Statins use and COVID-19 outcomes in hospitalized patients

Samuel K Ayeh; Enoch J Abbey; Banda A A Khalifa; Richard D Nudotor; Albert Danso Osei; Vignesh Chidambaram; Ngozi Osuji; Samiha Khan; Emmanuella L Salia; Modupe O Oduwole; Hasiya E Yusuf; Oluwatobi Lasisi; Esosa Nosakhare; Petros C Karakousis

doi:10.1371/journal.pone.0256899

. 2021 Sep 10;16(9):e0256899. doi: 10.1371/journal.pone.0256899

Statins use and COVID-19 outcomes in hospitalized patients

Samuel K Ayeh ¹, Enoch J Abbey ¹, Banda A A Khalifa ², Richard D Nudotor ³, Albert Danso Osei ⁴, Vignesh Chidambaram ¹, Ngozi Osuji ¹, Samiha Khan ¹, Emmanuella L Salia ⁵, Modupe O Oduwole ¹, Hasiya E Yusuf ⁶, Oluwatobi Lasisi ⁷, Esosa Nosakhare ⁸, Petros C Karakousis ^1,^9,^*

Editor: Aleksandar R Zivkovic¹⁰

¹Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America

²Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America

³Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, United States of America

⁴Department of Internal Medicine, Medstar Union Memorial Hospital, Baltimore, MD, United States of America

⁵Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States of America

⁶Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, United States of America

⁷Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, United States of America

⁸Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine, Baltimore, MD, United States of America

⁹Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America

¹⁰Heidelberg University Hospital, GERMANY

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: petros@jhmi.edu

Roles

Samuel K Ayeh: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Enoch J Abbey: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Banda A A Khalifa: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Richard D Nudotor: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Albert Danso Osei: Writing – review & editing

Vignesh Chidambaram: Writing – original draft, Writing – review & editing

Ngozi Osuji: Writing – original draft, Writing – review & editing

Samiha Khan: Writing – original draft, Writing – review & editing

Emmanuella L Salia: Conceptualization, Writing – original draft, Writing – review & editing

Modupe O Oduwole: Conceptualization, Writing – original draft, Writing – review & editing

Hasiya E Yusuf: Conceptualization, Writing – original draft, Writing – review & editing

Oluwatobi Lasisi: Conceptualization, Writing – original draft, Writing – review & editing

Esosa Nosakhare: Writing – review & editing

Petros C Karakousis: Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing

Aleksandar R Zivkovic: Editor

PMCID: PMC8432819 PMID: 34506533

Abstract

Background

There is an urgent need for novel therapeutic strategies for reversing COVID-19-related lung inflammation. Recent evidence has demonstrated that the cholesterol-lowering agents, statins, are associated with reduced mortality in patients with various respiratory infections. We sought to investigate the relationship between statin use and COVID-19 disease severity in hospitalized patients.

Methods

A retrospective analysis of COVID-19 patients admitted to the Johns Hopkins Medical Institutions between March 1, 2020 and June 30, 2020 was performed. The outcomes of interest were mortality and severe COVID-19 infection, as defined by prolonged hospital stay (≥ 7 days) and/ or invasive mechanical ventilation. Logistic regression, Cox proportional hazards regression and propensity score matching were used to obtain both univariable and multivariable associations between covariates and outcomes in addition to the average treatment effect of statin use.

Results

Of the 4,447 patients who met our inclusion criteria, 594 (13.4%) patients were exposed to statins on admission, of which 340 (57.2%) were male. The mean age was higher in statin users compared to non-users [64.9 ± 13.4 vs. 45.5 ± 16.6 years, p <0.001]. The average treatment effect of statin use on COVID-19-related mortality was RR = 1.00 (95% CI: 0.99–1.01, p = 0.928), while its effect on severe COVID-19 infection was RR = 1.18 (95% CI: 1.11–1.27, p <0.001).

Conclusion

Statin use was not associated with altered mortality, but with an 18% increased risk of severe COVID-19 infection.

1. Background

A novel beta-coronavirus, now known as SARS-CoV-2, was first reported to cause severe pneumonia in China’s Wuhan province in late December 2019 [1]. Despite early efforts to contain the virus, coronavirus disease 2019 (COVID-19) has been reported in almost all other countries, attaining pandemic status by March 2020 [1].

Although vaccines against COVID-19 have shown promising results, treatment modalities such as remdesivir, dexamethasone, and the monoclonal antibody treatment REGEN-COV2 continue to play essential roles in treating high-risk infected patients or those with moderate to severe disease [2]. The medical community has continued to look for inexpensive, practical, and rapidly deployable agents to improve mortality and reduce the need for mechanical ventilation among hospitalized patients. Recently, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have gained attention for their potential utility as adjunctive, host-directed therapies against various infectious diseases [3]. In preclinical tuberculosis (TB) models, adjunctive statin therapy enhanced the bactericidal activity of the first-line antitubercular regimen [4, 5] and shortened the duration of curative TB treatment [6]. Similarly, statins have also been shown to potentiate host antiviral responses in preclinical models [7]. For example, statins inhibit HIV replication in CD4⁺ T cells and suppress cytomegalovirus and respiratory syncytial virus loads in mice [8–10]. When added as a vaccine adjuvant, simvastatin enhanced protection relative to influenza A/PR8 hemagglutinin A1 alone against influenza challenge in mice and macaques [11]. Apart from inhibiting the first step of cholesterol biosynthesis, statins possess anti-inflammatory and immune-modulating functions [12, 13]. These effects have been attributed to their modulation of various host molecular pathways, including inhibition of activation of the mechanistic target of rapamycin complex 1 (mTORC1), activation of AMP-activated protein kinase (AMPK), enhanced nuclear translocation of transcription factor EB (TFEB), modulation of NF-κB activity, as well as inhibition of protein prenylation [14–17].

A randomized control trial found that statins, when added to the standard treatment, reduced mortality in elderly patients with community-acquired pneumonia and sepsis [18]. Several retrospective studies have concluded that statin use is associated with reduced mortality in patients with bacteremia, sepsis, and pneumonia [19]. The use of statins was also associated with lower death rates and intubation in patients admitted with viral pneumonia [20]. More recently, a retrospective study in an elderly care facility reported that statin use in residents diagnosed with COVID-19 was associated with less severe symptoms and improved clinical outcomes [21]. Several studies have suggested that statin use is also associated with reduced COVID-19-related mortality [22–24]. However, prior work showed that expression of the ACE2 receptor, which is required for SARS‐CoV‐2 entry [25] into airway epithelial cells, is upregulated by statin therapy in various tissues [26, 27], raising theoretical concerns about the use of statins in the context of COVID‐19 infection.

