Remdesivir in combination with dexamethasone for patients hospitalized with COVID-19: A retrospective multicenter study.

BACKGROUND: Dexamethasone is standard of care for the treatment of patients with COVID-19 requiring oxygen. The objective is to assess the clinical benefit of adding remdesivir to dexamethasone. PATIENTS AND METHODS: A retrospective cohort study of hospitalized patients with COVID-19 pneumonia requesting low-flow oxygen who received dexamethasone. Patients admitted to infectious diseases wards also received remdesivir. Primary outcome was duration of hospitalization after oxygen initiation. Secondary outcomes were in-hospital death, and death and/or transfer to the intensive care unit. To handle potential confounding by indication bias, outcome comparison was performed on propensity score-matched populations. Propensity score was estimated by a multivariable logistic model including prognostic covariates; then 1:1 matching was performed without replacement, using the nearest neighbor algorithm with a caliper of 0.10 fold the standard deviation of the propensity score as the maximal distance. Balance after matching was checked on standardized mean differences.
RESULTS: From August 15th 2020, to February 28th, 2021, 325 patients were included, 101 of whom received remdesivir. At admission median time from symptoms onset was 7 days, median age: 68 years, male sex; 61%, >1 comorbidity: 58.5%. Overall 180 patients matched on propensity score were analyzed, 90 each received remdesivir plus dexamethasone or dexamethasone alone. Median duration of hospitalization was 9 (IQR: 7-13) and 9 (IQR: 5-18) days with and without remdesivir, respectively (p = 0.37). In-hospital death rates and rates of transfer to the intensive care unit or death were 8.9 and 17.8% (HR: 0.46, 95% CI: 0.21-1.02, p = 0.06) and 20.0 and 35.6% with and without remdesivir, respectively (HR: 0.45, 95% CI: 0.23-0.89, p = 0.015).
CONCLUSION: In hospitalized patients with COVID-19 pneumonia receiving low-flow oxygen and dexamethasone, the addition of remdesivir was not associated with shorter hospitalization or lower in-hospital mortality but may have reduced the combined outcome of death and transfer to the intensive care unit.

Introduction

Since December 2019, the COVID-19 pandemic has rapidly spread and overwhelmed healthcare systems worldwide with more than 260 million global cases and more than 5.2 million deaths as of December 4th, 2021 [1, 2]. The disease ranges from asymptomatic cases to acute respiratory distress syndrome and death. Numerous pharmacologic agents have been studied to improve clinical outcome, and medical practice has evolved with results from clinical trials. Dexamethasone is now standard of care for the treatment of hospitalized patients with COVID-19 pneumonia requiring oxygen following the release of the results from the RECOVERY trial in July 2020 which showed a significant reduction in mortality, presumably through the control of the deleterious inflammatory response to SARS-COV-2 infection in severe patients [3, 4].

Other treatments aiming at inhibiting viral replication have been investigated. Among them, remdesivir, a nucleotide analogue prodrug with in vitro activity against a broad array of RNA viruses including SARS-CoV-2 has been studied in multiple clinical trials and cohort studies [5]. Initial randomized placebo-controlled trials have shown a faster time to recovery with remdesivir, but no survival benefit was demonstrated [6, 7]. Subsequent open-label randomized trials and cohort studies yielded mixed results. The two large randomized SOLIDARITY and DISCOVERY trials could not show a clinical benefit with remdesivir, and there was no evidence of reduced mortality [8, 9]. A meta-analysis not including data from the DISCOVERY trial showed a non-significant trend toward a reduction of mortality in the subgroup of non-ventilated patients receiving remdesivir and low or high-flow oxygen (RR: 0.83, 95%CI: 0.63;1.01) [8]. Large cohort studies have also reported improved clinical outcomes with remdesivir [10, 11]. In the ACTT-1 trial, the benefit of remdesivir was also most apparent in patients receiving low-flow oxygen [6]. The use of remdesivir still remains controversial especially among moderately severe patients on low-flow oxygen hospitalized in medical wards [12]. NIH guidelines recommend remdesivir for patients requiring low-flow oxygen, alone or in combination with dexamethasone while WHO issued a conditional recommendation against remdesivir in hospitalized patients with COVID-19 [13, 14]. Other guidelines, such as French guidelines, do not recommend the use of remdesivir, in particular following the release in January 2021 of the results of the DISCOVERY trial [9, 15].

