A Retrospective Observational Cohort Study on the Efficacy and Safety of Methylprednisolone Pulse Therapy for COVID-19 Pneumonia

Round 1

Reviewer 1 Report

I believe that the article is well written. The results are interesting, but they have the limitations of the retrospective study. 

Author Response

Thank you for your positive comments and invaluable suggestions. As you have pointed out, this study is a retrospective study with limitations. We have mentioned this as a limitation of the study in the Discussion section (lines 309-310, page 10), with the following comment:

The limitations of this study include a small sample size, having an open-label, non-randomized retrospective design, and potentially biased evaluators.

Author Response File: Author Response.pdf

Reviewer 2 Report

This is an interesting retrospective study comparing conventional dexametasone therapy and methylprednisolone pulse therapy in hospitalized patients with COVID pneumonie in terms of differences on mortality, average length in ICU, duration of invasive mechanical aventilation, adverse effects and laboratory parameters.  It is a small study (only 70 pts) with desigual distribution between the 2 groups of treatment (24 vs 48). Authors describe a total mortality of 11.4% occurring within 1 month of hospitalizatio (lower in the  methylprednisolone pulse therapy: 4.5% vs 14.6%.

JAK inhibitors or anti IL-6 receptor antibodies were used in the study? Also Data on remdesivir and favipiravir use would be of interest and their correlation with the study outcomes.

Recently, NIH guide lines and several studies have described better outcomes after using higher doses of dexamethasone respect to conventional dosis (Eur resp J Taboada M 201, Intensive care Med Granholm 2021 should be cited)

Author Response

Reviewer: 2

1. JAK inhibitors or anti IL-6 receptor antibodies were used in the study? Also Data on remdesivir and favipiravir use would be of interest and their correlation with the study outcomes.

Thank you for pointing this out. JAK inhibitors were not used in the study. Only one patient was treated with anti-IL-6 receptor antibodies. Therefore, the correlation between anti-IL-6 receptor antibodies use and the results of this study could not be evaluated. In this study, remdesivir was used in 38 patients, and favipiravir was used in 10 patients. In detail, remdesivir was used in 15 of 22 patients (68.2%) in the methylprednisolone pulse therapy group and 23 of 48 patients (48.0%) in the dexamethasone therapy group, and the methylprednisolone pulse therapy group was used more frequently than the dexamethasone therapy group. Favipiravir was used in 3 of 22 patients (13.6%) in the methylprednisolone pulse therapy group and 7 of 48 patients (14.6%) in the dexamethasone therapy group, and the frequency of use was almost the same in both groups. In addition, in the methylprednisolone pulse therapy group, 1/15 patients (6.7%) died with the use of remdesivir and 0/3 patients (0.0%) died with favipiravir. On the other hand, in the dexamethasone therapy group, 3/23 patients (13.0%) died with the use of remdesivir, and 3/7 patients (42.9%) died with favipiravir. Therefore, it was considered that the methylprednisolone pulse therapy group used remdesivir more frequently than the dexamethasone therapy group, which may have correlated with the study outcomes.

Based on the above, the following comments were added to the Materials and Methods, Results, and Discussion sections (lines 114-129, page 3, lines 191-195, page 6, and lines 312-314, page 10).

 

Lines 114-129, page 3

2.3. Treatment protocol

        The initial management included supportive care by oxygenation aimed at achieving SpO2 ≥95%. In the absence of contraindications for antiviral drugs, remdesivir (n=38) or favipiravir (n=10) was administered at the time of hospitalization. In detail, Remdesivir was used in 15 of 22 patients (68.2%) in the methylprednisolone pulse therapy group and 23 of 48 patients (48.0%) in the dexamethasone therapy group, and the methylprednisolone pulse therapy group was used more frequently than the dexamethasone therapy group. Favipiravir was used in 3 of 22 patients (13.6%) in the methylprednisolone pulse therapy group and 7 of 48 patients (14.6%) in the dexamethasone therapy group, and the frequency of use was almost the same in both groups. The patients then received either methylprednisolone pulse therapy (methylprednisolone 1000 mg/day injected intravenously for 3 days, followed by intravenous or oral administration of dexamethasone 6 mg/day) or dexamethasone therapy (dexamethasone 6 mg/day administered intravenously or orally daily), according to physicians’ decisions. The dosage of dexamethasone was decreased gradually every week and eventually discontinued. JAK inhibitors were not used in this study, and only one patient was treated with anti-IL-6 receptor antibodies.