In this retrospective study, we sought to investigate the relationship between statin use and COVID-19 mortality and disease severity in patients admitted to the Johns Hopkins health system.

2. Materials and methods

2.1. Study design and participants

This is a retrospective, multi-center cohort study of 4,447 patients hospitalized at the Johns Hopkins Hospital and affiliated hospitals (Johns Hopkins Bayview Medical Center, Howard County General Hospital, Sibley Memorial Hospital, and Suburban Hospital) with a diagnosis of SARS-CoV-2 infection between March 1, 2020 and June 30, 2020. The study inclusion criteria included: 1) inpatients diagnosed with COVID-19; 2) age ≥ 18 years old. There were no specific exclusion criteria. The data source was the Johns Hopkins Crown database, which contains comprehensive information on study participants, including detailed demographics, past medical history, medications, and hospital course. The study was approved by the Johns Hopkins Institutional Review Board and the Johns Hopkins Covid-19 and Data Research Evaluation (CADRE) Committees.

2.2. Exposure and outcomes

The primary endpoints were mortality (in-hospital death) and severe COVID-19 infection, defined as prolonged hospital stay (≥ 7 days) and/or need for invasive mechanical ventilation. The main exposure of interest was statin use, based on the medication administration record. Follow-up in this study was defined as the period between hospital admission and the occurrence of an outcome, until discharge, or until the time of administrative censoring (June 30, 2020), whichever occurred first. Demographic data included age, sex, race, and employment status. Relevant clinical data shown to be associated with mortality and poor outcomes in prior studies [28], such as body mass index (BMI), Elixhauser comorbidity index, history of hypertension (≥140 mm Hg systolic / ≥ 90 mm Hg diastolic), diabetes mellitus, chronic kidney disease patients on interval dialysis, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), and serum Interleukins-6 (IL-6) levels, were extracted from the database. BMI was categorized as normal (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²) and obese (≥ 30.0kg/m²). Generic names of statins and angiotensin-converting enzyme (ACE) inhibitors/ARB prescribed are listed in S1 and S2 Tables. Serum IL-6 was categorized as a binary variable, i.e., either high (>3.2 pg/ml) or normal (≤ 3.1 pg/ml). Employment status was divided into the following categories: employed, unemployed, student, and retired/disabled. The AHRQ-Elixhauser comorbidity index, designed to assess the risk of in-hospital mortality and 30-day readmission, was used [29], with each condition assigned an index weight.

2.3. Statistical analyses

Cohort baseline and time-specific characteristics were compared by statin treatment status, as indicated in Table 1. Single measure baseline comparisons were made using Chi-square (χ²) tests for categorical variables and one-way ANOVA or Kruskal-Wallis tests for continuous variables.

Table 1. Baseline characteristics of statin users versus statin non-users.

Characteristics	Statin use	No statin use	p-value
Characteristics	(n = 594)	(n = 3853)	p-value
Age, years Mean (SD)	64.9 (13.4) *	45.5 (16.6) *	<0.001
Male–No. (%)	340 (57.2)	1882 (48.9)	<0.001
Race			<0.001
*Black*	257 (46.6)	1248 (34.5)
*Other*	105 (19.0)	1553 (42.9)
BMI (kg/m ² )			<0.001
Overweight (25.0–29.9)	133 (23.2)	705 (18.6)
Obese (≥30.0)	337 (58.8)	2,609 (68.8)
Hypertension	439 (80.3)	973 (28.4)	<0.001
Diabetes	317 (57.9)	503 (14.7)	<0.001
ACE inhibitor /ARB use	214 (36.0)	267 (9.8)	<0.001
Interval Dialysis	41 (6.9)	28 (0.7)	<0.001
IL-6 (High)	9 (1.5)	56 (1.5)	0.91
Employment Status
*Unemployed*	140 (23.6)	1,294 (34.1)	<0.001
*Students*	1 (0.2)	56 (1.5)
*Retired/ Disabled*	318 (53.6)	612 (16.1)
Total Elixhauser Score	7.3 (11.3) *	1.7 (7.6) *	<0.001

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N/n: Number of patients, %: percent of patients, CI: 95% confidence interval, BMI: Body mass index, Kg/m², */SD: standard deviation, ACE/ARB: Angiotensin converting enzyme inhibitor or Aldosterone receptor blocker. Significant p-values <0.05.

The association (risk factor analyses) between covariates and primary outcomes (mortality and severe COVID-19 infection) was evaluated using Cox proportional hazards regression and logistic regression to obtain both univariable and multivariable regression models and point estimates (Tables 2 and 3). Variables used in the regression models were based on both a conceptual framework and stepwise regression using a p-value of <0.05. Backward stepwise regression models were conducted after a model had been designed based on a conceptual framework. The final model for mortality contained the following variables: age, sex, race, statin-use, and Elixhauser comorbidity index; while that of severe COVID-19 infection included the following variables: age, sex, IL-6 levels, statin-use, ACE inhibitor/ ARB use, hypertension, diabetes mellitus, and chronic kidney disease. Model selection for propensity score matching (PSM) involved backward stepwise regression, Akaike information criterion, and model fit determined using Hosmer-Lemeshow test. PSM involved a 1:1 nearest neighbor matching with replacement to minimize conditional bias. The balance of the propensity model between the treated and control groups was assessed by comparing the raw and matched standard differences and variance ratios. A well-balanced matching model produces a standard difference value close to 0 and a variance ratio close to 1 for each covariate, as well as a balanced boxplot (S3 and S4 Tables and S1 and S2 Figs). All statistical analyses were performed using STATA® (Statistical Data Analysis Package version 16.0 IC, College Station, TX–USA).

Table 2. Cox proportional regression showing association between covariables and mortality.