However there has been limited data and no randomized trial assessing the combination of dexamethasone and remdesivir in hospitalized patients with COVID-19 pneumonia requiring low-flow oxygen [11].

We wished to assess the potential benefit on clinical outcome of the combination of remdesivir plus dexamethasone compared to dexamethasone among hospitalized patients with COVID-19 requiring low-flow oxygen and performed a retrospective analysis of patients admitted to our institution between August, 15th 2020 and February 28th, 2021.

Patients and methods

Study design and patient selection

We conducted a retrospective cohort study assessing in-hospital clinical outcomes among adult patients admitted for COVID-19 in five medical wards (infectious diseases (n = 2), internal medicine (n = 2) and pneumology (n = 1)) of the Saint-Louis and Lariboisière Hospitals in Paris, France, between August 15th, 2020 and February 28th, 2021. This study was approved by the ethic research committee of the French infectious disease society (IRB00011642; COVID-2021-02) which considered the study as minimal risk and patients or their relatives were informed that their data would be used anonymously for this analysis. This study was conducted during the second wave of the pandemic in France when the circulation of the SARS CoV-2 alpha variant was still limited to < 15% of the isolates in the Paris region.

During the study period, dexamethasone (6 mg/d for 10 days) was standard of care in all wards among patients with COVID-19 pneumonia requiring oxygen following the results of the Recovery trial. The combination of remdesivir to dexamethasone was only used in the two infectious diseases wards of the Saint-Louis and Lariboisière hospitals. Supplemental oxygen (< 15 L/min) was given to maintain SpO2 ≥94% during hospitalization using a mask or nasal prongs. High-flow oxygen (> 15l/min) and non-invasive ventilation were not used in the medical wards and required transfer to the ICU. Remdesivir was given at the same time as dexamethasone, as a 5-day intravenous infusion of 200 mg the first day and 100 mg/d the following days. Remdesivir was not used in patients with a creatinine clearance of < 50 ml/min or with an alanine or aspartate aminotransferase level of more than 5 times the upper limit of normal as recommended. This study was conducted before the favorable results of the Recovery trial with tocilizumab were available (online publication February 25, 2021) and tocilizumab was only used in two patients who did not receive remdesivir during the study period [16].

Patients directly admitted to the intensive care unit (ICU) or directly transferred from the emergency room to the ICU were not included in the study since we wished to assess the impact of remdesivir and dexamethasone on clinical outcome including transfer to the ICU.

All adult patients identified through the pharmacy lists as having received dexamethasone or remdesivir during the study period were assessed through their electronic health records (EHR) and included in the study if they had a confirmed SARS-CoV-2 infection defined by positive nasopharyngeal polymerase chain reaction (PCR) test with pulmonary infiltrates on chest X-ray of pulmonary CT-scanner. Exclusion criteria included direct admission to the ICU (or from the emergency room to the ICU), no oxygen-therapy during hospitalization or no corticosteroid prescription.

Data collection

Clinical and laboratory data from the infectious diseases wards and from the internal medicine ward of the Saint-Louis hospital were retrospectively collected from patients EHR by two trained physicians (SG and VE). Data from patients admitted to the Pneumology ward of the Saint Louis Hospital and the Internal Medicine ward of the Lariboisière Hospital were collected prospectively by two other physicians (LC and DS). When remdesivir was prematurely discontinued, the patient EHR was analyzed to identify the reason for discontinuation. Severity at admission was evaluated using the WHO clinical progression scale, ranging from 0 (uninfected) to 10 (dead): moderate disease scores were 4 (hospitalized but no oxygen therapy) or 5 (hospitalized and oxygen delivered by nasal prongs or facial mask) [17].

