Dear Dr. Zivkovic
Ref. No.: PONE-D-21-18432
Thank you for your email message dated July 12, 2021, regarding our manuscript, “Possibility
of deterioration of respiratory status when steroids precede antiviral drugs in patients
with COVID-19 pneumonia.”
We have revised our manuscript accordingly and have provided a point-by-point response
to the reviewers’ comments. This is attached herewith. The changes to the manuscript
are shown in red font.
We have corrected the ethics approval number from 11111 to 3929.
We added following sentence in Study design and materials of Material and methods:
The source of the data analyzed in this study was the medical records, Chiba University
Hospital.
We believe that our revised manuscript has suitably incorporated the reviewers’ suggestions
and is significantly improved over our initial submission. We trust that it is now
suitable for publication in PLOS ONE.
Thank you for considering our paper for publication.
Sincerely,
Response to Reviewer #1’s comments
Response:
We wish to express our strong appreciation for your insightful comments on our manuscript.
The comments have helped us to significantly improve the manuscript. We have marked
the relevant changes in red that so you can easily find them.
Comment #1: This was a retrospective study; hence, other treatment modalities could
have been different in the two groups, e.g. anticoagulants. Did all or some of the
patients receive anticoagulants / Was anticoagulant a part of treatment protocol?
Response:
Thank you for this comment.
According to our institute’s protocol, when D-dimer is > 3.0 mg/dL, we administered
direct oral anticoagulants for non-ICU patients. Patients with a hemorrhagic diathesis
or elderly patients were not administered anticoagulants (in two cases). Two patients
who originally taken aspirin, we continued aspirin in non-ICU patients. There were
no patients who had originally taken direct oral anticoagulants. For ICU patients
we administered heparin routinely.
There was no significant difference in the anticoagulant or aspirin use between the
steroids-first group (S-A group) and the antiviral-drugs-first group (A-S group) (n
= 13, 81.3% vs. n = 32, 62.8% p=0.169).
Based on a comment by Reviewer 3, we revised the name “S-A group” to “steroids-first
group” and “A-S group” to “antiviral-drugs-first group.”
Additionally, we administered antibiotics to some patients who were suspected to have
complications of bacterial pneumonia. These drugs did not have any influence on COVID-19;
hence we do not think that they affected the results of our study.
Accordingly, we added the following wording to the methods section and Table 2.
(Page 7, lines 121-127)
Added: “According to our institute’s protocol, when the D-dimer level was > 3.0 mg/dL,
we administered direct oral anticoagulants in non-ICU patients, but withheld anticoagulants
in elderly patients and patients with a hemorrhagic diathesis (two patients). We continued
aspirin in in non-ICU patients who had originally taken aspirin (two patients). There
were no patients who had originally taken direct oral anticoagulants. We administered
heparin routinely to ICU patients.”
Comment #2: The authors need to comment on this. Line no. 171, “...incidence of intubation
and ECMO." should be changed to “... the duration of intubation and ECMO." as per
the data presented in table 2.
Response:
According to the comment, we have reworded the related sentence as follows:
(Page 10, line 182)
Original: “In contrast, there was no significant difference in mortality, the duration
of ICU admission, or the incidence of intubation and ECMO between the two groups.”
Revised: “In contrast, there was no significant difference in the duration of ICU
admission, or the duration of intubation and ECMO between the two groups.”
Comment #3: The following issues may be commented on / added in the discussion section.
Along with the duration of symptom onset, clinical evaluation/hypoxia is also an essential
factor to decide regarding initiation of steroids in Covid-19 infection. However,
today's dilemma is that robust evidence regarding the absolute beneficial role of
antivirals in covid-19 is lacking. No specific drugs have been approved for COVID-19
disease to date. (1) Other than the timing of corticosteroid, duration of corticosteroid
therapy in covid-19 infection is also an important factor, and as evidenced from the
RECOVERY trial, the patients were administered steroid therapy up to 10 days. (2)
Also, corticosteroids may potentially have a procoagulant effect in covid-19; hence
the addition of anticoagulant therapy may also be considered in the treatment protocol
of covid-19. This could have been a potential factor, wherein steroid therapy aggravated
the treatment outcomes in the absence of an antiviral, which could potentially have
controlled the viremia associated procoagulant effect of the covid-19 infection at
an earlier stage of the disease. (3)
The study presents a very logical finding that steroid therapy without the cover of
antiviral therapy may be detrimental.