Covariable	Unadjusted Hazard Ratio (95% CI)	Adjusted Hazard Ratio (95% CI)
Age (years)	1.04 (1.02–1.07)	1.04 (1.01–1.06)
Male	1.48 (0.87–2.52)	1.78 (1.01–3.17)
Race
*Black*	0.70 (0.40–1.24)	0.97 (0.53–1.76)
*other*	0.44 (0.20–0.93)	0.78 (0.34–1.81)
BMI
*Overweight*	0.56 (0.27–1.15)	-
*Obese*	0.57 (0.31–1.04)
Hypertension	1.39 (0.81–2.38)	-
Diabetes	1.96 (1.18–3.28)	-
ACE/ ARB Use	0.69 (0.40–1.18)	-
Interval Dialysis	1.02 (0.41–2.56)	-
IL-6 (High)	-	-
Employment Status
*Unemployed*	1.08 (0.44–2.67)	-
*Students*	-
*Retired/ Disabled*	3.75 (1.88–7.49)
Total Elixhauser Score	1.05 (1.03–1.07)	1.03 (1.01–1.05)

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Table 3. Logistic regression showing association between covariables and severe COVID-19 infection.

Covariable	Unadjusted Relative Risk	Adjusted Relative Risk
Age (years)	1.04 (1.03–1.04)	1.80 (1.38–2.35)
Male	1.48 (1.24–1.76)	1.50 (1.21–1.85)
Race		-
*Black*	0.86 (0.69–1.07)
*Other*	0.53 (0.42–0.66)
BMI		-
*Overweight*	1.13 (0.85–1.50)
*Obese*	0.67 (0.52–0.86)
Hypertension	2.95 (2.46–3.54)	0.74 (0.57–0.97)
Diabetes	3.48 (2.87–4.20)	1.66 (1.30–2.12)
ACE/ ARB Use	10.07 (8.13–12.48)	7.18 (5.64–9.14)
Interval Dialysis	11.56 (7.05–18.96)	3.49 (1.94–6.28)
IL-6 (High)	3.19 (1.88–5.41)	2.85 (1.55–5.24)
Employment Status		-
*Unemployed*	1.22 (0.98–1.52)
*Students*	0.52 (0.16–1.67)
*Retired/ Disabled*	3.07 (2.49–3.79)
Total Elixhauser Score	1.03 (1.03–1.04)	-

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3. Results

3.1. Patient characteristics

A total of 4,447 inpatients with COVID-19 met study eligibility criteria, with 594 (13.4%) receiving statins upon admission (Table 1). Statin users were significantly more likely to be male (57.2% vs. 48.9%, p <0.001) and older (64.9 ± 13.4 vs. 45.5 ± 16.6, p <0.001) compared to statin non-users. The largest percentage of statin users were Black (46.6%) and had hypertension (73.9%) and diabetes (53.4%). Statin users were more likely to be receiving ACE inhibitors/ARBs compared to non-statin users and to experience more frequent episodes of interval dialysis, possibly due to more profound disease and/or the presence of more comorbidities. Most statin users had higher Elixhauser comorbidity scores than non-users (7.3 ± 11.3 vs 1.7 ± 7.6, p <0.001).

3.2. Risk factors for COVID-19-related mortality

The association between patient characteristics and in-hospital mortality was evaluated via univariable and multivariable analysis using Cox proportional regression (Table 3). Based on the univariable analysis, every yearly increase in age was associated with a 4% increased hazard of death among inpatients [HR = 1.04, 95% CI (1.02–1.07)] and this was similar in the adjusted model [HR = 1.04, 95% CI (1.01–1.06)]. Although statin use was associated with an increased hazard of death in the unadjusted model, the adjusted model (Table 4) showed a protective effect of HR = 0.92, 95% CI (0.53–1.59). However, this effect was not statistically significant. On the other hand, male patients with COVID-19 experienced increased mortality in both the unadjusted (HR = 1.48, 95% CI [0.87–2.52]) and adjusted (HR = 1.78, 95% CI [1.01–3.17]) models. Increasing Elixhauser scores were associated with an increased hazard of death, both in univariable and multivariable analyses [HR = 1.05, 95% CI (1.03–1.07); multivariable-adjusted HR = 1.03, [95% CI (1.01–1.05)] (Table 4).

Table 4. Risk for mortality and severe COVID-19 infection in statin users versus statin non-users.

Outcome	Crude Risk	MV-adjusted Risk	PSM-Relative Risk
Mortality
Statin versus non-statin	HR = 1.16 (0.70–1.92)	HR = 0.92 (0.53–1.59)	RR = 1.00 (0.99–1.01)
Severe COVID-19
Statin versus non-statin	RR = 6.17 (5.07–7.52)	RR = 1.80 (1.38–2.35)	RR = 1.18 (1.11–1.27)

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The propensity-score matching analysis created 2,789 matches in the statin use (exposure) and statin non-use (control) groups. All assessed variables were balanced between treatment and control groups, as demonstrated by the standardized differences and variance ratios provided in S3 Table. The average treatment effect of statin use on COVID-19-related mortality in the matched groups was not statistically significant (RR = 1.00; 95% CI [0.99–1.01]).

3.3. Risk factors for severe COVID-19 infection

Increasing age and male sex were both associated with an increased risk of severe COVID-19 infection by univariable and multivariable analysis (Table 3). Similarly, the presence of diabetes and elevated IL-6 levels, and exposure to interval dialysis were associated with an increased risk of severe COVID-19 infection among inpatients by univariable and multivariable analyses. Also, the risk for severe COVID-19 infection was higher with the use of ACE inhibitors or ARBs (Table 3, MV-adjusted RR = 7.18 95% CI [5.64–9.14]), as well as statin use (Table 4, MV-adjusted, RR = 1.80; 95% CI [1.38–2.35], even after adjusting for other relevant covariables. The propensity-score matching analysis created 2,789 matches in the statin group and the statin non-use group. All assessed variables were balanced between the two groups, as demonstrated by the standardized differences and variance ratios provided in S4 Table. Statin use was associated with an 18% increased risk of severe disease among hospitalized patients (RR = 1.18, 95% CI [1.11–1.27]) (Table 4).

4. Discussion

Our study sought to investigate the potential association between statin use and COVID-19 disease severity or mortality. We found no association between statin use and mortality in this cohort, but there was a statistically significant association between statin use and increased COVID-19 disease severity, defined as prolonged hospital stay (≥ 7 days) and/or need for invasive mechanical ventilation. This association was demonstrated by multivariable logistic regression and was sustained in the analysis after propensity score matching.

