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Crude mortality rate (percentage, orange boxes, absolute numbers, blue boxes) according to age of the patients included in the study.
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Background. The COVID-19 outbreak challenges the Spanish health system since March 2020. Some available therapies (antimalarials, antivirals, biological agents) were grounded on clinical case observations or basic science data. The aim of this study is to describe the characteristics and impact of different therapies on clinical outcomes in a cohor...
Contexts in source publication
Context 1
... collected data on a total of 607 patients (Fig. 1S). The median age in the cohort was 69 years [22]; 34¢98% were female (table 1). At the end of the study period, 194 (31¢92%) remained in the hospital and were followed until 12th May 2020. During the in-hospital follow-up, 466 patients survived (76¢08%) and 141 died (23¢2%) À with a strong weight on the older ones (Fig. 1). Table 2 ...
Context 2
... a total of 607 patients (Fig. 1S). The median age in the cohort was 69 years [22]; 34¢98% were female (table 1). At the end of the study period, 194 (31¢92%) remained in the hospital and were followed until 12th May 2020. During the in-hospital follow-up, 466 patients survived (76¢08%) and 141 died (23¢2%) À with a strong weight on the older ones (Fig. 1). Table 2 shows the inhospital mortality relative to the given therapy. The median in-hospital overall length of stay was 8¢0 [9¢0] ...
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Methods:
Thi...
Background
COVID-19 is an ongoing viral pandemic produced by SARS-CoV-2. In light of in vitro efficacy, several medications were repurposed for its management. During clinical use, many of these medications produced inconsistent results or had varying limitations.
Objective
The purpose of this literature review is to explain the variable efficacy...
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has emerged as a major cause of morbidity and mortality worldwide, placing unprecedented pressure on healthcare. Cardiomyopathy is described in patients with severe COVID-19 and increasing evidence suggests that cardiovascular involvement portends a high mo...
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Introduction: The severity of COVID-19 may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity has been associated with using some medications in the management of COVID-19 patients. However, limited studies had systematically investigated the evidence of drug-induced live...
Citations
... Although the mean age of the sample was high since patients aged 18 and under were not included in the study, it was similar to patient ages reported in previous studies conducted in Turkey (Gedik et al. 2023;Kokturk et al. 2021). In our study, as in similar retrospective studies, hypertension and diabetes mellitus were determined to be the two most common comorbidities (Fang et al. 2020;Guisado-Vasco et al. 2020). We found the median LOHS to be 6 days, consistent with previous research indicating that this value ranges from 5 to 17 days (Rees et al. 2020;Alwafi et al. 2021;Birhanu et al. 2022;Guo et al. 2021). ...
... Mortality rates were reported to be 2% and 4.5% in two studies conducted with inpatients with COVID-19 in Turkey (Kokturk et al. 2021;Fang et al. 2020), and these values were much lower than the rate we found in our study. However, when COVID-19 inpatients from other countries are examined, this rate ranges from 20.2 to 25.7% (Guisado-Vasco et al. 2020;Quah et al. 2020;Horwitz et al. 2021). In a meta-analysis reviewing similar studies on inpatients with COVID-19, an average mortality rate of 17.1% was found (Macedo et al. 2021), which is very similar to the mortality rate obtained from our study. ...
Purpose
Coronavirus disease 2019 (COVID-19) has affected millions of people worldwide and caused mortality. Many factors have been reported to affect the prognosis of COVID-19. In this study, we aimed to investigate the effects of drug therapy and vaccination on prognosis in patients hospitalized with a COVID-19 diagnosis.
Methods
In this single-center, cross-sectional study, data were retrospectively collected from patients receiving inpatient treatment at a university hospital with a diagnosis of COVID-19 between January 1, 2020, and April 30, 2022. The patients’ demographic and clinical characteristics were recorded. The Chi-square, Cox and logistic regression was performed, P < 0.05 was considered statistically significant.
Results
Total 1723 patients (50.1% were men, mean age: 60.6 ± 16.90) who had not been vaccinated rate was 27.0% (> 3 doses: 45.7%). Mortality rate was 17.0%. Increasing age, male, a high Charlson Comorbidity Index (CCI), and no vaccination significantly increased mortality (P < 0.05). The mortality rate was significantly lower in the chloroquine treatment group than in the other treatment groups. Increasing age, male, and a high CCI were determined to be factors that significantly increased the length of hospital stay (LOHS). LOHS found to be significantly lower in the favipiravir or chloroquine groups compared to the remaining treatment groups (P < 0.001). Both mortality and the LOHS significantly differed according to AST, d-dimer, ferritin, and GFR.
Conclusion
This study primarily investigated the effect of treatment and vaccination on the prognosis of COVID-19. This was determined to be prepared for another potential pandemic that may arise due to COVID-19.
... Факторы риска летального исхода: возраст старше 57,5 года, индекс массы тела более 30 кг/м 2 , сатурация ниже 85,5 % в день применения ИИЛ-6. Длительность госпитализации составила 18,5 (14-24) дня против 18 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) д ней, р = 0,778. ВЫВОДЫ: Циклоспорин А в дополнение к ГКС и ИИЛ-6 для терапии COVID-19 может способствовать снижению летальности, частоты поступления в ОРИТ и потребности в респираторной поддержке. ...