References:
1. Frediansyah A, Tiwari R, Sharun K, Dhama K, Harapan H. Antivirals for COVID-19:
A critical review [Internet]. Vol. 9, Clinical Epidemiology and Global Health. Elsevier
B.V.; 2021 [cited 2021 Jun 24]. p. 90–8. Available from: https://pubmed.ncbi.nlm.nih.gov/33521390/
2. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. N Engl
J Med [Internet]. 2020 Jul 17 [cited 2020 Oct 30]; Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
3. Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration
of therapy. Lancet Respir Med [Internet]. 2021 Jan 1 [cited 2021 Jan 1];9(1): e8.
Available from: https://doi.org/10.1016/S2213-2600(20)30530-0
Response:
Thank you for this insightful feedback and recommendation of useful reports.
As you pointed, we have also been aware of the lack of evidence for antiviral drugs
and the potential impact of the double-edged sword of steroids in COVID-19 throughout
our clinical practice. Your recommended issues were useful to further highlight the
results of our study.
Accordingly, we added following wording:
(Page 12, lines 213-224)
Added: “In this study, remdesivir (n = 45, 67.1%) and favipiravir (n = 38, 56.7%)
were used and other antiviral drugs, such as lopinavir/ritonavir, were not. Several
antiviral drugs have been assessed for COVID-19 [9], but remdesivir is the only Food
and Drug Administration-approved drug for the treatment of COVID-19, based on the
result of ACTT-1 trial [10]. Routine use of remdesivir is not recommended according
to the results of some studies and the National Institutes of Health guidelines [11-13].
In cases where patients are at a particularly high risk of clinical deterioration
or require minimal supplemental oxygen, remdesivir administration should be considered
[11]. Our institute’s protocol is to initiate antiviral drugs according to the severity
and risk factors. In this study, the differences in the antiviral drugs used may have
affected the prognosis; however, there is a lack of strong evidence regarding the
benefits of antiviral drugs in COVID-19.”
(Page 13, line 244 to page 14, line 256)
Original: “In some cases, administered steroid, including dexamethasone administration,
early in the viral response phase could exacerbate the disease and increase the need
for critical care.”
Revised: “A higher viral load leads to apoptosis of pneumocytes and endothelial cells,
which in turn activates platelets and induces coagulation factors [24]. COVID-19 has
a high rate of thromboembolic complications [25], and thromboembolic complications
are associated with poor prognosis [26]. Furthermore, Mishra et al. [27] pointed out
that steroid use itself may be associated with thromboembolic complications because
steroids tend to increase clotting factors and fibrinogen concentrations. This pathophysiology
in COVID-19 is poorly understood. Early administration of steroids may be associated
with a higher viral load, leading to an exacerbation of the respiratory condition,
and a possible increase in the risk of thromboembolic complications, and so steroid
use may increase the need for critical care in some patients with COVID-19.”
(Page 15, line 290 to page 16, line 300)
Original: “Further case accumulation will be required to clarify the appropriate timing
and order of administering steroids.”
Revised: “According to RECOVERY trial [3], dexamethasone was administered at a dose
of 6 mg once a day for up to 10 days. In some cases, methylprednisolone, prednisolone,
or hydrocortisone were administered. In addition to the timing of steroid administration,
the appropriate duration and doses of steroids are also unclear. Pinzon et al. [29]
reported that high-dose methylprednisolone for three days followed by oral prednisone
for 14 days decreased recovery time and need for intensive care compared with 6 mg
dexamethasone for 7 to 10 days. Mishra et al. [27] pointed out that long-term steroid
use for COVID-19 may cause adverse drug reactions such as thrombosis. Further case
accumulation will be required to clarify the appropriate timing, duration, and doses
of steroids and combination of drugs, including steroids and their order of use.”
Response to Reviewer #2’s comments
Comment: The authors report on an interesting and relevant topic with respect to the
ongoing pandemic. However, a few fundamental flaws are present in the manuscript
Response:
We appreciate that you consider our report to be interesting and we wish to express
our strong appreciation for this comment.
