ABSTRACT
The pandemic caused by SARS-CoV-2 is still a major health problem. Newly emerging variants and long-COVID-19 represent a challenge for the global health system. In particular, individuals in developing countries with insufficient health care need easily accessible, affordable and effective treatments of COVID-19. Previous studies have demonstrated the efficacy of functional inhibitors of acid sphingomyelinase (FIASMA) against infections with various viruses, including early variants of SARS-CoV-2. This work investigated whether the acid sphingomyelinase inhibitors fluoxetine and sertraline, usually used as antidepressant molecules in clinical practice, can inhibit the replication of the former and recently emerged SARS-CoV-2 variants in vitro. Fluoxetine and sertraline potently inhibited the infection with pseudotyped virus like particles and SARS-CoV-2 variants D614G, alpha, delta, omicron BA.1 and omicron BA.5. These results highlight fluoxetine and sertraline as priority candidates for large-scale phase 3 clinical trials at different stages of SARS-CoV-2 infections, either alone or in combination with other medications.
Subject(s)
Severe Acute Respiratory Syndrome , Addison Disease , COVID-19ABSTRACT
In the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19), a better understanding of the underlying mechanisms is essential to reduce morbidity and mortality and treat post-COVID-19 disease. Here, we analyzed alterations of sphingolipids and their metabolizing enzymes in 125 men and 74 women tested positive for SARS-CoV-2 and hospitalized with mild, moderate or severe symptoms or after convalescence. The activities of acid and neutral sphingomyelinases (ASM, NSM), which hydrolyze sphingomyelin to ceramide, were significantly increased in COVID-19 patients, while the activity of neutral ceramidase (NC), which hydrolyzes ceramide to sphingosine, was reduced. These alterations could each contribute to elevated ceramide levels in patients. Accordingly, liquid chromatography tandem-mass spectrometry (LC-MS/MS) yielded increased levels of ceramides 16:0 and 18:0 with highest levels in severely affected patients and similar effects for dihydroceramides 16:0 and 18:0, whereas levels of (dihydro-)ceramides 24:0 were reduced. Furthermore, sphingomyelin 20:0; 22:0 and 24:0 as substrates of ASM and NSM as well as their dihydrosphingomyelin counterparts were reduced in patients as well as sphingosine-1-phosphate further downstream of NC activity. Effects of NSM, NC, ceramides and sphingomyelins remained significant after Bonferroni correction. SARS-CoV-2 antibody levels in convalescent patients were associated with age but none of the sphingolipid parameters. Based on our data, COVID-19 is associated with a dysregulation of sphingolipid homeostasis in a severity-dependent manner, particularly focused around a reduction of sphingomyelins and an accumulation of ceramides by increased enzyme activities leading to ceramide elevation (ASM, NSM) combined with a decreased activity of enzymes (NC) reducing ceramide levels. The potential of a combined sphingolipid/enzyme pattern as a diagnostic and prognostic marker and therapeutic target deserves further exploration.
Subject(s)
Coronavirus Infections , Multiple Sclerosis , COVID-19ABSTRACT
Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter retrospective study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) who were taking a FIASMA medication, and 1,060 patients (41.4%) who were not. Taking a FIASMA medication was associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p<0.001) and the primary IPW (HR=0.58; 95%CI=0.46-0.72; p<0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one FIASMA class or medication. These results show the potential importance of the ASM/ceramide system as a treatment target in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.
Subject(s)
COVID-19 , DeathABSTRACT
ObjectiveTo examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalized for COVID-19. MethodsWe conducted an observational multicenter retrospective cohort study at AP-HP Greater Paris University hospitals. The sample involved 14,381 adult patients hospitalized for COVID-19. 686 (4.8%) inpatients received a BZRA within at the time of hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (SD=25.4). The study baseline was the date of hospital admission and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex, obesity and comorbidity) and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). ResultsOver a mean follow-up of 14.5 days (SD=18.1), the primary endpoint occurred in 186 patients (27.1%) who received a BZRA and in 1,134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (HR=3.20; 95% CI=2.74-3.74; p<0.01) and in the primary IPW analysis (HR=1.61; 95% CI=1.31-1.98, p<0.01), with a significant dose-dependent relationship (HR=1.55; 95% CI=1.08-2.22; p=0.02). This association remained significant in multiple sensitivity analyses. ConclusionsBZRA use was associated with increased mortality among patients hospitalized for COVID-19 with a dose-dependent relationship, suggesting a potential benefit of decreasing dose or tapering off these medications when possible in these patients.