In a similar retrospective cohort study from Belgium, De Spiegeleer et al. found statin use to be independently associated with the absence of symptoms during COVID-19, but not with severe or fatal infection among a limited sample of 154 elderly nursing home residents with COVID-19 [21]. Another retrospective study of 87 patients admitted to the ICU with COVID-19 linked statin non-use to a 73% higher probability of more rapid progression to mortality after adjusting for age, hypertension, cardiovascular disease, invasive mechanical ventilation, disease severity, and other adjuvant therapies [30]. However, the authors did not obtain consistent results with the chi-square test (p-value = 0.20) between statin use and mortality. Additionally, the sample size was low in the study (< 25 patients receiving statin therapy. A recent meta-analysis of 9 observational studies using unadjusted data showed that statin use was not associated with increased mortality or severe disease [31].

Our study findings are in contrast to those of Daniels et al., who reported that statin use in the month prior to hospitalization was associated with a 71% percent risk reduction in severe COVID-19 disease [22] and those of Rossi et al., who reported a non-significant reduction in mortality with statin use [23]. A similar finding of 24% reduction in COVID-19-related mortality among statin users was reported by Peymani et al. [24]. In contrast to these reported studies, we found that statin use had no effect on COVID-19-related mortality but increased the risk of COVID-19 disease severity by 18%. Our discrepant findings may be explained by the much smaller sample sizes in the studies by Daniels et al. (170 patients with COVID-19; 46 statin users) [22], Rossi et al. (71 patients with COVID-19; 42 statin users) [23], and Peymani et al. (150 study participants; 75 statin users) [24]. In contrast, our study included a total of 4,447 inpatients with COVID-19, 594 of whom were statin users, allowing us to avoid making a type I error related to statin use and mortality due to small sample size. The endpoints in our study differed from those of the previously published studies. For example, our study defined severe COIVD-19 disease as prolonged hospital stay (≥ 7 days) and/or need for invasive mechanical ventilation, whereas this parameter was defined as death or admission to the intensive care unit by Daniels et al. [22]. Alternatively, the divergent findings may be due to differences in the demographic makeup of participants in each study (e.g., elderly individuals or those identifying as Black or Latinx) and/or differences in the prevalence of co-morbidities, such as diabetes mellitus or cardiovascular disease, which are known to be associated with worse COVID-19 clinical outcomes. Our findings are consistent with recently published data highlighting the potential deleterious effects of statins on COVID-19 clinical outcomes, such as mortality within 7 and 28 days of hospital admission and the need for tracheal intubation in patients with type 2 diabetes [32].

Plausible mechanisms of statin-induced exacerbation of COVID-19 infection includes activation of Toll‐like receptors and signaling through myeloid differentiation primary response 88 (MyD88) and NF‐κB, thereby increasing lung inflammation [33, 34]. As in the case of sepsis, community-acquired pneumonia and TB [35–37], hypolipidemia in patients with COVID-19 has been associated with increased disease severity, and inflammatory markers, such as C-reactive protein and IL-6 were inversely correlated with serum total cholesterol and low-density lipoprotein (LDL) levels [38]. However, it is unclear if statin-mediated reduction in circulating lipid levels is causally linked to more extensive lung inflammation in COVID-19. SARS-CoV-2 reduces the biosynthesis of LDL by altering liver function and increasing vascular permeability, causing a leakage of plasma cholesterol and lipid molecules into alveolar spaces, thereby reducing plasma lipid levels.

Statins have been shown to increase cellular expression of angiotensin-converting enzyme 2 (ACE2) [27], the primary receptor used by SARS-CoV 2 to gain entry into lung cells [39]. Of note, the patient populations most likely to be prescribed statins for their cardioprotective effects, i.e., males, the elderly, and those with hypertension, diabetes, dyslipidemia, and cardiovascular disease, are also the same populations at greatest risk for COVID-19-related mortality [34]. Although generally statins are well tolerated, their use may be associated with rhabdomyolysis and related kidney injury, as well as liver toxicity, which may compound COVID-19 systemic disease [40, 41]. Since most statins are substrates of the hepatic cytochrome P450 system, co-administration of statins with protease inhibitor-based antiretroviral agents or certain immunosuppressive drugs may markedly increase the risks of adverse effects in patients with COVID-19 due to drug interactions [34, 42]. Despite these considerations, continuation of statin therapy is recommended in patients with newly diagnosed COVID-19 infection due to their proven beneficial effects on cardiovascular outcomes in appropriate clinical settings [34].

The heterogeneous nature of our study population and the large sample size, allowed us to assess the relationship between COVID-19 mortality/severity and statin use among a widely varied patient population, thus improving our study’s generalizability to other hospitalized patients with COVID-19. The utilization of a backward stepwise regression approach made for a reproducible method for predictor selection in this study, helping to reduce the potential for bias in selecting predictor variables for inclusion in our regression models. Additionally, the use of propensity score matching when comparing statin and non-statin users reduced the potential for selection bias (confounding by indication) and provided a more statistically robust estimate of our primary and secondary outcomes. Furthermore, use of the Elixhauser Score to account for comorbidities in our statistical models provided a more comprehensive approach to account for comorbidities.

Our study has certain limitations. Due to the retrospective study design, it is possible that all potential confounding factors were not properly adjusted. We did not specifically analyze the effects of different types of statins (e.g., lipophilic vs. hydrophilic), as the vast majority of our participants were prescribed atorvastatin, or statin dosing, as this information was not readily available from the database. Furthermore, the possibility of residual confounding and confounding from historical exposure to statins before in-hospital admission/ follow-up could have impacted the association between statin use and the outcomes of interest.

Despite the apparent beneficial effect of statins on outcomes of various infectious diseases, our study revealed that their use was associated with increased COVID-19 disease severity among hospitalized patients. Our findings merit laboratory-based investigations to determine the potential mechanism(s) by which statins may contribute to excessive lung inflammation. Follow-up clinical studies are needed to determine if temporary discontinuation of statins is warranted, particularly among hospitalized patients with COVID-19. Additional studies may also seek to identify if there are specific patient populations with COVID-19 that may benefit from statin therapy.

Supporting information

S1 Fig. Balance plot of raw and matched box and whisker plots of statin use versus statin non-use in COVID-19-related mortality.

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S2 Fig. Balance plot of raw and matched box and whisker plots of statin use versus statin non-use in severe COVID-19 infections.

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S1 Table. Statin medications prescribed at the time of admission.

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S2 Table. ACE inhibitors/ARBs prescribed at the time of admission.

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S3 Table. Means and variances in raw and balanced data for statin effect on COVID-19-related mortality.