We have marked the respective changes with underlined text to make them easily identifiable.
Comment #1. The manuscript report on the possibility of harm when steroid use precede
antiviral drugs in patients with COVID 19 disease, without elaborating the mechanism
supported by data.
Response:
Thank you for raising this concern.
As you pointed out, because our study is a small number retrospective study, we regret
that our discussion of the mechanism of steroids use for COVID-19 was insufficient
due to a lack of data.
Therefore, we have added the results of the analysis, and new references to the discussion
based on your comments and the other reviewers' comments.
Additionally, we provide more details in our responses to each comment below.
Comment #2. The title does not provide the study design.
Response:
In accordance with the reviewer’s comment, we have revised the title as follows:
(p1. Title)
Original: “Possibility of deterioration of respiratory status when steroids precede
antiviral drugs in patients with COVID-19 pneumonia”
Revised: “Possibility of deterioration of respiratory status when steroids precede
antiviral drugs in patients with COVID-19 pneumonia: a retrospective study”
Comment #3. Introduction: Manuscript mention that in RECOVERY trial, use of Dexamethasone
administration among patient who did not receive any respiratory support was unclear.
It’s not understandable that how a retrospective design would answer this question
and trump a RCT.
Response:
Thank you for this important comment.
Our results did not validate the effect of dexamethasone in patients without respiratory
support, but rather the effects of early administration of steroids and sequencing
with antiviral drugs in COVID-19. In the RECOVERY trial, any apparent significance
of dexamethasone at less than seven days of onset was not mentioned. Furthermore,
in Japan, the results of the RECOVERY trial led to the insurance approval of dexamethasone,
although there are no definite rules regarding the timing of administration of dexamethasone.
As a result, dexamethasone has tended to be liberally administered at the discretion
of clinicians even in early onset or mild cases of COVID-19.
Accordingly, we modified the relevant sentences as follows:
(Page 4, lines 63-71)
Original: “However, there was no clear effect of dexamethasone administration among
patients who did not receive any respiratory support. Thus, the timing of drug administration,
including antiviral drugs, is unclear and the most effective therapeutic approach
has not been determined.”
Revised: “However, the results of the RECOVERY trial did not mention any apparent
significance of dexamethasone given within 7 days of onset in COVID-19. Thus, the
timing of drug administration, including antiviral drugs, is unclear and the most
effective therapeutic approach has not been determined. Additionally, in Japan, the
results of the RECOVERY trial led to the insurance approval of dexamethasone, although
the Japanese guidelines for COVID-19 treatment do not provide definite rules regarding
the timing of administration of dexamethasone. As a result, dexamethasone tends to
be liberally administered at the discretion of clinicians, even in early onset or
mild cases of COVID-19.”
Comment #4. Manuscript mentions that early administration of steroids may provoke
viral replication and cytokine storm of greater severity resulting in more severe
respiratory failure. The RECOVERY trial, in there pre specified subgroup analysis,
did not find the above observation-much more larger sample size and better design
(point estimate 1.01, CI 0.87,1.17).
Response:
Thank you for this comment.
As your comment, we thought the following sentence was overstatement, then we removed
it, “Thus, early administration of steroids may provoke more viral replication and
cytokine storms of greater severity, resulting in more severe respiratory failure.”
Accordingly, we removed following sentences.
(Page 5, lines 81-83)
Original: “In the RECOVERY Trial, dexamethasone was found to be beneficial to patients
who were treated more than 7 days after symptom onset [3]. Thus, early administration
of steroids may provoke more viral replication and cytokine storms of greater severity,
resulting in more severe respiratory failure.”
Revised: “In the RECOVERY Trial, dexamethasone was found to be beneficial to patients
who were treated more than 7 days after symptom onset [3].”
The RECOVERY trial did not show that the positive efficacy of administering steroids
less than seven days after symptom onset.