Subject(s)
COVID-19 , Obesity , DeathABSTRACT
ABSTRACT Prior preclinical and clinical evidence suggests that the acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications with functional inhibition of acid sphingomyelinase, called FIASMA psychotropic medications, against COVID-19. We examined the potential usefulness of FIASMA psychotropic medication use among patients with mental disorder hospitalized for severe COVID-19, in an observational multicenter retrospective study conducted at AP-HP Greater Paris University hospitals. Of 545 adult patients with mental disorder hospitalized for severe COVID-19, 164 (30.1%) received a psychotropic FIASMA medication at study baseline, which was defined as the date of hospital admission for COVID-19. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and psychotropic and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). There was a significant association between FIASMA psychotropic medication use at baseline and reduced risk of intubation or death both in the crude analysis (HR=0.42; 95%CI=0.31-0.57; p<0.01) and in the primary IPW analysis (HR=0.50; 95%CI=0.37-0.67; p<0.01). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggested that this association was not specific to one FIASMA psychotropic class or medication. These results suggest the usefulness of the ASM/ceramide system framework in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.
Subject(s)
Mental Disorders , COVID-19ABSTRACT
The COVID-19 pandemic is a major global societal, economic and health threat. The availability of COVID-19 vaccines has raised hopes for a decline in the pandemic. We built upon a stochastic agent-based microsimulation model of the COVID-19 epidemic in France. We examined the potential impact of different vaccination strategies, defined according to the age, medical conditions, and expected vaccination acceptance of the target non-immunized adult population, on disease cumulative incidence, mortality, and number of hospital admissions. Specifically, we examined whether these vaccination strategies would allow to lift all non-pharmacological interventions (NPIs), based on a sufficiently low cumulative mortality and number of hospital admissions. While vaccinating the full adult non-immunized population, if performed immediately, would be highly effective in reducing incidence, mortality and hospital-bed occupancy, and would allow discontinuing all NPIs, this strategy would require a large number of vaccine doses. Vaccinating only adults at higher risk for severe SARS-CoV-2 infection, i.e. those aged over 65 years or with medical conditions, would be insufficient to lift NPIs. Immediately vaccinating only adults aged over 45 years, or only adults aged over 55 years with mandatory vaccination of those aged over 65 years, would enable lifting all NPIs with a substantially lower number of vaccine doses, particularly with the latter vaccination strategy. Benefits of these strategies would be markedly reduced if the vaccination was delayed, was less effective than expected on virus transmission or in preventing COVID-19 among older adults, or was not widely accepted.
Subject(s)
COVID-19 , Addison DiseaseABSTRACT
The COVID-19 pandemic is a major global societal, economic and health threat. The availability of COVID-19 vaccines has raised hopes for a decline in the pandemic. We built upon a stochastic agent-based microsimulation model of the COVID-19 epidemic in France. We examined the potential impact of different vaccination strategies, defined according to the age, medical conditions, and expected vaccination acceptance of the target non-immunized adult population, on disease cumulative incidence, mortality, and number of hospital admissions. Specifically, we examined whether these vaccination strategies would allow to lift all non-pharmacological interventions (NPIs), based on a sufficiently low cumulative mortality and number of hospital admissions. While vaccinating the full adult non-immunized population, if performed immediately, would be highly effective in reducing incidence, mortality and hospital-bed occupancy, and would allow discontinuing all NPIs, this strategy would require a large number of vaccine doses. Vaccinating only adults at higher risk for severe SARS-CoV-2 infection, i.e. those aged over 65 years or with medical conditions, would be insufficient to lift NPIs. Immediately vaccinating only adults aged over 45 years, or only adults aged over 55 years with mandatory vaccination of those aged over 65 years, would enable lifting all NPIs with a substantially lower number of vaccine doses, particularly with the latter vaccination strategy. Benefits of these strategies would be markedly reduced if the vaccination was delayed, was less effective than expected on virus transmission or in preventing COVID-19 among older adults, or was not widely accepted.