Outcomes

The primary outcome was the length of hospital stay after oxygen initiation. Secondary outcomes wished to assess disease progression to severe forms of the disease and included in-hospital death, in-hospital death and/or transfer to the ICU and in-hospital death and/or mechanical ventilation (MV). Safety of remdesivir was also assessed by the analysis of EHR collecting drug-related adverse events and premature treatment discontinuations.

Statistical analysis

Categorical variables were expressed as percentages, and quantitative variables as median [interquartile range]. In-hospital mortality and other outcome measures of interest (transfer to the ICU or MV) were measured from the day of oxygen therapy initiation. Comparison of baseline characteristics between groups were based on Wilcoxon rank sum tests or exact Fisher tests, and a multivariate logistic model was used to identify predictive factors of outcomes (including age, gender, BMI, comorbidities, WHO severity score at admission and any confounding factor identified by univariate analyses). In order to account for indication bias resulting from potential differences between the two treatment groups (dexamethasone alone or dexamethasone with remdesivir), a propensity score matching analysis was performed with the main analysis to assess primary and secondary outcomes conducted on the matched populations [18, 19]. The propensity score was estimated from a multivariable logistic regression, including age, sex, obesity (BMI > 30 kg/m2), diabetes, hypertension, cardiovascular comorbidity, chronic kidney disease, hematological or solid cancer, solid organ or stem cell transplantation, time from onset of symptoms to oxygen initiation, initial oxygen flow, and CRP level at admission. To each patient in the remdesivir plus dexamethasone group, one patient in the dexamethasone group was matched on the basis of the closeness of their propensity score, using the nearest neighbor algorithm. Matching was performed without replacement (once chosen, the patient in the dexamethasone group could not be chosen thereafter), using a caliper of 0.10 fold the standard deviation of the propensity score as the maximal tolerance criterion [20, 21]. The performance of the score to balance treatment groups was assessed using standardized mean differences (SMD) computed before and after matching. Estimation of treatment effect was based on the matched cohort of 180 patients (90 remdesivir plus dexamethasone and 90 dexamethasone alone), measured on the hazard of events, using Cox model with robust variance estimate to handle the matching, as well as on the prevalence of events using generalized linear models. We then tested treatment-by-subset interaction using the Gail and Simon statistics [22], considering 2 groups of time of treatment initiation (within 5 days, > 5 days from disease onset). All analyses were performed on R version 4.0.3 statistical software using the R survival package [23].

Results

Population

Between August 15th 2020 and February 28th 2021, 386 patients were identified through electronic queries from the pharmacy. Remdesivir was requested for 118 patients and we included 101 patients in the final analysis for the remdesivir + dexamethasone group (R+DXM), excluding 11 patients who did not receive dexamethasone, 5 directly admitted to the ICU from the emergency room, and 1 who did not receive oxygen. Remdesivir was only prescribed to patients admitted to the infectious disease wards: 95.6% (87/91) of those admitted at the Saint-Louis hospital and 18.7% (14/75) of those admitted at the Lariboisière hospital). Dexamethasone without remdesivir was requested for 343 patients, and we excluded 119 patients, 53 patients without a confirmed COVID-19 diagnosis, 28 who did not receive dexamethasone, 28 directly admitted to the ICU from the emergency room, and 10 who did not receive oxygen. Overall, 224 patients receiving dexamethasone without remdesivir (DXM group) were included in the analysis.

Patient characteristics at the time of admission are shown in Table 1. Overall, median age was 68 (IQR 58–80) years, male sex 61%, median BMI 27 (IQR 23.7–31) kg/m2. Approximately 58.5% of patients had at least two comorbidities including hypertension (53%), diabetes mellitus (33%) and cardiovascular disease (20.5%). Solid or hematological malignancies were significantly more frequent in the R+DXM than in the DXM group (23.7% vs 9.4%, respectively, p = 0.0009) whereas active smoking was significantly less frequent in the R+DXM than in the DXM group (7.3% vs 18.5%, p = 0.016).

Table 1

Baseline demographic and clinical characteristics of the patients (unmatched and matched cohorts).

