day duration)

- why did the authors choose to study cumulative dexamethasone dosing by quartiles? (most cited studies included high intensity vs lower intensity vs placebo, high intensity dosing was usually 20mg daily for 5 days followed by 10mg daily for 5 days, total 150mg; although one study did include 8mg 3x daily for 10 days, 240 mg total)

- why was the primary outcome in-hospital mortality? (most of the cited studies used 28 day mortality, 28d VFD, and 60 day mortality)

- please check references, #2 and #3 do not have functional links

- P13 L237-238: please rewrite, "this causal relationship", impossible to determine a causal relationship with a retrospective study

Additional issues to address:

- please correct grammar, several instances of awkward wording throughout

- P4 L62-66: please update reference for pathogenesis and treatment, link does not work

- P9 L152: why was lymphocyte count used, but white blood cell count not included?

- why were the inclusion criteria limited to patients requiring oxygen therapy? (several cited studies included patients not requiring oxygen therapy)

- please edit "hospital mortality" to "in-hospital mortality" throughout

Reviewer #2: Thank you for the opportunity to review this manuscript. Teeratakulpisarn et al. present a retrospective study of patients with COVID-19 to determine associations between corticosteroid dosages and patient outcomes. While this is interesting, I am concerned that this study may no longer be as timely and most institutions have specific, predefined dosages at this point in time. The strains/variants have also changed considerably and it is unclear how pertinent this data would be.

Major:

1) The study is single-center, across almost 18 months only. This should be further elaborated upon in the limitations as it has a considerable impact on generalizability. Moreover, the emergence of new variants should be discussed as a limitation of the study.

2) While the primary outcome is hospital mortality and secondary outcomes are mortality at different time points, the actual causes of death are not reported. This would be important to note and if unavailable, this is a major limitation as it is unclear as to the mechanism of death.

3) Hospital-acquired infections should be defined and noted with respect to how they were identified.

4) The result section reports median (IQR) but the abstract is in mean (SD) for often the same variables (e.g. dosage). As per the methods, depending on the distribution, the authors should select one and be consistent.

5) The authors should justify and provide references for why and how these quartiles were decided upon.

6) The confidence intervals, particularly for ECMO and ventilator use in Table S1 are extremely wide and depending on the data type (e.g. large number of 0s relative to 1s), the authors should consider other techniques such as negative binomial regressions (https://stats.oarc.ucla.edu/stata/dae/negative-binomial-regression/)

Minor:

1) Title: Consider rephrasing to "The association between corticosteroid dosage and clinical outcomes in COVID-19 pneumonia: A retrospective cohort study" or something similar

2) Abstract - Conclusion: The authors should ensure all data is presented in the form of associations rather than causal given the study design. Consider changing "risk factor" to "associated with"

3) Through out the manuscript causal language is used (e.g. "increased"). This should all be reworded to "higher" or "lower," etc.

4) Key message: Please clarify what a "J-curve" really means, especially in the key message section. "Linked" should also be modified to "associated."

5) Introduction: The first paragraph, especially the first sentence should be revised to reflect the current climate of COVID-19. Specifically, I would not call it "emerging" at this point in time.

6) Introduction, Lines 79-80: The authors should consider including trials which have indeed looked at steroid dosages (e.g. https://jamanetwork.com/journals/jama/fullarticle/2785529)

7) All acronyms need to be defined (e.g. ECMO, PF, etc). Some percentages in the results are also inadvertently subscripted.

8) Tables: The number of decimal places for the data should be consistent. They would all benefit from inclusion of abbreviation definitions at the bottom of all main and supplementary tables

9) The study would benefit from an English grammar review

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

**********

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10.1371/journal.pone.0308069.r002
Author response to Decision Letter 0
Submission Version1
29 May 2024

Professor Jiawen Deng

Editor-in-Chief,

PLOS ONE Journal

May 25th, 2024

Answer to review of: PONE-D-24-03848 ‘Effects of Corticosteroid Intensity on Clinical Outcomes in Hypoxic COVID-19 Patients

Professor Jiawen Deng

Thank you for your potential interest in publishing our work. We appreciate the valuable comments from the reviewers and believe that their suggestion improved our work. We have revised and added information to our manuscript in response to the reviewers’ comments, and below we provide responses to each issue raised.