 

Lines 191-195, page 6

In addition, in the methylprednisolone pulse therapy group, 1/15 patients (6.7%) died with the use of remdesivir and 0/3 patients (0.0%) died with favipiravir. On the other hand, in the dexamethasone therapy group, 3/23 patients (13.0%) died with the use of remdesivir, and 3/7 patients (42.9%) died with favipiravir.

 

Lines 312-314, page 10

Also, the methylprednisolone pulse therapy group used remdesivir more frequently than the dexamethasone therapy group, which may have correlated with the study outcomes. Further investigation is needed in this regard.

 

2. Recently, NIH guide lines and several studies have described better outcomes after using higher doses of dexamethasone respect to conventional dosis (Eur resp J Taboada M 201, Intensive care Med Granholm 2021 should be cited)

 

Thank you for suggesting an important article with clinical significance. We have cited the article as suggested. Based on the above, the following sentences were added to the Introduction section (lines 61-72, page 2).

 

　 Additionally, in a randomized clinical trial of moderate and severe COVID-19 pneumonia conducted in Spain in 2021, a high dose of dexamethasone (20 mg once daily for 5 days, followed by 10 mg once daily for an additional 5 days) compared with a low dose of dexamethasone (6 mg once daily for 10 days) significantly decreased clinical worsening within 11 days (7). A high dose of dexamethasone was not associated with an increased risk of treatment-related serious adverse events in this population with COVID-19 pneumonia. Furthermore, in a randomized clinical trial of severe COVID-19 pneumonia conducted in Denmark, India, Sweden, and Switzerland in 2020 and 2021, a higher dose of dexamethasone (12 mg once daily for maximum 10 days) compared with the currently recommended dose of dexamethasone (6 mg once daily for maximum 10 days) had significantly lower mortality and fewer serious treatment-related adverse events at day 28 (8).

Author Response File: Author Response.pdf

Reviewer 3 Report

Dear Authors

 

Your study is interesting since it demonstrates the promising efficacy of the therapeutic approach adopted. Nonetheless, some comments are to be considered:

Abstract.

Lines 28-30. "The aver age length of intensive care unit stay was shorter in the methylprednisolone pulse therapy group (11.5±6.1 days) than in the dexamethasone therapy group (22.3±23.1 days) (p=0.793)" 

Since the difference is not statistically significant, I think this statement is not true.

2. Lines 30-32. IDEM 

Material and methods

What about the exclusion criteria? 

Results

Figure 1 needs to be improved (resolution).

I think that some differences between the two groups could be biased by the difference in the number of patients enrolled (22 vs 48). This should be explained or justified.

Lines 170-187. The p values showed that the differences were not statistically significant and the comparisons were made without considering this!!!!!

Figure 2. Please highlight the statistical differences clearely. 

Discussion

Although no serious treatment-related adverse events in the methylprednisolone pulse therapy group were observed, I think an important parameter was missing: Glycemia. Authors should discuss this limitation.

 

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Author Response

Reviewer: 3

1. Abstract

Lines 28-30. "The average length of intensive care unit stay was shorter in the methylprednisolone pulse therapy group (11.5±6.1 days) than in the dexamethasone therapy group (22.3±23.1 days) (p=0.793)"

 

Since the difference is not statistically significant, I think this statement is not true.

 

2. Lines 30-32. IDEM

 

Thank you for pointing this out. We agree with the reviewer’s comments.

As suggested, the following text was modified in the Abstract section (lines 28-32, page 1).

 

Also, without statistical significance, the average length of intensive care unit stay tended to be shorter in the methylprednisolone pulse therapy group (11.5±6.1 days) than in the dexamethasone therapy group (22.3±23.1 days) (p=0.793). The average duration of invasive mechanical ventilation also tended to be shorter in the methylprednisolone pulse therapy group (15.3±10.1 vs. 28.8±9.2 days, p=0.120).