	Unmatched cohort			Matched cohort
	DXM	R+DXM	p-value	DXM	R+DXM	p-value
	(n = 224)	(n = 101)		n = 90	n = 90
Age (years)	68.6 [58.8; 79.5]	67.7 [58.7; 77.0]	0.69	67.0 [58.8; 77.9]	68.6 [58.8; 77.9]	0.72
Female (%)	85 (38%)	43 (43%)	0.46	35 (39%)	37 (41%)	0.88
Ethnicity			0.46			0.94
White	163 (73%)	65 (64%)		62 (69%)	58 (64%)
Black	17 (8%)	8 (8%)		7 (8%)	8 (9%)
Asian	4 (2%)	4 (4%)		2 (2%)	4 (4%)
Other	40 (17%)	24 (24%)		19 (21%)	20 (22%)
BMI (kg/m2)	27.8 [23.7; 31.2]	26.9 [24.0; 31.2]	0.77	27.8 [24.8; 32.4]	27.0 [24.2; 31.2]	0.30
Obesity (BMI > 30 kg/m2)	50 (22%)	28 (27%)	1.00	25 (28%)	25 (28%)	1.00
Hypertension	119 (53%)	54 (53%)	1.00	45 (50%)	46 (51%)	1.00
Diabetes	75 (33%)	33 (33%)	1.00	15 (28%)	28 (31%)	0.74
Cardiovascular disease	40 (20%)	21 (21%)	1.00	21 (24%)	16 (18%)	0.36
Pulmonary disease	36 (16%)	11 (11%)	0.24	11 (12%)	11 (12%)	1.00
Tobacco usage	30 (19%)	7 (7%)	0.016	14 (15%)	7 (8%)	0.16
Chronic renal failure	35 (16%)	11 (11%)	0.30	10 (11%)	10 (11%)	1.00
Neurological disease	38 (17%)	17 (17%)	1.00	10 (11%)	15 (17%)	0.39
Hemopathy or solid cancer	21 (9%)	24 (24%)	0.0009	13 (14%)	13 (14%)	1.00
Solid organ transplant or hematopoietic stem cell transplant	9 (4.84%)	3 (2.97%)	0.55	6 (6%)	3 (3%)	0.50
Number of comorbidities			0.16			0.44
0	36 (16%)	9 (9%)		11 (12%)	9 (10%)
1	57 (26%)	32 (32%)		22 (24%)	30 (33%)
≥2	130 (58%)	60 (59%)		57 (63%)	51 (57%)
WHO scale score at admission			<0.0001			<0.0001
4: hospitalized but no oxygen therapy	73 (33%)	10 (10%)		31 (34%)	8 (9%)
5: hospitalized with oxygen by nasal prongs or mask	151 (67%)	91 (90%)		59 (66%)	82 (91%)
Time from symptoms to initiation of oxygen-therapy (days)	7 [4; 10]	7 [4; 10]	0.88	7 [4;10]	7 [4; 10]	0.92
Initial oxygen requirement (for SpO2 >94%) (L/min)	2.25 [2; 4]	2 [2; 3]	0.01	2 [1; 3]	2 [2; 3]	0.23
Laboratory tests at admission
Lymphocytes (G/L)	0.94 [0.63; 1.25]	0.86 [0.6; 1.15]	0.14	1.00 [0.66; 1.29]	0.91 [0.64; 1.16]	0.20
CRP (mg/L)	40 [2; 87]	32 [2; 66.5]	0.11	37 [2; 78.8]	34.5 [2; 68]	0.90
D-dimers (ng/mL)	1055 [648.2; 1672]	850 [495.5; 1575]	0.058	1030 [672; 1539]	850 [502; 1575]	0.18
Serum creatinine (mg/dL)	0.97 [0.80; 1.22]	0.85 [0.73; 1.11]	0.025	0.83 [0.66; 0.98]	0.75 [0.64; 0.98]	0.39

Severity at admission evaluated through the WHO clinical progression scale, was greater in the R+DXM group than in the DXM group with a higher proportion of patients with a WHO score of 5 (90% vs. 67%, respectively, p<0.0001). Median time from onset of symptoms to oxygen initiation was similar in the two groups (7 days (IQR 4–10)) and the median time from admission to oxygen initiation was 0 day (IQR: 0–0).