All comments are restated below followed by our responses and description of the substance and location of any resulting changes made to the revised manuscript.

Yours sincerely

Napassorn Teeratakulpisarn

Thummaporn Naorungroj

Asso. Prof. Ranistha Ratanarat

Department of Intensive Care

Faculty of Medicine Siriraj Hospital Mahidol University

 

Response to Reviewers

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

RESPONSE: Thank you for your recommendation. We informed the reviewer that this study is a retrospective study. Thus, we haven’t published a preplanned laboratory research protocol. However, we have provided our data in supporting files.

Reviewer #1:

- Why did the authors choose to study an intervention duration of 14 days? (most of the cited studies included 10 days duration)

RESPONSE: We thank the reviewer for this comment. We informed the reviewer that the patients including in this study were received the treatments during the pandemic era of the delta variant before the publication of RECOVRY or REMAP-CAP study. In our institute, we have followed the local guideline adopted from the WHO guideline for corticosteroid tailoring based on individual patient characteristics, severity, and risk factors (1). Moreover, 71.2% of the patients in this study receiving one of systemic corticosteroids for more than 10 days. Hence, we decided to present corticosteroid dosing in a cumulative dexamethasone dose over 14 days.

Reference

1 Ratanarat R, Thitayanapong A. Rational use of corticosteroid treatment in the early phase of severe COVID-19: Corticosteroid in COVID-19. Clin Crit Care [Internet]. 2023 Jun. 26 [cited 2024 May 5];31(1):2023:e0010.

- Why did the authors choose to study cumulative dexamethasone dosing by quartiles? (most cited studies included high intensity vs lower intensity vs placebo, high intensity dosing was usually 20mg daily for 5 days followed by 10mg daily for 5 days, total 150mg; although one study did include 8mg 3x daily for 10 days, 240 mg total)

RESPONSE: We thank the reviewer for this thoughtful comment. There were some reasons why we have chosen to study cumulative dexamethasone dosing by quartiles. First, the characteristics of our patients were more severe COVID-19 compared to most cited studies (1-4) (Supplementary table S4), with a median PF ratio of 151.4 (IQR: 104.8, 224.0) and 53.5% of patients requiring mechanical ventilator support. In our cohort, the median dose of corticosteroid was 165 mg which was exceeding high-intensity dose using in CoDEX trial (5). Furthermore, we did not enroll the patient who did not receive corticosteroid so we did not have placebo group. Second, this study aimed to observe a correlation between the optimal dose (neither too low nor too high) and favorable clinical outcomes in our center, as well as in a previous study conducted by Maia et al (6). Third, we, indeed, have conducted an analysis comparing high vs low intensity dosing, and the results showed there was no significant difference in mortality. However, we hypothesized that the cumulative dose of corticosteroids may not a linear correlation. Therefore, we have attempted to present the corticosteroid dosing in more granular data as shown in this study. Fourth, in the statistical view, dividing cumulative dexamethasone dosing into quartiles would give equal data for each group and it is concordance with box plot analysis.

Reference

1 Durr KM, Hendin A, Perry JJ. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. CJEM. 2022 Apr;24(3):266-267.

2 Maskin LP, Bonelli I, Olarte GL, Palizas F Jr, Velo AE, Lurbet MF, et al. High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-Related Acute Respiratory Distress Syndrome: A Multicenter, Randomized Open-Label Clinical Trial. J Intensive Care Med. 2022 Apr;37(4):491-499.

3 Toroghi N, Abbasian L, Nourian A, Davoudi-Monfared E, Khalili H, Hasannezhad M, et al. Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a three-arm randomized clinical trial. Pharmacol Rep. 2022 Feb;74(1):229-240.

4 Bouaddma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, Guitton C, Schwebel C, Cohen Y, Bruel C, Marzouk M, Geri G, Cerf C, Megarbane B, Garcon P, Kipnis E, Visseaux B, Beldjoudi N, Chevret S, Timsit JF; COVIDICUS Study Group. High-Dose Dexamethasone And Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022 Sep 1;182(9):906-916.

5 Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316.