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S4 Table. Means and variances in raw and balanced data for statin effect on severe COVID-19 disease.

(DOCX)

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Data Availability

Data cannot be shared publicly because it is a hospital-based data. Data are available from the Johns Hopkins Medicine Institutional Data Access / Ethics Committee (contact via ictr@jhmi.edu) for researchers who meet the criteria for access to confidential data.

Funding Statement

This retrospective cohort study was supported by the National Institute of Allergy and Infectious Diseases (NIAID)/ National Institutes of Health (NIH) grants UH3AI122309 and K24AI143447 to P.C.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0256899.r001

Decision Letter 0

Aleksandar R Zivkovic

4 Jun 2021

PONE-D-21-15364

Statins use and COVID-19 outcomes in hospitalized patients

PLOS ONE

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Reviewers' comments:

Reviewer #1: The authors have done evaluation from the secondary data regarding the statin use and severe covid-19. My comments are

1. Taking the conclusion in statin use in COVID -19 should be carefull. We should take into account, type, dose statin use, how long the statin have been use before the subject got infection. As we know statin needed time to work the anti inflammmation. should be discussed this issue in the discussion

2. In the results showed that, age, BMI, comorbidity related to the risk of COVID-19. Was the statin use related to severe covid-19 or because any interaction or confounder with comorbidity because they with many co morbidity tend to use statin? should also be discussed.

3. Take the conclusion from the retrospective study should be carefully. May be covid-19 did not improved covid-19 outcome, however further randomized study should confirm this result,

Reviewer #2: First of all, I compliment the authors for their excellent work, which is well-written. In fact, the potential benefit of statins in the COVID-19 scenario is a very important issue, and one that is still controversial.

Below, I respectfully present to the authors my suggestions for improving the manuscript. Please consider the suggestions that you think are relevant.

ABSTRACT

- In Methods: Were patients diagnosed with COVID-19 by laboratory tests? I suggest: "A retrospective analysis of patients with laboratory-confirmed COVID-19 admitted to the Johns Hopkins Medical Institutions between..."

- Please, "risk ratio (RR)".

- In the results, I suggest describing "After propensity-score matching, the average treatment effect..." and/or "after adjusting for age, etc..."

- In Conclusion, I believe that the authors could draw attention to the importance of using PSM, but that, on the other hand, the data should be viewed with caution, given that the study is retrospective.

BACKGROUND

- The first paragraph contains information that has already been published extensively (... firts reported to cause severe pneumonia in China's Wuhan... pandemic

status by March 2020...). Thus, I suggest that the authors start by going more directly to the point, excluding the first paragraph, or at least reducing it.

- The introduction can be enriched with some information on the thrombotic risk and inflammation of COVID-19 and the potential benefit of statins in this context (e.g

Ferrari et al. 2021. COVID-19 and Thromboinflammation: Is There a Role for Statins? https://www.scielo.br/pdf/clin/v76/1807-5932-clin-76-e2518.pdf).

Second paragraph

- Wouldn't it be "REGN-COV2"?

- I suggest "human immunodeficiency virus (HIV)".

- I suggest "nuclear factor-κB (NF-κB)".

- I suggest "angiotensin converting enzyme-2 (ACE2) receptor".

MATERIALS AND METHODS

- Please add the patient's form of diagnosis (Positive SARS-CoV-2 PCR? Others?)

- Approval of the study: is there an identification number that can be specified?

Exposure and outcomes

- I suggest "serum interleukin-6" and not "serum interleukinS-6".

Line 13

- Only "ACE inhibitors" and not "angiotensin-converting enzyme (ACE) inhibitors", and "ARBs" and not "ARB".

RESULTS

- I suggest adding "years-old" to the values "(64.9 +- 13 vs 45.5 +- 16.6), to make it clear to the reader that they are referring to years of age.

- The authors classify primary outcomes were mortality, defined as prolonged hospital stay and/or need for invasive mechanical ventilation. I miss information regarding the percentage of patients who required the use of mechanical ventilation (statin users vs. statin non-users). The use of statins favored or increased the risk of needing mechanical ventilation? If available, I suggest that they are also in the abstract.

- Are there details about the anti-viral drugs that the patients received?

Risk factors for severe COVID-19 infection

- Only "PSM" and not "propensity-score matching".

DISCUSSION

- Only "PSM" and not "propensity-score matching".

- Please "intensive care unit (ICU)".

- Fifth paragraph: Only "ACE2" and not "angiotensin-converting enzyme 2 (ACE2)".

- Sixth paragraph: Only "PSM" and not "propensity-score matching".

- In the sentence: "The heterogeneous nature of our study, and the large sample size, allowed us to assess the relationship between COVID-19... thus improving your study's generalizability to other hospitalized patients with COVID-19... Additionally, the use of PSM...", i suggest that the authors are not so emphatic. I don't think it's such a large sample of patients using statins, and even using PSM, the study is still retrospective, with its potential biases, even though they are minimized by PSM, as commented by the authors.

Reviewer #3: The manuscript by Samuel K. Ayeh et al investigates the relationship between statin use and COVID-19 mortality and disease severity in patients admitted to the Johns Hopkins health system.

Major Comments

1. The Authors chose the IL-6 level as one of the parameters assessed. What about other inflammatory markers such as CRP and procalcitonin?

2. There is no information on the antiviral treatment (remdesivir?) hospitalized patients.

3. The Authors should provide (or at least discuss in the limitations) value of chest CT quantitative pulmonary inflammation index (PII), passive oxygen therapy, HFNOT therapy, oxygen saturation in hospitalized patients.

4. The strengths and limitations of the study should be deeply addressed, taking into account sources of potential bias or imprecision: Discuss both direction and magnitude of any potential bias.

Minor comments

1. Employment status is unnecessary

2. The Authors should add list of abbreviations

Reviewer #4: Interesting study that showed that statin use is not associated with reduced mortality in those with COVID-19. These results are in contrast to some of the previous findings wherein it was noted that statin use is beneficial to those with COVD-19.

Is it possible that only some types of statins show the beneficial action but not all. Such subgroup analysis may be done and commented upon by the authors. Perhaps, the number of study subjects is not sufficient for such a

subgroup analysis.

Another caveat could be the dose of statins used. Authors may comment on this.

Is it possible that the statins used, their dose and the duration of treatment is not sufficient to reduce plasma levels of IL-6, TNF and other inflammatory cytokines to show their beneficial action. Authors need to comment on this.