There was no difference between the two groups regarding baseline lymphocyte count, CRP or D-dimers levels at admission. Baseline serum creatinine was slightly but significantly higher in the DXM group than in the R+DXM group (0.97 mg/dL [0.80;1.22] versus 0.85 mg/dL [0.73;1.11] respectively, p = 0.025). In the multivariable analysis, mortality was associated with older age (p<0.001), cardiovascular disease (p< 0.01), receipt of an organ or stem cell transplant (p< 0.001) and higher initial oxygen flow (p<0.001).

Using propensity score, 90 of the 101 patients receiving remdesivir (89%) were matched on PS to 90 control patients who only received dexamethasone. Baseline characteristics of these two matched groups are shown in Table 1. The median length of hospital stay from oxygen initiation was not significantly different between DXM and R+DXM groups: 9 days vs 9 days respectively; p = 0.37) (Table 2). Overall, 24 patients died, 8 in the R+DXM group (8.9%) versus 16 (17.8%) in the DXM group (HR: 0.47, 95% CI: 0.21–1.04, p = 0.06), and 50 patients died or were admitted to the ICU because of clinical worsening: 18 in the R+DXM group (20%) versus 32 (35.56%) in the DXM group (HR: 0.43, 95% CI: 0.23–0.81, p = 0.008). Similarly, the rate of in-hospital death or MV was 11.11% and 25.56% in the R+DXM and DXM groups, respectively (OR: 0.86, 956% CI: 0.77–0.97, p = 0.012) (Fig 1). Results were not markedly modified when further adjusting on the residual imbalance in the OMS scale at study entry (Table 2). Moreover, the forest-plot in Fig 2 showed a positive quantitative interaction (p = 0.024) between early initiation of remdesivir (within the first 5 days of symptoms onset) and treatment effect on disease progression (death or mechanical ventilation).

Table 2

Outcomes according to treatment group in the propensity score matched populations.

	Dexamethasone only (n = 90)	Remdesivir+Dexamethasone (n = 90)	Effect measure (95%CI); p-value
			Unadjusted	Adjusted on WHO scale at baseline
			Mean difference
Mean Length of stay (days)	9 [5; 18]	9 [7; 13]	1.9 [-2.3; 6.1]; P = 0.37	1.4 [-3.5; 6.3]; P = 0.58
			Hazard Ratio (HR)
In-hospital Death rate (n, %)	16 (18%)	8 (9%)	0.47 [0.21; 1.04]; P = 0.06	0.46 [0.21; 1.03]; P = 0.059
In-hospital Death rate or ICU admission (n, %)	32 (35.56%)	18 (20%)	HR: 0.43 [0.23; 0.81]; P = 0.008	0.42 [0.23; 0.80]; P = 0.008
			Odds Ratio (HR)
In-hospital Death rate or MV (n,%)	23 (26%)	10 (11%)	0.86 [0.77; 0.97]; P = 0.012	0.87 [0.77; 0.97]; P = 0.019

DXM: Dexamethasone. R+DXM: Remdesivir plus dexamethasone. MV: Mechanical ventilation. ICU: Intensive care unit.

*Either mean difference for duration of hospitalization or hazard ratio for the censored outcomes. DXM: Dexamethasone. R+DXM: Remdesivir plus dexamethasone. MV: Mechanical ventilation. ICU: Intensive care unit.

Fig 1

Estimated outcomes (survival in upper plot, survival free of transfer to the ICU in lower plot) in the matched cohort.

Fig 2

Forest plot HR of rate of death and/or MV between DXM and R+DMX groups in the matched population according to duration of symptoms before treatment initiation: A) ≥5 days, B) ≤ 5 days.