6 Maia R, Melo L, Mendes JJ, Freitas PT. Corticosteroids in COVID-19: A double-edged sword—a retrospective study. Med Intensiva (Engl Ed). 2022 Apr;46(4):229-231.

- Why was the primary outcome in-hospital mortality? (most of the cited studies used 28-day mortality, 28d VFD, and 60-day mortality)

RESPONSE: We thank the reviewer for your comment. We have to use the in-hospital mortality instead of 28-day mortality for primary outcome because according to retrospective data during the pandemic, there was a significant missing data for the 28-day mortality data. Therefore, we have selected in-hospital mortality, which was the most complete mortality outcome, as the primary outcome.

- Please check references, #2 and #3 do not have functional links

RESPONSE: We apologized the reviewer for these errors. We have already corrected the functional links for reference 2 and 3 in our revised manuscript.

- P13 L237-238: please rewrite, "this causal relationship", impossible to determine a causal relationship with a retrospective study

RESPONSE: We thank the reviewer for this comment. We have already changed “this causal relationship” to “this correlation” in our revised manuscript on page 16

- Please correct grammar, several instances of awkward wording throughout

RESPONSE: We thank the reviewer for this comment. We have rechecked the grammar and made it more appropriately.

- P4 L62-66: please update reference for pathogenesis and treatment, link does not work

RESPONSE: We thank the reviewer for this comment and We apologized for the error. We have already updated the reference for pathogenesis and treatment of COVID-19 and also corrected the functional links in our revised manuscript.

- P9 L152: why was lymphocyte count used, but white blood cell count not included?

RESPONSE: We thank the reviewer for your thoughtful comment. We used the lymphocyte count rather than white blood cell counts because there was a significant association between low lymphocyte count and higher severity.

References:

1 Hedayati-Ch M, Ebrahim-Saraie HS, Bakhshi A. Clinical and immunological comparison of COVID-19 disease between critical and non-critical courses: a systematic review and meta-analysis. Front Immunol. 2024;15:1341168. Published 2024 Apr 16.

2 Montiel-Cervantes LA, Medina G, Pilar Cruz-Domínguez M, et al. Poor Survival in COVID-19 Associated with Lymphopenia and Higher Neutrophile-Lymphocyte Ratio. Isr Med Assoc J. 2021;23(3):153-159.

- Why were the inclusion criteria limited to patients requiring oxygen therapy? (several cited studies included patients not requiring oxygen therapy)

RESPONSE: According to the COVID-19 treatment guidelines, systemic corticosteroids should be administered to patients requiring oxygen therapy. Therefore, we recruited only patients who receiving oxygen therapy for our study.

Reference:

1 NIH. COVID-19 Treatment Guidelines. Clinical Management Summary. Last Updated: February 29, 2024. Available at:

https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/clinical-management-of-adults-summary/.

- Please edit "hospital mortality" to "in-hospital mortality" throughout

RESPONSE: We thank the reviewer for the comment. We have already changed "hospital mortality" to "in-hospital mortality" in our revised manuscript.

Reviewer #2:

Major:

1) The study is single-center, across almost 18 months only. This should be further elaborated upon in the limitations as it has a considerable impact on generalizability. Moreover, the emergence of new variants should be discussed as a limitation of the study.

RESPONSE: We thank the reviewer for this comment. We have already added this information in limitation in our revised manuscript as following:

“The patients in the study were recruited only in our institute in the specific time period which was in the delta variant pandemic of SARS-CoV-2. Thus, these results were limited on generalizability and may be inapplicable to the current variant.”

2) While the primary outcome is hospital mortality and secondary outcomes are mortality at different time points, the actual causes of death are not reported. This would be important to note and if unavailable, this is a major limitation as it is unclear as to the mechanism of death.

RESPONSE: We thank the reviewer for these comments and we agreed with the reviewer that this is an important issue. We did not report the actual cause of death for each patient. Thus, we have added this information in limitation of our revised manuscript as following

“Our study reported hospital mortality as the primary outcome and mortality at different time points as secondary outcomes. We did not report the actual cause of death for each patient, which could result in an unknown mechanism of death that might not be related to COVID-19.”

3) Hospital-acquired infections should be defined and noted with respect to how they were identified.