As stated previously, COVID-19 has a viral response phase and a host inflammatory
response phase. Some studies of SARS or Middle East respiratory syndrome reported
the use of steroids may delay virus clearance and be associated higher plasma viral
load. This was not about COVID-19 and the report showed that steroids use for COVID-19
did not delay virus clearance. However, in COVID-19 patients, administered steroids
early in the disease may have delayed virus clearance and steroid use may be associated
with a higher plasma viral load. Some reports have shown that higher viral load might
be related to severity in COVID-19. This pathophysiology in COVID-19 is poorly understood.
The early administration of steroids may be associated with a higher viral load, then
the respiratory condition may deteriorate and the need for critical care may increase
in some COVID-19 patients.
Accordingly, we removed the following sentence in Introduction and added the following
sentence in Discussion.
(Page 13, line 239 to page 14, line 256)
Original: “While Liu et al., reported that administration of steroid does not affect
clearance of SARS-CoV-2 [9], Russell et al., reported that the use of anti-inflammatory
therapy early in the course of the disease may not have a therapeutic effect and can
induce increased viral replication in patients with influenza and SARS [10]. In some
cases, administered steroid, including dexamethasone administration, early in the
viral response phase could exacerbate the disease and increase the need for critical
care.”
Revised: “Some studies of SARS or Middle East respiratory syndrome found that steroid
use may delay virus clearance and be associated higher viral concentrations [14, 15].
Furthermore, Lee et al. [15] did not recommend early steroid use without effective
antiviral drugs in SARS. However, the study by Lee et al. was not about COVID-19 and
some studies reported that the administration of steroids to patients with COVID-19
may not affect clearance of SARS-CoV-2 [16-21]. Evidence of the effect of steroid
use on clearance of SARS-CoV-2 is currently inconclusive. Some reports showed the
viral load may correlate with the severity of COVID-19 [22, 23]. A higher viral load
leads to apoptosis of pneumocytes and endothelial cells, which in turn activates platelets
and induces coagulation factors [24]. COVID-19 has a high rate of thromboembolic complications
[25], and thromboembolic complications are associated with poor prognosis [26]. Furthermore,
Mishra et al. [27] pointed out that steroid use itself may be associated with thromboembolic
complications because steroids tend to increase clotting factors and fibrinogen concentrations.
This pathophysiology in COVID-19 is poorly understood. Early administration of steroids
may be associated with a higher viral load, leading to an exacerbation of the respiratory
condition, and a possible increase in the risk of thromboembolic complications, and
so steroid use may increase the need for critical care in some patients with COVID-19.”
Comment #5. Authors cite a meta analysis and conclude that combination therapy was
more effective than monotherpy is incorrect, The meta analysis looked at role of steroid
alone and found its association with reduced mortality.(ref 7).
Response:
Thank you for this comment and we apologize for our mistake.
Ref 7 was wrong, and Ref 6 was correct, so we revised the sentences and the reference
number in the manuscript.
Original: “A World Health Organization working group reported that a meta-analysis
showed that combination therapy was more effective than monotherapy for treating COVID-19
[7].”
Revised: “Cantini et al. [6] reported that a meta-analysis showed that combination
therapy was more effective than monotherapy for treating COVID-19.”
Methods:
Comment #1. The exclusion of patients who were symptomatic and initially treated with
steroids is unclear. Why were they excluded? How their inclusion could have changed
the study estimates?
Response:
Thank you for this comment.
We apologize for our confusing description. In this study, patients who received only
symptomatic treatment or those who were originally treated with steroids or immunosuppressive
drugs because of their complications, such as rheumatoid arthritis were excluded.
This retrospective study aimed to determine the effectiveness of specific drugs for
COVID-19 such as antiviral drugs, steroids, and anti-inflammatories, hence we excluded
patients who originally treated with steroids or immunosuppressive drugs because of
complications.
Accordingly, we revised the following sentence.
(Page 6, lines 103-104)
Original: “Patients who received only symptomatic treatment and those who were initially
treated with steroids or immunosuppressive drugs were excluded.”
Revised: “Patients who received only symptomatic treatment or those who were originally
treated with steroids or immunosuppressive drugs because of their complications were
excluded.”
(Page 8, lines 149-150)
Original: “Of these patients, 129 were excluded because they received only symptomatic
treatment (n = 117) or were using steroids or immunosuppressive drugs (n = 12).”