Finally, we did not observe any severe adverse event related to the use of the combination of remdesivir and dexamethasone in our study. Remdesivir was prematurely stopped in 5/101 patients (5%) patients due to transient and asymptomatic elevation of liver enzymes. All enzyme elevation rapidly returned to normal within days after drug discontinuation.

Discussion

In this study, we wished to assess the potential clinical benefit of adding remdesivir to dexamethasone in adult patients with moderately severe COVID-19 pneumonia hospitalized in medical wards and requiring low-flow oxygen therapy.

Indeed, whereas dexamethasone is standard of care for patients with COVID-19 pneumonia requiring oxygen supplementation, the benefit of adding remdesivir remains largely unknown.

This issue has not been addressed in randomized trials yet: in the Recovery trial, only 3 of the 2104 patients received remdesivir in the dexamethasone group, in the ACTT-1 trial only 23% received corticosteroids and remdesivir and in the SOLIDARITY trial 47.7% of patients in the remdesivir arm received corticosteroids [8].

In our study, we compared clinical outcomes in two groups of patients: those who received only dexamethasone at the time of oxygen initiation (DXM group) and those who received remdesivir in combination with dexamethasone (R+DXM group). Indeed, during the study period, 70.7% (87/123) and 18.7% (14/75) of patients admitted to the infectious disease wards of the Saint-Louis and Lariboisière hospitals, respectively, received remdesivir in combination with dexamethasone. To account for potential prescription bias, we used propensity scores and were able to match 90 (89%) of patients who received remdesivir plus dexamethasone to 90 patients who received only dexamethasone. In our propensity score-matched cohort, the association of remdesivir and dexamethasone did not reduce the length of hospital stay as we had hypothesized. This finding seems contradictory to prior reports showing in placebo-controlled studies a faster time to recovery with remdesivir but are in agreement with the results of large open-label trials. Also, a recent meta-analysis of remdesivir trials found no effect of remdesivir on length of hospital stay [24].

Of interest secondary clinical outcomes in this PS matched populations showed a reduced in-hospital death in the R+DMX group as compared to the DXM group, though non statistically significant (HR: 0.47, p = 0.06) and a significantly lowered clinical progression to in-hospital death or transfer to the ICU or to in-hospital death and MV (HR: 0.43 and OR: 0.86, p = 0.008 and 0.012, respectively) in the R+DXM as compared to the DXM group.

These findings are contradictory to those of the Recovery trial where no benefit was found in the subgroup of patients receiving remdesivir and dexamethasone [3]. Similarly, in the DISCOVERY trial where most patients also received corticosteroids with remdesivir, no clinical benefit was seen [9]. However, both trials aimed at assessing the clinical benefit of remdesivir and not the combination, and unlike in our study both drugs were not administered simultaneously. Our results are in agreement with those of a nationwide population-base study in Denmark reporting reduced mortality rate and need for mechanical ventilation in patients receiving remdesivir and dexamethasone as compared to standard of care, but patients in the standard of care arm did not receive dexamethasone and were not enrolled at the same time [25]. Another large retrospective cohort study in the United States reported a shorter time to clinical improvement with remdesivir as compared to matched controls but the combination of remdesivir and dexamethasone was not associated with reduced mortality compared to remdesivir alone [11]. There is therefore a need to conduct randomized trials assessing the potential clinical benefit of combining remdesivir to dexamethasone in patients with COVID-19 pneumonia requiring low-flow oxygen.

In our study, we also found a significant interaction between treatment effect and the time from symptoms onset to treatment initiation with improved effect on severe clinical outcome in patients with treatment onset within 5 days, which is consistent with previous reports showing a larger benefit of remdesivir when given early in the disease [6, 7, 26]. This is in agreement with the recent results of the Pinetree study demonstrating that a 3-day course of remdesivir was highly effective at preventing COVID-19 related hospitalization or death in high-risk non-hospitalized COVID-19 patients [27]. This finding is also consistent with the mode of action of remdesivir, which may be beneficial in the early phase of the disease with high level of viral replication, since no survival benefit was seen in patients admitted to the ICU or requiring high-flow oxygen [6, 8].