Reviewer #5: Statins use and COVID-19 outcomes in hospitalized patients

I thank you for the opportunity to comment this study. The topic of the research is topical.

The conclusion is the following: Statin use was not associated with altered mortality, but with an 18% increased risk of severe COVID-19 infection.

Comments

I want to first highlight how the severe SARS-CoV-2 infection is defined. As an example, I give one example,

For epidemiologic purposes, severe Covid-19 in adults is defined as dyspnea, a respiratory rate of 30 or more breaths per minute, a blood oxygen saturation of 93% or less, a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao2:Fio2) of less than 300 mm Hg, or infiltrates in more than 50% of the lung field (JAMA 2020;323:1239-42).

In this study the severe COVID-19 was defined as follows: prolonged hospital stay (≥ 7 days) and/or need for invasive mechanical ventilation.

Authors should mention in the methodology and in the discussion this issue.

Comparison with other studies

Spiegeleer et al., 2020 (J Am Med Dir Assoc) used the following definition for severe COVID-19: serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset.

Daniels et al., 2020 (Am J Cardiol) don’t seem define severe COVID-19 in detailed: “The primary outcome was severe disease, defined as either admission to the ICU or death.

Authors mention in the discussion Rossi et al., 2020, but in this study, patients were not divided according to the severity of the infection. This applies also for the study by Peymanni et al., 2021 (Transl Med Commun).

Authors mention also the meta-analysis by Hariyanto & Kurniawan, 2020 (Diabetes Metab Syndr Clin Res Rev) which possibly seems to support the authors findings. This meta-analysis is uniquely Google Scholar based which is not ensuring that major studies were involved in this analysis. I didn’t find any classification based on severity of COVID-19 in this study. Unfortunately, authors don’t mention f. ex. the larger meta-analysis which has been carried out among hospitalized COVID-19 patients (Kow & Hasan, 2020). In this meta-analysis the findings were different.

It seems that the comparison with other studies is not carried out carefully and objectively. Authors need to be much more specific in comparisons. Currently, there are several studies regarding statin use among hospitalised patients. The current discussion seems to select subjectively those studies supporting the current finding in this study.

Medications

Authors have detailed collected data regarding statin treatment. Why was the dose of statins not collected? There is also data regarding ACE inhibitors. But the date regarding other medications is not collected among these patients. I can’t understand why. There is also no data regarding possible corticosteroid or antiviral medications.

It has been shown in many studies involving hospitalization and statin treatment that statin treatment is discontinued during the hospitalization (Torres-Peña et al. Drugs 2021).

In this well-designed study. It can be calculated that over 60% of hospitalized patients with COVID-19 had for unknown reasons stopped their statin consumption during the hospitalization period. How did the authors monitor statin use in this study?

It is also known that many patients use statins irregularly or even have prescriptions and don’t use them. How was this sorted out? An additional question is how long these patients have used statins?

Mechanisms

Regarding Dashti-Khavidaki & Khalili, 2020 (Pharmacotherapy) they recommend continuing statin use if patient with COVID-19 is hospitalised.

Regarding references [35-37] I understand that they are not related to statins. I can’t see the relevance of them. Please, modify this part of the discussion.

Regarding the ACE2, please, refer to Lei et al. 2021 (SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE2, Circulation Research) and find the complexity regarding ACE2 upregulation or downregulation.

Conclusion

I think that it is not justified to carry out studies continually in which statins are discontinued among the hospitalised patients. Please adjust this conclusion.

**********

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Reviewer #1: Yes: Andree Kurniawan

Reviewer #2: Yes: Filipe Ferrari

Reviewer #3: No

Reviewer #4: Yes: Undurti N Das

Reviewer #5: Yes: Alpo Vuorio

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PLoS One. 2021 Sep 10;16(9):e0256899. doi: 10.1371/journal.pone.0256899.r002

Author response to Decision Letter 0

13 Aug 2021

Reviewer Recommendations and Comments for Manuscript Number PONE-D-21-15364

Reviewer: #1

The authors have done evaluation from the secondary data regarding the statin use and severe covid-19. My comments are

Response: We thank the Reviewer for the comment. We have modified the text in the revised Discussion to temper the conclusions, and to emphasize the lack of information on statin type, dose, and duration of therapy prior to COVID-19 infection.

Response: We appreciate the Reviewer’s comment. As the Reviewer suggests, atherosclerotic cardiovascular disease (ASCVD) is associated with increasing age and BMI. Alhough these co-morbidities may confound outcomes associated with statin use, we took them into consideration in the multi-variable regression models. Nevertheless, we have listed the possibility of additional confounding factors associated with statin use as a limitation of our study in the revised Discussion.

3. Take the conclusion from the retrospective study should be carefully. May be covid-19 did not improved covid-19 outcome, however further randomized study should confirm this result,

Response: We agree with the Reviewer. As such, in the revised Discussion, we acknowledge the limitations of our retrospective study design, and emphasize the need for randomized trials to address the effect of statins on clinical outcomes following COVID-19 infection.

Reviewer: #2

First of all, I compliment the authors for their excellent work, which is well-written. In fact, the potential benefit of statins in the COVID-19 scenario is a very important issue, and one that is still controversial.

Below, I respectfully present to the authors my suggestions for improving the manuscript. Please consider the suggestions that you think are relevant.

We appreciate the Reviewer’s positive feedback on our study.

ABSTRACT

Response: We appreciate the Reviewer’s suggestion, and the proposed modification has been made in the revised Abstract (Methods), as well as in the Materials and Methods (“2.1. Study design and participants” section).

- Please, "risk ratio (RR)".

Response: The abbreviation “RR” has been expanded as “risk ratio” in the “Results” section of the revised Abstract and in the “Risk factors for COVID-19-related mortality” of the Results.

- In the results, I suggest describing "After propensity-score matching, the average treatment effect..." and/or "after adjusting for age, etc..."

Response: We appreciate the Reviewer’s suggestion. We have modified the text as suggested in the “Results” section of the revised Abstract.

Response: We appreciate the suggestion, and have modified the Conclusions of the Abstract accordingly.

BACKGROUND

- The first paragraph contains information that has already been published extensively (... firts reported to cause severe pneumonia in China's Wuhan... pandemic

status by March 2020...). Thus, I suggest that the authors start by going more directly to the point, excluding the first paragraph, or at least reducing it.