Subject(s)
COVID-19 , Addison DiseaseABSTRACT
Objective: To examine the association between hydroxyzine use and mortality in patients hospitalized for COVID-19, based on its anti-inflammatory and antiviral properties. Design: Multicenter observational retrospective cohort study. Setting: Greater Paris University hospitals, France. Participants: 7,345 adults hospitalized for COVID-19 between 24 January and 1 April 2020, including 138 patients (1.9%) who received hydroxyzine during the visit at a mean dose of 49.8 mg (SD=51.5) for an average of 22.4 days (SD=25.9). Data source: Assistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measures: The study endpoint was death. We compared this endpoint between patients who received hydroxyzine and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), clinical and biological markers of disease severity, and use of other medications. The primary analysis was a multivariable Cox model with inverse probability weighting. Sensitivity analyses included a multivariable Cox model and a univariate Cox regression model in a 1:1 ratio matched analytic sample. Results: Over a mean follow-up of 20.3 days (SD=27.5), 994 patients (13.5%) had a primary end-point event. The primary multivariable analysis with inverse probability weighting showed a significant association between hydroxyzine use and reduced mortality (HR, 0.42; 95% CI, 0.25 to 0.71; p=0.001) with a significant dose-effect relationship (HR, 0.10; 95% CI, 0.02 to 0.45; p=0.003). This association was similar in sensitivity analyses. In secondary analyses conducted among subsamples of patients, we found a significant association between hydroxyzine use and a faster decrease in biological inflammatory markers associated with COVID-19-related mortality, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCRP), and circulating interleukin 6 levels (IL-6) (all p<0.016), with a significant dose-effect relationship for NLR and LCRP (both p<0.037). Conclusions: In this retrospective observational study, hydroxyzine use was associated with reduced mortality in patients hospitalized for COVID-19. This association may be partially mediated by specific anti-inflammatory properties of H1 antihistamines. Double-blind controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results.
Subject(s)
COVID-19 , DeathABSTRACT
Objective: To examine the association between dexamethasone use and mortality among hospitalized patients for COVID-19. Design: Multicenter observational retrospective cohort study. Setting: Greater Paris University hospitals, France. Participants: 12,217 adults hospitalized with COVID-19 between 24 January and 20 May 2020, including 171 patients (1.4%) who received dexamethasone orally or by intravenous perfusion during the visit. Data source: Assistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measures: The primary endpoint was time to death. We compared this endpoint between patients who received dexamethasone and those who did not in time-to-event analyses adjusting for sex, age, obesity, current smoking status, any medical condition associated with increased COVID-19-related mortality, and clinical and biological severity of COVID-19 at admission, while stratifying by the need of respiratory support (i.e., oxygen or intubation). The primary analysis was a multivariable Cox model and the secondary analysis used a univariate Cox regression in a matched analytic sample. Results: Among patients who required respiratory support, the end-point event of death occurred in 10 patients (15.9%) who received dexamethasone and 298 patients (26.4%) who did not. In this group of patients, there was a significant association between dexamethasone use and reduced mortality in both the crude, unadjusted analysis (hazard ratio (HR), 0.40; 95% CI, 0.18 to 0.87, p=0.021) and the adjusted multivariable analysis (HR, 0.46; 95% CI, 0.22 to 0.96, p=0.039). In the sensitivity analysis, the univariate Cox regression model in the matched analytic sample yielded a same tendency, albeit non-significant (HR, 0.31; 95% CI, 0.08 to 1.14, p=0.077). Among patients without respiratory support, the end-point event of death occurred in 14 patients (13.0%) who received dexamethasone and 1,086 patients (10.0%) who did not. In this group of patients, there was no significant association between dexamethasone use and the endpoint. When examining the association between the cumulative dose of dexamethasone received during the visit and the endpoint, we found that the administration of a cumulative dose between 60 mg to 150 mg among patients who required respiratory support was significantly associated with a lower risk of death in the crude, unadjusted analysis (HR, 0.28; SE, 0.58, p=0.028), the adjusted multivariable analysis (HR, 0.24; SE, 0.65, p=0.030), and in the univariate Cox regression model in the matched analytic sample (HR, 0.32; SE, 0.58, p=0.048), whereas no significant association was observed with a different dose. Among patients without respiratory support, there was no significant association between the cumulative dose of dexamethasone and the endpoint in the crude and in the adjusted multivariable analyses. Conclusions: In this observational study involving patients with Covid-19 who had been admitted to the hospital, dexamethasone use administered either orally or by intravenous injection at a cumulative dose between 60 mg and 150 mg was associated with decreased mortality among those requiring respiratory support.