In addition, we did not observe any deleterious effect of remdesivir in our study and the safety profile of a 5-day course of remdesivir was favorable with only 5% of patients prematurely discontinuing remdesivir because of liver enzyme elevations.

Our study has however several limitations. First, it is a retrospective, observational cohort study and despite the use of propensity score to match populations, we cannot exclude residual and unmeasured confounders that may have biased our estimates of treatment effect. Second, the number of patients included in our study remains low, especially when the analysis was restricted to the matched groups, and the validity of our results needs to be confirmed in larger studies.

In conclusion, our study showed that in mild to moderately severe patients hospitalized for COVID-19 pneumonia and requiring oxygen the association of remdesivir and dexamethasone did not reduce the length of admission or the rate of in-hospital death but may have reduced the progression to severe disease defined as in-hospital death or transfer to the ICU. Clinical trials dedicated to this specific population are needed to confirm our results and assess whether patient prognosis can be improved with early administration of remdesivir in patients initiating dexamethasone.

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Line 42: Abstract: You can describe how you performed propensity score matching as you can add another 49 words.

Line 44-51: Methods: Please mention somewhere that you analyzed and presented data of 180 matched patients

Line 100: Informed consent can be taken from the relatives of the patients; I am not sure whether we could use data without any kind of consent. Please clarify this

Looking forward to a revised version.

Reviewer #2: Gressens et al report here the effect of the combination of dexamethasone + remdesivir compared to dexamethasone alone in hospitalized French patients with COVID-19 pneumonia. The authors state that in hospitalized patients with COVID-19 pneumonia receiving low-flow oxygen the addition of remdesivir to dexamethasone was not associated with shorter hospitalization or lower in-hospital mortality but may have reduced the combined outcome of death and transfer to the ICU.

The manuscript is enticing because it brings new light to the positive effect of remdesivir on COVID-19 infection. Results on this topic have been contradictory so far.

This reviewer can raise some points needing clarification by the authors.

Major points

1.Why different mortality outcomes were selected in this study: In-hospital death, in-hospital death and/or transfer to the ICU, in-hospital death and/or endotracheal intubation (Page 9, lines 134-140)

2.”In-hospital death rates were 8.9% and 20%, with and without remdesivir (p=0.06)!. This is a not-significant trend (p>0.05). perhaps due to the low number of patients included in the study (Page 16, line 275). This not-significant comparison might be confusing for the reader and perhaps it might be deleted from the abstract

Minor points

1. Could you actualize the worlwide COVID-19 information to November 2021? (Page 5, lines 59-60)

2. Could you explain further the expression “matched without replacement, using a caliper of 0.10 the standard deviation of the propensity…” (Page 19, lines 159-160). It is rather confusing in this form.

3. Could you change “endotracheal intubation (ETI)” to “mechanical ventilation”?

4. Could you change “OMS scale” to “WHO scale” in Table 1?

Reviewer #3: The manuscript by Gressens et al is concise and well-written. Although several retrospective studies of the same kind have been published this study adds another dataset to the our understanding of the potential benefits of remdesivir treatment.

Minor: The authors should mention the pinetree study in the discussion section.

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Reviewer #1: Yes: Mahbub-Ul Alam

Reviewer #2: No

Reviewer #3: No

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5 Dec 2021

Reviewer #1: Thanks for sending the paper for review. This is a well written draft. My specific comments are:

Line 42: Abstract: You can describe how you performed propensity score matching as you can add another 49 words.

- Answer: We thank the reviewer for her/his kind comment. The description of the propensity score matching has been added in the abstract, as suggested by the Reviewer.

Line 44-51: Methods: Please mention somewhere that you analyzed and presented data of 180 matched patients

- Answer: This has been more clearly stated in the revised abstract and Methods sections of the manuscript.