Response: We thank the Reviewer for the suggestion. We have reduced the first paragraph of the revised Background section, as suggested.

- The introduction can be enriched with some information on the thrombotic risk and inflammation of COVID-19 and the potential benefit of statins in this context (e.g

Ferrari et al. 2021. COVID-19 and Thromboinflammation: Is There a Role for Statins? https://www.scielo.br/pdf/clin/v76/1807-5932-clin-76-e2518.pdf).

Response: We thank the Reviewer for the suggestion. In the revised Background, we have included the potential theoretical benefit of statins in reducing the thrombotic risk associated with COVID-19 and have cited the suggested reference.

Second paragraph

- Wouldn't it be "REGN-COV2"?

Response: Yes, correct. This change has been made.

- I suggest "human immunodeficiency virus (HIV)".

Response: We have made this suggested correction.

- I suggest "nuclear factor-κB (NF-κB)".Response: We have made this suggested correction.

- I suggest "angiotensin converting enzyme-2 (ACE2) receptor".

Response: We have made this suggested correction.

MATERIALS AND METHODS

- Please add the patient's form of diagnosis (Positive SARS-CoV-2 PCR? Others?)

Response: We thank the Reviewer for the suggestion and have added this information in the revised Materials and Methods section.

- Approval of the study: is there an identification number that can be specified?

Response: As per our institutional policy, we have excluded this information from the manuscript, but are happy to share it with the Editor/Reviewers: IRB00251829.

Exposure and outcomes

- I suggest "serum interleukin-6" and not "serum interleukinS-6".

Response: We have made these suggested changes.

Line 13

- Only "ACE inhibitors" and not "angiotensin-converting enzyme (ACE) inhibitors", and "ARBs" and not "ARB".

Response: We have made these corrections, as suggested.

RESULTS

- I suggest adding "years-old" to the values "(64.9 +- 13 vs 45.5 +- 16.6), to make it clear to the reader that they are referring to years of age.

Response: We thank the Reviewer for the suggestion, and have made the requested changes.

Response: We appreciate the Reviewer’s comment. Since the proportion of patients requiring invasive mechanical ventilation was considered as part of the composite outcome (severe COVID-19), we have not reported it in the Abstract or Table 1 as a separate outcome.

- Are there details about the anti-viral drugs that the patients received?

Response: We appreciate the Reviewers comment. We have included a table containing all the anti-viral drugs that were prescribed to this cohort of hospitalized patients (Supplementary Table S5).

Risk factors for severe COVID-19 infection

- Only "PSM" and not "propensity-score matching".

Response: We thank the Reviewer for drawing our attention to this repetition. We have substituted “PSM” throughout the revised text after the first instance in which the term/abbreviation has been introduced.

DISCUSSION

- Only "PSM" and not "propensity-score matching".

Response: The suggested change has been made, as indicated above.

- Please "intensive care unit (ICU)".

Response: The suggested change has been made.

- Fifth paragraph: Only "ACE2" and not "angiotensin-converting enzyme 2 (ACE2)".

Response: This correction has been made in the revised Discussion.

- Sixth paragraph: Only "PSM" and not "propensity-score matching".

Response: This change has been made, as suggested, in the revised Discussion.

Response: We agree with the Reviewer’s comment. We have revised the text in the Discussion so that it is less emphatic, while highlighting the limitations of the study.

Major Comments

1. The Authors chose the IL-6 level as one of the parameters assessed. What about other inflammatory markers such as CRP and procalcitonin?

Response: We appreciate the Reviewer’s comment. Given the recent attention on the significant role of IL-6 in activating STAT3 and the NF-κB pathway, resulting in increased production of pro-inflammatory cytokines and chemokines (Huang C et al. 2020 and Rothan HA et al. 2020), we decided to focus on this analyte. We have included a justification in the revised Methods section.

2. There is no information on the antiviral treatment (remdesivir?) hospitalized patients.

Response: We thank the Reviewer for the comment. Remdesivir use was not captured in our dataset. However, as described above, we have included a table containing all anti-viral medications administered during hospitalization (Supplementary table S5).

Response: We appreciate the Reviewer’s comment. This information was not extracted from the database. In the revised Discussion, we have acknowledged this as a limitation of our study and have listed these parameters as additional potentially useful markers of disease severity.

The strengths and limitations of the study should be deeply addressed, taking into account sources of potential bias or imprecision: Discuss both direction and magnitude of any potential bias.

Response: We thank the Reviewer for the suggestion. In the revised manuscript, we have included an in-depth discussion of sources of potential bias, as well as the anticipated direction/magnitude of the bias.

Minor comments -

1. Employment status is unnecessary

Response: We appreciate the Reviewer’s comment. We have included employment status as a surrogate for socioeconomic status, since earlier publications (e.g., Lassale et al. 2020) found an association between socioeconomic status and COVID-19 outcomes.

2. The Authors should add list of abbreviations

Response: We thank the Reviewer for the suggestion. A complete list of abbreviations have been included in the revised manuscript.

Response: We appreciate the Reviewer’s comment. Although our findings differed from those of previously published studies, we would like to highlight that they are consistent with those of others (Song et al. 2020, Saeed et al. 2020, and Tan et al. 2020). We agree that a subgroup analysis could potentially shed light on whether COVID-19 outcomes are statin type-specific. However, we were unable to perform such an analysis since over three quarters of our cohort were receiving atorvastatin, and very few patients received any other statin.

Another caveat could be the dose of statins used. Authors may comment on this.

Response: We appreciate the Reviewer’s comment. We have addressed the issue of statin dose in the revised Discussion.

Response: We appreciate the Reviewer’s comment. Multivariable adjustments did not include the inflammatory cytokine, IL-6 when assessing for mortality, but this parameter was included when assessing for severe COVID-19 infection for statistical reasons. The direct relationship between IL-6 and statin use was not explored since it did not make it into the final model. In the revised Discussion, we have addressed the possibility that statin dose/duration of therapy was insufficient to demonstrate a potential beneficial action.

Reviewer #5: Statins use and COVID-19 outcomes in hospitalized patients

I thank you for the opportunity to comment this study. The topic of the research is topical.

The conclusion is the following: Statin use was not associated with altered mortality, but with an 18% increased risk of severe COVID-19 infection.

Comments

I want to first highlight how the severe SARS-CoV-2 infection is defined. As an example, I give one example,

In this study the severe COVID-19 was defined as follows: prolonged hospital stay (≥ 7 days) and/or need for invasive mechanical ventilation.