RESPONSE: We thank the reviewer for this comment. We have added the definition of “Hospital-acquired infection” in method at P7 L 122-124 as the following

“hospital-acquired infections were including hospital acquired pneumonia, urinary tract infection, bacteremia, catheter related bloodstream infection, and skin and soft tissue infection”.

4) The result section reports median (IQR) but the abstract is in mean (SD) for often the same variables (e.g. dosage). As per the methods, depending on the distribution, the authors should select one and be consistent.

RESPONSE: We thank the reviewer for these comments and we apologized for these errors. We have already corrected the results and have reported the median (interquartile range) according to the distribution for every section in the manuscript.

5) The authors should justify and provide references for why and how these quartiles were decided upon.

RESPONSE: RESPONSE: We thank the reviewer for this thoughtful comment. There were some reasons why we have chosen to study cumulative dexamethasone dosing by quartiles. First, the characteristics of our patients were more severe COVID-19 compared to most cited studies (1-4) (Supplementary table S4), with a median PF ratio of 151.4 (IQR: 104.8, 224.0) and 53.5% of patients requiring mechanical ventilator support. In our cohort, the median dose of corticosteroid was 165 mg which was exceeding high-intensity dose using in CoDEX (5). Furthermore, we did not enroll the patient who did not receive corticosteroid so we did not have placebo group. Second, this study aimed to observe a correlation between the optimal dose (neither too low nor too high) and favorable clinical outcomes in our center, as well as in a previous study conducted by Maia et al (6). Third, we, indeed, have conducted an analysis comparing high vs low intensity dosing, and the results showed there was no significant difference in mortality. However, we hypothesized that the cumulative dose of corticosteroids may not a linear correlation. Therefore, we have attempted to present the corticosteroid dosing in more granular data as shown in this study. Fourth, in the statistical view, dividing cumulative dexamethasone dosing into quartiles would give equal data for each group and it is concordance with box plot analysis.

Reference

1 Durr KM, Hendin A, Perry JJ. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. CJEM. 2022 Apr;24(3):266-267.

2 Maskin LP, Bonelli I, Olarte GL, Palizas F Jr, Velo AE, Lurbet MF, et al. High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-Related Acute Respiratory Distress Syndrome: A Multicenter, Randomized Open-Label Clinical Trial. J Intensive Care Med. 2022 Apr;37(4):491-499.

3 Toroghi N, Abbasian L, Nourian A, Davoudi-Monfared E, Khalili H, Hasannezhad M, et al. Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a three-arm randomized clinical trial. Pharmacol Rep. 2022 Feb;74(1):229-240.

4 Bouaddma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, Guitton C, Schwebel C, Cohen Y, Bruel C, Marzouk M, Geri G, Cerf C, Megarbane B, Garcon P, Kipnis E, Visseaux B, Beldjoudi N, Chevret S, Timsit JF; COVIDICUS Study Group. High-Dose Dexamethasone And Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022 Sep 1;182(9):906-916.

5 Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316.

6 Maia R, Melo L, Mendes JJ, Freitas PT. Corticosteroids in COVID-19: A double-edged sword—a retrospective study. Med Intensiva (Engl Ed). 2022 Apr;46(4):229-231.

6) The confidence intervals, particularly for ECMO and ventilator use in Table S1 are extremely wide and depending on the data type (e.g. large number of 0s relative to 1s), the authors should consider other techniques such as negative binomial regressions (https://stats.oarc.ucla.edu/stata/dae/negative-binomial-regression/)

RESPONSE: We thank the reviewer for your thoughtful comment. We have discussed our data with statistician and we have determined that the negative binomial regression is typically used for modeling count variables, usually for over-dispersed count outcome variables. However, since our data uses hospital mortality as an outcome, which is a binary outcome, we have opted to use binomial logistic regression for the analysis.