 

3. Material and methods

What about the exclusion criteria?

 

Following the reviewer’s suggestion, we have added the exclusion criteria in the Materials and Methods section (line 113-114, page 3) as follows.

 

Exclusion criteria were; pregnant or lactating females, active malignancies, or

aggressive treatment undesired.

 

4. Results

Figure 1 needs to be improved (resolution).

 

　 Thank you for your valuable comments. We have now improved the resolution of Figure 1 (Upper side, page 6).

 

5. I think that some differences between the two groups could be biased by the difference in the number of patients enrolled (22 vs 48). This should be explained or justified.

 

As you pointed out, some of the covariates were possibly unbalanced after the propensity score weighting due to the sample size limitation. It might be a limitation of our study, and noted in the Results and Discussion section (lines 162-166, page 4 and lines 311-313, page 10).

 

Lines 162-166, page 4

Before performing an adjustment based on the propensity score-based IPW, the STD values of the body mass index, severe case, hypertension, CRP, LDH, and neutrophil count were all >0.1. However, following the adjustment, the STD values decreased below 0.1 for most of these variables, and the distribution of variables was relatively well balanced.

 

Lines 311-313, page 10

In addition, due to sample size constraints, some variables may not be well balanced even after IPW and are one of the limitations of this study.

 

6. Lines 170-187. The p values showed that the differences were not statistically significant and the comparisons were made without considering this!!!!!

 

Thank you for pointing this out. We agree with the reviewer’s comments.

As suggested, the following text was revised in the Results section (lines 200-207, page 6).

 

　 Although not statistically significant, the average length of ICU-stay in the methylprednisolone pulse therapy group was 11.5±6.1 days, which tended to be 10.8 days shorter than that in the dexamethasone therapy group (22.3±23.1 days) (p=0.793). A total of 11 patients (five in the methylprednisolone pulse therapy group and six in the dexamethasone therapy group) underwent invasive mechanical ventilation. The average duration of invasive mechanical ventilation in the methylprednisolone pulse therapy group was 15.3±10.1 days, which tended to be 13.5 days shorter than that in the dexamethasone therapy group (28.8±9.2 days) (p=0.120).

 

7. Figure 2. Please highlight the statistical differences clearly.

 

Thank you for your valuable suggestion. Following the reviewer’s suggestion, we have highlighted the statistical differences clearly in the Results section (lines 217-220, page 7 and 234-236, page 9), Figure 2 (lower side, page 8), and Figure 2 legend (lines 223-229, pages 8-9) as follows:

 

Lines 217-220, page 7

Blood biochemical tests revealed a significant reduction in serum CRP levels from the pretreatment values on day 3 and 7 of treatment in both groups (p<0.01 for all) (Fig. 2A and B).

 

Lines 234-236, page 9

The serum LDH levels significantly decreased on days 3 and 7 of therapy compared to the pretreatment level in the methylprednisolone pulse therapy group (p<0.01 for all) (Fig. 2C).

 

Lines 223-229, pages 8-9

Figure 2. Serum CRP, LDH, and plasma D-dimer levels before and after initiating methylprednisolone pulse therapy or dexamethasone therapy.

The changes in CRP (A and B), LDH (C and D), and D-dimer (E and F) levels before treatment and on days 3 and 7 after treatment initiation in the methylprednisolone pulse therapy and dexamethasone therapy groups. Values are presented as mean ± SEM. *P<0.05, **P<0.01. CRP = C-reactive protein; LDH = lactate dehydrogenase; SEM = standard error of the mean.

 

8. Discussion

Although no serious treatment-related adverse events in the methylprednisolone pulse therapy group were observed, I think an important parameter was missing: Glycemia. Authors should discuss this limitation.

 

Thank you for your comment. We have added the limitation to the Discussion section (lines 316-318, page 10) as follows.

Because some diabetics may develop in severe COVID-19 pneumonia, attention should be paid for exacerbation of impaired glucose tolerance when initiating methylprednisolone pulse therapy.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

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