Line 100: Informed consent can be taken from the relatives of the patients; I am not sure whether we could use data without any kind of consent. Please clarify this

Answer: In agreement with French bio-ethics law, as this was a retrospective study on data from patients charts, signed informed consent was not requested and patients or their relatives were informed that their anonymized data will be used for this analysis. They could refuse to have their data analyzed. This study was approved by the ethic research committee of the French ID society. This point has been clarified in the revised manuscript.

Looking forward to a revised version.

Reviewer #2: Gressens et al report here the effect of the combination of dexamethasone + remdesivir compared to dexamethasone alone in hospitalized French patients with COVID-19 pneumonia. The authors state that in hospitalized patients with COVID-19 pneumonia receiving low-flow oxygen the addition of remdesivir to dexamethasone was not associated with shorter hospitalization or lower in-hospital mortality but may have reduced the combined outcome of death and transfer to the ICU.

The manuscript is enticing because it brings new light to the positive effect of remdesivir on COVID-19 infection. Results on this topic have been contradictory so far.

This reviewer can raise some points needing clarification by the authors.

Major points

1.Why different mortality outcomes were selected in this study: In-hospital death, in-hospital death and/or transfer to the ICU, in-hospital death and/or endotracheal intubation (Page 9, lines 134-140)

Answer: due to the small size of our cohort and the small number of deaths, we did not expect to see a difference in in-hospital mortality between arms. We wished however to assess the potential impact of adding remdesivir on severe outcomes, and to increase our statistical power we use composite outcomes including death and/or transfer to the ICU or death and/or mechanical ventilation.

2.”In-hospital death rates were 8.9% and 20%, with and without remdesivir (p=0.06)!. This is a not-significant trend (p>0.05). perhaps due to the low number of patients included in the study (Page 16, line 275). This not-significant comparison might be confusing for the reader and perhaps it might be deleted from the abstract

Answer: We are not claiming that the difference between arms in in-hospital mortality is significant but feel that it is still important to provide data on mortality since it has been the main outcome used in clinical trials that have impacted guidelines (steroids, tocilizumab ..).

Minor points

1. Could you actualize the worlwide COVID-19 information to November 2021? (Page 5, lines 59-60)

Answer: As suggested data have been uptdated in the revised manuscript.

2. Could you explain further the expression “matched without replacement, using a caliper of 0.10 the standard deviation of the propensity…” (Page 19, lines 159-160). It is rather confusing in this form.

- Answer: This means that each patient in the Remdesivir group was matched to one patient in the dexamethasone group based on the closeness of their propensity score on a logit scale, using the nearest neighbor algorithm, with a tolerated maximal distance set at 0.10 fold the standard deviation of the PS. This has been rephrased in the revised manuscript.

3. Could you change “endotracheal intubation (ETI)” to “mechanical ventilation”?

Answer : it has been changed as suggested

4. Could you change “OMS scale” to “WHO scale” in Table 1?

Answer : it has been changed as suggested

Reviewer #3: The manuscript by Gressens et al is concise and well-written. Although several retrospective studies of the same kind have been published this study adds another dataset to the our understanding of the potential benefits of remdesivir treatment.

We thank the reviewer for this kind comment.

Minor: The authors should mention the pinetree study in the discussion section.

Answer: The Pinetree study has not yet been presented when we submitted this manuscript but is now added in the discussion.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

30 Dec 2021

Remdesivir in combination with dexamethasone for patients hospitalized with COVID-19: a retrospective multicenter study

PONE-D-21-27196R1

Dear Dr. Gressens,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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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Kind regards,

Maria Elena Flacco, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: I am pleased with the revised version of this manuscript. The authors have answered all the queries raised by me and by the other reviewers . In my opinion this manuscript now it might be accepted in PLOS ONE

Reviewer #3: Comments have been adressed. No additional comments. The manuscript is well written and concise. The manuscript merits publication.

**********

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Reviewer #2: Yes: VICTOR ASENSI

Reviewer #3: No

8 Feb 2022

PONE-D-21-27196R1

Remdesivir in combination with dexamethasone for patients hospitalized with COVID-19: a retrospective multicenter study

Dear Dr. Gressens:

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

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. Maria Elena Flacco

Academic Editor

PLOS ONE