Revised: “Of these patients, 129 were excluded because they received only symptomatic
treatment (n = 117) or were originally using steroids or immunosuppressive drugs because
of complications (n = 12).”
Comment #2. Authors have a policy to start antiviral drugs first based on severity
and risk factor. That means more sicker patients or patients with risk factors must
have received antiviral and steroids within the short span of time with further deterioration,
it’s unclear how prognostic balance was achieved in both the group for comparison
without randomization.
Comment #3. The division of patients into two groups - S-A and A-S, is arbitrary as
manuscript does not tell us what was the time period difference between the two drugs.
Was it 24 hour /48 hours/72 hours?
Response:
Thank you for these comments.
We have been aware of that this study had the limitation of confirming our conclusion
from the results because this study was not a randomized controlled trial but a retrospective
study.
While this study was not a randomized control trial and small population, baseline
characteristics that are shown in Table 1 were not different between two groups other
than age. The antiviral-drugs-first group (A-S group*) being older than the steroid-first
group (S-A group) is a limitation of this study. However, the antiviral-first group
had a better prognosis, and the other risk factors were not different between the
two groups. Therefore, we think that the risk factors did not contribute to the difference
in prognosis between groups in this study.
*Based on Reviewer #3’s comments, we revised S-A group to steroids-first group and
A-S group to antiviral-drugs-first group.
Accordingly, we added the following wording:
(Page 12, lines 205-208)
Added: “Older age is known to be a risk factor exacerbating COVID-19 [8]. The antiviral-drugs-first
group were significantly older than the steroids-first group. Despite the antiviral
drugs-first group being older than the steroid-first group, the antiviral drugs-first
group had a better prognosis.
According to our institute’s protocol, if respiratory failure worsened steroids were
added to patients who had been administered antiviral drugs already. If a patient
needs fraction of inspiratory oxygen > 0.4 at the time of admission, antiviral drugs
and dexamethasone were administered almost the same time, but antiviral drugs were
administered 3 to 6 hours ahead.
Additionally, the average time of administered antiviral drugs to steroids were 2.7
± 1.9 days.
As you pointed out, we analyzed ICU admission rate, incubation rate, ECMO induction
rate between two groups depending on the time difference between antiviral drugs administration
to dexamethasone administration within 24 hours, 48 hours, and 72 hours.
The results show in new S3 table.
New S3 table. The time difference between antiviral drugs administration to dexamethasone
administration.
Parameter Steroids-first group
(N=16) Antiviral-drugs-first group (N=51)
within 24 hours
(n=33) within 48 hours
(n=40) within 72 hours
(n=44)
ICU admission, n (%) 13 (81.3) 13 (39.4) † 16 (46.9) † 16 (36.4) †
Intubation, n (%) 12 (75.0) 11 (33.3) † 14 (35.0) † 14 (31.8) †
ECMO, n (%) 5 (31.3) 3 (9.1) * 3 (7.5) * 3 (6.8) *
ECMO, Extracorporeal membrane oxygenation. ICU, Intensive care unit.
versus Steroids-first group, * P<0.05, † P<0.01
The patients in the antiviral-drugs-first group had a lower rate of ICU admission,
incubation. and ECMO induction than patients in steroids-first group in all timings
of administration of steroids. The patients with shorter time differences between
antiviral drug and steroid initiation may have been sicker patients. Comparison between
them and patients in steroid-first group, the patients in the antiviral-drugs-first
group had a better prognosis.
This study was not randomized control study; thus, it is possible that sicker patients
tend to be treated with steroids first. However, from our results, it appears that
administering antiviral drugs first might be better than administering steroids first.
Accordingly, we revised and added wording to the manuscript. Furthermore, we added
new S3 table.
(Page 6, line 117 to page 7, line 1)
Original: “Then, if respiratory failure worsened, steroids (mostly dexamethasone)
were administered.”
Revised: “Then, if respiratory failure worsened, steroids (mostly dexamethasone) were
administered, and if patients needed a fraction of inspiratory oxygen > 0.4 at the
time of admission, antiviral drugs and dexamethasone were initiated at almost the
same time, but antiviral drugs were initiated 3 to 6 hours ahead of dexamethasone.”