References:

1 Statistical Method and Data Analytics [Internet]. UCLA. LOGISTIC REGRESSION | STATA DATA ANALYSIS EXAMPLES [cited 2024 May 12]. Available from:

https://stats.oarc.ucla.edu/stata/dae/logistic-regression/

2 Statistical Method and Data Analytics [Internet]. UCLA. NEGATIVE BINOMIAL REGRESSION | STATA DATA ANALYSIS EXAMPLES [cited 2024 May 12]. Available from:

https://stats.oarc.ucla.edu/stata/dae/negative-binomial-regression/

Attachment Submitted filename: Response to Reviewers.docx

10.1371/journal.pone.0308069.r003
Decision Letter 1
Deng Jiawen Academic Editor
© 2024 Jiawen Deng
2024
Jiawen Deng
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
19 Jun 2024

PONE-D-24-03848R1The association between corticosteroid dosage and clinical outcomes in COVID-19 pneumonia: A retrospective cohort studyPLOS ONE

Dear Dr. Ratanarat,

Thank you for submitting your revised manuscript to PLOS ONE. While the reviewers no longer have major comments on the revised article, they raised a few minor points that need to be addressed. Specifically, I agree with the reviewers that your manuscript could benefit from English editing.

Please submit your revised manuscript by Aug 03 2024 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.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

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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.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Jiawen Deng

Academic Editor

PLOS ONE

Journal Requirements:

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.

[Note: HTML markup is below. Please do not edit.]

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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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 #1: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

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 #1: Yes

Reviewer #2: Yes

**********

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 #1: Yes

Reviewer #2: Yes

**********

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 #1: Thank you for the opportunity to review the revised manuscript "The association between corticosteroid dosage and clinical outcomes in COVID-19 pneumonia: A retrospective cohort study"

- if the patient population factored into the decision to study dexamethasone quartiles, the title should reflect that this is a study in severe, hypoxemic COVID-19 pneumonia

- having no patients receiving corticosteroid or no placebo group should be mentioned in the limitations section

- while greatly improved, there are still many instances where the wording is awkward or confusing, while I do not have a specific institute/agency recommendation in mind, this manuscript would benefit from further English grammar review

Reviewer #2: I thank the authors for their careful consideration of my comments and their thoughtful replies. I do not have additional recommendations given this thorough revision.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0308069.r004
Author response to Decision Letter 1
Submission Version2
11 Jul 2024

Reviewer #1:

- If the patient population factored into the decision to study dexamethasone quartiles, the title should reflected thst this is a study in severe, hypoxemic COVID-19 pneumonia

RESPONSE: We thank the reviewer for this comment. We have changed the title to “Associations between corticosteroid dosage and clinical outcomes in patients with hypoxemic COVID-19 pneumonia: A retrospective cohort study”

- having no patients receiving corticosteroid or no placebo group should be mentioned in the limitations section

RESPONSE: We thank the reviewer for this thoughtful comment. We added the seventh limitation in P18, L 289-292 that “we recruited only hypoxemic patients requiring corticosteroids, and thus, we could not compare the outcomes of these patients with those of patients not receiving corticosteroids.”

- while greatly improved, there are still many instances where the wording is awkward or confusing, while I do not have a specific institute/agency recommendation in mind, this manuscript would benefit from further English grammar review

RESPONSE: We thank the reviewer for your comment. We have sent our manuscript to AJE academic English editing services for a grammar review and have corrected our manuscript according to their suggestions.

Attachment Submitted filename: Response to Reviewers July 8th, 2024.docx

10.1371/journal.pone.0308069.r005
Decision Letter 2
Deng Jiawen Academic Editor
© 2024 Jiawen Deng
2024
Jiawen Deng
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version2
17 Jul 2024

Associations between corticosteroid dosage and clinical outcomes in patients with hypoxemic COVID-19 pneumonia: A retrospective cohort study

PONE-D-24-03848R2

Dear Dr. Ratanarat,

Your manuscript has improved significantly over the last two rounds of revisions. As such, we can now accept your submission for publication in PLOS ONE. Thank you for your insightful submission.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Jiawen Deng

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

10.1371/journal.pone.0308069.r006
Acceptance letter
Deng Jiawen Academic Editor
© 2024 Jiawen Deng
2024
Jiawen Deng
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
26 Jul 2024

PONE-D-24-03848R2

PLOS ONE

Dear Dr. Ratanarat,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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on behalf of

Dr. Jiawen Deng

Academic Editor

PLOS ONE
==== Refs
References

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