Subject(s)
COVID-19 , Obesity , DeathABSTRACT
Background: Haloperidol, a widely used antipsychotic, has been suggested as potential effective treatment for Covid-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2. Methods: We examined the association between haloperidol use and respiratory failure at AP-HP Greater Paris University hospitals. Data were obtained regarding all adult patients hospitalized with Covid-19 since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. We compared outcomes between patients who were exposed to haloperidol and those who were not, using a multivariable Cox regression model with inverse probability weighting according to the propensity score. Results: Of the 13,279 hospitalized adult patients with positive Covid-19 RT-PCR test, 667 patients (5.0%) were excluded because of missing data. Of the remaining 12,612 patients, 104 (0.8%) were exposed to haloperidol. Over a mean follow-up of 20.8 days, the primary endpoint of respiratory failure respectively occurred in 27 patients (26.0%) exposed to haloperidol and 1,700 patients (13.6%) who were not. Among survivors, the secondary endpoint of discharge home occurred in 26 patients (32.1%) who received haloperidol and 6,110 patients (55.3%) who did not. In the main analysis, there were no significant associations between haloperidol use and the primary (HR, 1.09; 95% CI, 0.60 to 1.97, p=0.772) and secondary (HR, 0.88; 95% CI, 0.50 to 1.53, p=0.643) endpoints. Results were similar in multiple sensitivity analyses. Conclusion: In this observational study involving patients with Covid-19 who had been admitted to the hospital, haloperidol use was not associated with risk of intubation or death, or with time to hospital discharge home. These results suggest that haloperidol is unlikely to have a clinical efficacy for Covid-19.
Subject(s)
COVID-19 , Respiratory Insufficiency , DeathABSTRACT
On the grounds of its anti-inflammatory and potential antiviral effects, chlorpromazine has been suggested to be effective treatment for Covid-19. We examined the association between chlorpromazine use and respiratory failure among all hospitalized adults with Covid-19 at the 39 Greater Paris University hospitals since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death in a time-to-event analysis adjusting for numerous potential confounders. We used a multivariable Cox model with inverse probability weighting according to the propensity score. Of the 12,217 adult inpatients with a positive Covid-19 RT-PCR test included in the analyses, 57 (0.47%) received chlorpromazine. Over a mean follow-up of 20.8 days, the primary endpoint occurred in 29 patients (50.9%) exposed to chlorpromazine and 1,899 patients (15.6%) who were not. In the main analysis, there was a positive significant association between chlorpromazine use and the outcome (HR, 1.67; 95% CI, 1.09 to 2.56, p=0.019), while a Cox regression in a matched analytic sample yielded non-significant association (1.38; 95% CI, 0.91 to 2.09, p=0.123). These findings suggest that chlorpromazine is unlikely to have a clinical efficacy for Covid-19.
Subject(s)
COVID-19ABSTRACT
ObjectiveTo examine the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19. DesignMulticenter observational retrospective cohort study. SettingGreater Paris University hospitals, France. Participants7,345 adults hospitalized with COVID-19 between 24 January and 1 April 2020, including 460 patients (6.3%) who received an antidepressant during the visit. Data sourceAssistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measuresThe primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), disease severity and other psychotropic medications. The primary analyses were multivariable Cox models with inverse probability weighting. ResultsOver a mean follow-up of 18.5 days (SD=27.1), 1,331 patients (18.1%) had a primary end-point event. Unadjusted hazard ratio estimates of the association between antidepressant use and the primary outcome stratified by age (i.e., 18-50, 51-70, 71-80, and 81+) were non-significant (all p>0.072), except in the group of patients aged 71-80 years (HR, 0.66; 95% CI, 0.45 to 0.98; p=0.041). Following adjustments, the primary analyses showed a significant association between use of any antidepressant (HR, 0.64; 95% CI, 0.51 to 0.80; p<0.001), SSRI (HR, 0.56; 95% CI, 0.42 to 0.75; p<0.001), and SNRI (HR, 0.57; 95% CI, 0.34 to 0.96; p=0.034), and reduced risk of intubation or death. Specifically, exposures to escitalopram, fluoxetine, and venlafaxine were significantly associated with lower risk of intubation or death (all p<0.05). These associations remain significant in multiple sensitivity analyses, except for the association between SNRI use and the outcome. ConclusionsSSRI use could be associated with lower risk of death or intubation in hospitalized patients with COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed. What is already known on this topicO_LIA prior meta-analysis, mainly including studies on selective serotonin reuptake