(Page 14, lines 265-267)
Added: “Furthermore, patients who received short-term steroids also had a significantly
lower rate of ICU admission, intubation, and ECMO induction than patients in the steroid-first
group (S3 Table).”
Comment #4. Authors use Kaplan Meier survival method for analysis. The basis for its
use is unclear as the outcome variables-admission rate, intubation rate, echo introduction
rate are short duration endpoints and knowing time to event is not helpful in understanding
the incidence.
Response:
Thank you for this comment.
COVID-19 generally progress rapidly. ICU admission, intubation, and ECMO induction
caused by COVID-19 occurs in a short period. In fact, the primary outcome of the RECOVERY
trial was 28-day mortality and, 64.8% of the patients were discharged within 28 days
in the RECOVERY trial. In our study, median time from symptom onset of ICU admission
was 9 days (n = 30, range 6 to 19); to intubation, 9 days (n = 27, range 6 to 19);
to ECMO induction, 9 days (n = 9, range 8 to 21). Therefore, we decided that the Kaplan-Meier
survival method applied to these events that occurred within 30 days and set discharge
or death as censoring events using this method.
We have subsequently consulted statisticians in our institute, who are mentioned in
the acknowledgements (Yuki Shiko, MS and Yoshihito Ozawa, MS. Biostatistics Section,
Clinical Research Center, Chiba University Hospital), regarding this point. They were
of the same opinion.
From the above, we think that the Kaplan-Meier survival method for analysis may be
useful in our study.
Comment #5a. Result: The S-A group ended up with too low numbers (n=16) to draw any
meaningful conclusion.
Response:
Thank you for this comment.
We mentioned that small population and the retrospective study design as limitations
in the study limitations subsection.
While it may be difficult to confirm our conclusion from this small population and
retrospective study, the results of our study provide some insight on the appropriate
use of steroids in COVID-19.
Comment #5b. There is a prognostic imbalance between the two groups - The lymphocyte
count was too low for the S-A group, along with other markers. This creates unequal
groups for comparison and unstable estimates.
Response:
Thank you for this comment.
Patients in the steroid-first group were administered steroids before being admitted
to our institute, therefore the lymphocyte count was lower than that of antiviral-drugs-first
group. We analyzed the blood test results undergone at our hospital admission, because
of the blood test results taken in former hospital were often incomplete.
Accordingly, we added the following text:
(Page 12, lines 208-212)
Added: “The steroid-first group patients were administered steroids before admission
to our hospital, therefore their lymphocyte count was significantly lower than that
of antiviral drugs-first group. The blood tests performed on admission to our hospital
were analyzed, because of the blood test results performed in the original hospital
were frequently incomplete.”
Comment #6. Discussion needs more elaborate evaluation of the author’s study findings
and clarity which is missing.
Response:
Thank you for this comment.
We revised the Discussion based on your comment and another reviewer’s comment.
Comment #7. The study’s primary finding is-In patients with early COVID-19, administering
steroids prior to initiating antiviral drugs in the first few days after symptom onset,
may aggravate respiratory disease severity. However, due to major limitations in study
design and low numbers, a meaningful conclusion appears difficult to draw.
Response:
Thank you for this comment.
The small sample size is a limitation of this study. While we do not think can confirm
our conclusion from this small population and retrospective study, the results provide
some useful insight.
Response to Reviewer #3’s comments
COMMENT: Nice manuscript on a hot topic
Response:
We appreciate that you consider our report to be interesting and we wish to express
our strong appreciation of this comment. We have marked the changes to the manuscript
in response to your comments with black highlights to make them easily identifiable.
Major Comment
Comment #1. Remove a S-A group and A-S group in the abstract
Call them in a simple, explicative way
Throughout all the manuscript, tables, and figures, please
Response:
Thank you for this comment.
As you pointed out, the group names can be confusing. Therefore, we revised S-A group
to “steroids-first group” and A-S group to “antiviral-drugs-first group”, to make
it easy for the reader to understand.
Accordingly, we revised the group names throughout the text, tables, figures.