Authors should mention in the methodology and in the discussion this issue.

Response: We appreciate the Reviewer’s comment and have highlighted how our definition of “severe COVID-19” differs from that of other epidemiological studies in the revised Methods and Discussion sections.

Comparison with other studies

Spiegeleer et al., 2020 (J Am Med Dir Assoc) used the following definition for severe COVID-19: serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset.

Daniels et al., 2020 (Am J Cardiol) don’t seem define severe COVID-19 in detailed: “The primary outcome was severe disease, defined as either admission to the ICU or death.

Response: We thank the Reviewer for these insights. We agree that there is no widely accepted, standard definition of “severe COVID-19” across studies. Therefore, we have clearly defined the term for the purposes of our study in the revised Methods section, and highlighted how our definition differs from that of other similar studies, as well as potential implications fot study outcomes, in the revised Discussion. Also, we thank the Reviewer for pointing out more recent studies on statin use and COVID-19 outcomes in hospitalized patients, which have been published since our paper was under review. We have cited these new references, including Kow & Hasan, 2020, in the revised manuscript.

Response: We appreciate the Reviewer’s feedback. We have reported the findings from the study by Rodriguez-Nava et al., 2020, which found a mortality benefit with statin use. We have cited additional recently published studies supporting and contradicting our findings in the revised Discussion.

Medications

It has been shown in many studies involving hospitalization and statin treatment that statin treatment is discontinued during the hospitalization (Torres-Peña et al. Drugs 2021).

Response: We thank the Reviewer for these insightful comments. In the revised manuscript, we have included a supplementary table containing information on antiviral drugs used (Table S5). Data on steroid use was not included in the study analysis, although we know from clinical experience that during the time period representing the clinical cohort, steroid use was very limited. Contrary to the study of Torres-Pena et al. statin use captured in this study refers to statins administered to patients during the period of their hospitalization, of which > 75% of patients received atorvastatin. Unfortunately, we cannot compare the statin usage pre- and post-hospitalization since prevalence of statin use before hospitalization is not captured by our study. Data about statin usage, dose, adherence, and length of use pre-hospitalization was unavailable to us. These points have been included as study limitations in the revised Discussion. It should be noted that there is no simple dosing conversion among different statins, as there is with opiates and steroids.

Mechanisms

Regarding Dashti-Khavidaki & Khalili, 2020 (Pharmacotherapy) they recommend continuing statin use if patient with COVID-19 is hospitalised.

Response: We thank the Reviewer and have included this in the revised Discussion. It is important to note, however, that this recommendation is based on expert opinion rather than robust empirical evidence.

Regarding references [35-37] I understand that they are not related to statins. I can’t see the relevance of them. Please, modify this part of the discussion.

Response: We thank the Reviewer for the comment and have removed these references (and related text) from the Discussion.

Response: We appreciate the Reviewer’s comment. We have included this information in the revised Discussion and cited the proper reference.

Conclusion

I think that it is not justified to carry out studies continually in which statins are discontinued among the hospitalized patients. Please adjust this conclusion.

Response: We appreciate the Reviewer’s comment and have modified the text in the revised conclusion accordingly.

Attachment

Submitted filename: Response to Reviewers Comments_PLoS One_08.2021.docx

Click here for additional data file.^{(110.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0256899.r003

Decision Letter 1

Aleksandar R Zivkovic

18 Aug 2021

Statins use and COVID-19 outcomes in hospitalized patients

PONE-D-21-15364R1

Dear Dr. Karakousis,

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.

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Academic Editor

PLOS ONE

PLoS One. doi: 10.1371/journal.pone.0256899.r004

Acceptance letter

Aleksandar R Zivkovic

1 Sep 2021

PONE-D-21-15364R1

Statins use and COVID-19 outcomes in hospitalized patients

Dear Dr. Karakousis:

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.

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on behalf of

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Balance plot of raw and matched box and whisker plots of statin use versus statin non-use in COVID-19-related mortality.

(DOCX)

Click here for additional data file.^{(55.8KB, docx)}

S2 Fig. Balance plot of raw and matched box and whisker plots of statin use versus statin non-use in severe COVID-19 infections.

(DOCX)

Click here for additional data file.^{(55.7KB, docx)}

S1 Table. Statin medications prescribed at the time of admission.

(DOCX)

Click here for additional data file.^{(12.7KB, docx)}

S2 Table. ACE inhibitors/ARBs prescribed at the time of admission.

(DOCX)

Click here for additional data file.^{(12.9KB, docx)}

S3 Table. Means and variances in raw and balanced data for statin effect on COVID-19-related mortality.

(DOCX)

Click here for additional data file.^{(13.6KB, docx)}

S4 Table. Means and variances in raw and balanced data for statin effect on severe COVID-19 disease.

(DOCX)

Click here for additional data file.^{(13.6KB, docx)}

Attachment

Submitted filename: Response to Reviewers Comments_PLoS One_08.2021.docx

Click here for additional data file.^{(110.7KB, docx)}

Data Availability Statement

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PERMALINK

Statins use and COVID-19 outcomes in hospitalized patients

Samuel K Ayeh

Enoch J Abbey

Banda A A Khalifa

Richard D Nudotor

Albert Danso Osei

Vignesh Chidambaram

Ngozi Osuji

Samiha Khan

Emmanuella L Salia

Modupe O Oduwole

Hasiya E Yusuf

Oluwatobi Lasisi

Esosa Nosakhare

Petros C Karakousis

Roles

Abstract

Background

Methods

Results

Conclusion

1. Background

2. Materials and methods

2.1. Study design and participants

2.2. Exposure and outcomes

2.3. Statistical analyses

Table 1. Baseline characteristics of statin users versus statin non-users.

Table 2. Cox proportional regression showing association between covariables and mortality.

Table 3. Logistic regression showing association between covariables and severe COVID-19 infection.

3. Results

3.1. Patient characteristics

3.2. Risk factors for COVID-19-related mortality

Table 4. Risk for mortality and severe COVID-19 infection in statin users versus statin non-users.

3.3. Risk factors for severe COVID-19 infection

4. Discussion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Aleksandar R Zivkovic

Roles

Author response to Decision Letter 0

Decision Letter 1

Aleksandar R Zivkovic

Roles

Acceptance letter

Aleksandar R Zivkovic

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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