inhibitors (SSRIs), showed that antidepressant use in major depressive disorder was associated with reduced levels of several pro-inflammatory cytokines, including IL-6, TNF-, and CCL-2, which have been suggested to be associated with severe COVID-19. C_LIO_LIA recent in-vitro study supports antiviral effects of the SSRI fluoxetine on SARS-CoV-2. C_LIO_LITo our knowledge, no study has examined the efficacy of antidepressants in patients with COVID-19. C_LI What this study addsO_LIIn a multicenter observational retrospective study, we examined the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19, adjusting for patient characteristics, disease severity and other psychotropic medications. C_LIO_LIAntidepressant use was significantly and substantially associated with reduced risk of intubation or death. C_LIO_LIAt the level of antidepressant classes, SSRI use was significantly and substantially associated with reduced risk of intubation or death, but not other antidepressant classes. C_LIO_LIAt the level of antidepressant medications, exposures to the SSRIs fluoxetine and escitalopram, and the SNRI venlafaxine were significantly associated with lower risk of intubation or death. C_LIO_LIDouble-blind controlled randomized clinical trials of these medications for COVID-19 are needed. C_LI
Subject(s)
COVID-19ABSTRACT
Most European countries have responded to the COVID-19 threat by nationwide implementation of barrier measures and lockdown. However, assuming that population immunity will build up through the epidemic, it is likely to rebound once these measures are relaxed, possibly leading to a second or multiple repeated lockdowns. In this report, we present results of epidemiological modelling that has helped inform policy making in France. We used a stochastic agent-based microsimulation model of the COVID-19 epidemic in France, and examined the potential impact of post-quarantine measures, including social distancing, mask-wearing, and shielding of the population the most vulnerable to severe COVID-19 infection, on the disease's cumulative incidence and mortality, and on ICU-bed occupancy. The model calibrated well and variation of model parameter values had little impact on outcome estimates. While quarantine is effective in containing the viral spread, it would be unlikely to prevent a rebound of the epidemic once lifted, regardless of its duration. Both social distancing and mask-wearing, although effective in slowing the epidemic and in reducing mortality, would also be ineffective in ultimately preventing the overwhelming of ICUs and a second lockdown. However, these measures coupled with shielding of vulnerable people would be associated with better outcomes, including lower cumulative incidence, mortality, and maintaining an adequate number of ICU beds to prevent a second lockdown. Benefits would nonetheless be markedly reduced if these measures were not applied by most people or not maintained for a sufficiently long period, as herd immunity progressively establishes in the less vulnerable population.
Subject(s)
COVID-19ABSTRACT
Global spread of coronavirus disease 2019 (COVID-19) has created an unprecedented infectious disease crisis worldwide. Despite uncertainties about COVID-19, model-based forecasting of competing mitigation measures on its course is urgently needed to inform mitigation policy. We used a stochastic agent-based microsimulation model of the COVID-19 epidemic in New York City and evaluated the potential impact of quarantine duration (from 4 to 16 weeks), quarantine lifting type (1-step lifting for all individuals versus a 2-step lifting according to age), post-quarantine screening, and use of a hypothetical effective treatment against COVID-19 on the disease's cumulative incidence and mortality, and on ICU-bed occupancy. The source code of the model has been deposited in a public source code repository. The model calibrated well and variation of model parameter values had little impact on outcome estimates. While quarantine is efficient to contain the viral spread, it is unlikely to prevent a rebound of the epidemic once lifted. We projected that lifting quarantine in a single step for the full population would be unlikely to substantially lower the cumulative mortality, regardless of quarantine duration. By contrast, a two-step quarantine lifting according to age was associated with a substantially lower cumulative mortality and incidence, up to 71% and 23%, respectively, as well as lower ICU-bed occupancy. Although post-quarantine screening was associated with diminished epidemic rebound, this strategy may not prevent ICUs from being overcrowded. It may even become deleterious after a 2-step quarantine lifting according to age if the herd immunity effect does not had sufficient time to become established in the younger population when the quarantine is lifted for the older population. An effective treatment against COVID-19 would considerably reduce the consequences of the epidemic, even more so if ICU capacity is not exceeded.