Comment #2. Early corticosteroids (patients not receiving oxygen) increase mortality
in covid19 patients according to a meta-analysis of RCTs
https://pubmed.ncbi.nlm.nih.gov/33298370/
Please extensively discuss this manuscript in the discussion.
Response:
Thank you for this insightful feedback and recommendation of this useful report.
The meta-analysis of randomized control trial, including the RECOVERY trial, showed
that administering steroids 1) for patients who required mechanical ventilation reduced
mortality; 2) for patients who did not required intubation did not have a significant
effect on mortality; and 3) for patients not requiring oxygen increased mortality.
Furthermore, steroid use was associated with a significantly lower risk of need for
mechanical ventilation. Thus, the effectiveness of steroid use for patients who did
not require intubation is unclear, but steroid use for patients not requiring oxygen
therapy may be harmful.
The authors of the meta-analysis that you recommended, noted that the initiation of
oxygen therapy and drugs were significantly different between studies and reported
this as a limitation.
Further study will be required to clarify the appropriate timing of administering
steroid and the combination of steroids and other drugs.
Accordingly, we revised following text:
(Page 15, line 282 to page 16, line 300)
Revised: “A meta-analysis of randomized control trials [28], showed that administering
steroids 1) to patients who required mechanical ventilation reduced mortality, 2)
to patients who did not require intubation did not have a significant effect on mortality,
and 3) for patients who did not require oxygen increased mortality. Furthermore, the
patients in whom steroids were used had a significantly lower risk of needing mechanical
ventilation. Thus, the effectiveness of steroid use for patients who did not require
intubation may be unclear, but steroid use for patients not requiring oxygen therapy
may be harmful. Authors of the meta-analysis stated the initiation of oxygen therapy
and drugs at significantly different between studies as a limitation. According to
RECOVERY trial [3], dexamethasone was administered at a dose of 6 mg once a day for
up to 10 days. In some cases, methylprednisolone, prednisolone, or hydrocortisone
were administered. In addition to the timing of steroid administration, the appropriate
duration and doses of steroids are also unclear. Pinzon et al. [29] reported that
high-dose methylprednisolone for three days followed by oral prednisone for 14 days
decreased recovery time and need for intensive care compared with 6 mg dexamethasone
for 7 to 10 days. Mishra et al. [27] pointed out that long-term steroid use for COVID-19
may cause adverse drug reactions such as thrombosis. Further case accumulation will
be required to clarify the appropriate timing, duration, and doses of steroids and
combination of drugs, including steroids and their order of use.”
Comment #3. p9 line 171 ECMO is increased and few lines later it is not increased
anymore. Please fix
Response:
According to the comment, we have reworded the related sentence as follows:
(Page 10, line 182)
Original: “In contrast, there was no significant difference in mortality, the duration
of ICU admission, or the incidence of intubation and ECMO between the two groups.”
Revised: “In contrast, there was no significant difference in the duration of ICU
admission, or the duration of intubation and ECMO between the two groups.”
Comment #4. Mortality is increased when using steroids first 18% vs 13%
The difference is not statistically significant, but there is a difference
There is no need to underline there is no difference
Please remove from the abstract, but there was no significant difference in mortality
Response:
We wish to thank the reviewer for this comment.
According to the comment, we have removed the sentence.
(p2. Results in Abstract)
Original: “The rate of intubation, ICU admission and ECMO induction were significantly
higher in the S-A group than in the A-S group (81.3% vs. 33.3, p<0.001, 75.0% vs.
29.4%, p=0.001, and 31.3% vs. 7.8%, p=0.017, respectively), but there was no significant
difference in mortality.”
Revised: “The rate of intubation, ICU admission and ECMO induction were significantly
higher in the steroids first group than in the antiviral drugs first group (81.3%
vs. 33.3, p<0.001, 75.0% vs. 29.4%, p=0.001, and 31.3% vs. 7.8%, p=0.017, respectively).”
(p10. Comparison of the outcomes among two groups in Results)
Original: “In contrast, there was no significant difference in mortality, the duration
of ICU admission, or the incidence of intubation and ECMO between the two groups.”
Revised: “In contrast, there was no significant difference in the duration of ICU
admission, or the duration of intubation and ECMO between the two groups.”
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