... Risk factors for death: age over 57.5 years, body mass index over 30 kg/m 2 , hemoglobin oxygen saturation below 85.5 % on the day of IIL-6 application. Duration of hospitalization was 18.5 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) days vs 18 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) days, р = 0.778. CONCLUSIONS: Cyclosporine A in addition to GCS and IIL-6 for COVID-19 therapy may reduce mortality, ICU admissions, and respiratory support requirements. ...
... Risk factors for death: age over 57.5 years, body mass index over 30 kg/m 2 , hemoglobin oxygen saturation below 85.5 % on the day of IIL-6 application. Duration of hospitalization was 18.5 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) days vs 18 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) days, р = 0.778. CONCLUSIONS: Cyclosporine A in addition to GCS and IIL-6 for COVID-19 therapy may reduce mortality, ICU admissions, and respiratory support requirements. ...
INTRODUCTION: Therapy of COVID-19 patients with progressive lung damage after the use of glucocorticosteroids (GCS) and interleukin-6 inhibitors (IIL-6) has not yet been developed. OBJECTIVE: Assessment of the effectiveness of cyclosporine A in patients with COVID-19 with progression of lung damage and hypoxemic acute respiratory failure, who received therapy with GCS and IIL-6. MATERIALS AND METHODS: A retrospective cohort propensity-score matched analysis (n = 98). Cyclosporine A was prescribed in the first 72–96 hours after IIL-6 administration when the patient's condition worsened. The patients of comparison group corresponded to the study group, but did not receive cyclosporine A therapy. The primary end point was in-hospital mortality. Secondary endpoints — duration of hospitalization, number of patients admitted to the intensive care unit (ICU), need for respiratory support. RESULTS: Mortality was 12 (22) % in the cyclosporine group and 27 (61) % in the comparison group, р = 0.001 (hazard ratio [HR] 2.00 (1.12–3.48), р = 0.018), ICU admission rate 14 (26) % vs 29 (66) %, р = 0.001, respectively. In the cyclosporine group on day 7 CT-4, there were 26 % of patients vs 52 % in the control group, р = 0.014, the need for respiratory support (37 % vs 63.6 %, р = 0.011); saturation 88 % (82–93) vs 80 % (70–86), р = 0.001, respectively. The need for respiratory support at day 11 after IIL-6 increased the likelihood of death (HR 7.10 (2.5–20), р = 0.001). Risk factors for death: age over 57.5 years, body mass index over 30 kg/m2, hemoglobin oxygen saturation below 85.5 % on the day of IIL-6 application. Duration of hospitalization was 18.5 (14–24) days vs 18 (12–24) days, р = 0.778. CONCLUSIONS: Cyclosporine A in addition to GCS and IIL-6 for COVID-19 therapy may reduce mortality, ICU admissions, and respiratory support requirements.
... 15,16 In addition, 2 clinical cohort studies reported better outcomes in KTRs with a SARS-CoV-2 infection when CsA was part of their maintenance immunosuppression. 17,18 Currently, the majority of KTRs have a CNI-based regimen as standard maintenance immunosuppression with a preference for tacrolimus over CsA because of its superiority on long-term renal graft function, allograft survival, and acute rejection rates. 4,19 Unlike CsA, voclosporin has demonstrated noninferiority to tacrolimus in KTRs to prevent graft rejection in a phase 2 randomized trial. ...
... Importantly, these results were in line with 2 other reported cohort studies demonstrating reduced risk of severe COVID-related complications in CsA-exposed KTRs compared to other immunosuppressants. 17,18 Collectively, both VOCOVID and AURORA-2 provided supporting evidence that voclosporin has antiviral effects on SARS-CoV-2 infection in immunocompromised kidney patients. ...
Introduction
Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus in vitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunocompromised patients.
Methods
First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a post hoc analysis on SARS-CoV-2 infections in 216 patients with lupus nephritis (LN) on standard immunosuppression who were randomly exposed to voclosporin or placebo as part of a clinical trial that was conducted during the worldwide COVID-19 pandemic.
Results
The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8–28) and tacrolimus-treated KTRs (median 12 days, IQR 4–16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (ΔCt 7.7 [3.4–10.7]) compared to tacrolimus-treated KTRs (ΔCt 2.7 [2.0-4.3]; P = 0.035). In voclosporin-exposed patients with LN, SARS-CoV-2 infection was detected in 6% (7/116) compared to 12% (12/100) in placebo-exposed patients (relative risk [RR] 1.4 [0.97–2.06]). Notably, no voclosporin-exposed patients with LN died from severe SARS-CoV-2 infection compared to 3% (3/100) in placebo-exposed patients (RR 2.2 [1.90–2.54]).
Conclusion
This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.
... Como resultado, los pacientes tratados con ciclosporina presentaron una significativa menor mortalidad. 40 Evidencias preliminares en individuos transplantados también revelaron que aquellos en uso de ICN presentaron mejores resultados. 41,42 El potencial efecto benéfico de los ICN en la replicación viral y modulación de la respuesta inflamatoria es contrapuesto por un potencial efecto negativo en la respuesta inmune adaptativa humoral, demostrado por una menor producción de anticuerpos neutralizantes después de la vacunación con los inmunizantes BNT162b2 (Pfizer-Biontech), mRNA-1273 (Moderna) y ChAdOx1-nCoV-19 (AstraZeneca). ...
Resumen: Los pacientes transplantados renales presentan una elevada tasa de letalidad después de la infección por síndrome respiratorio agudo grave 2(Sars-CoV-2). Además de esto, la respuesta inmune de vacuna es menor y menos duradera, lo que los torna más susceptibles a formas graves, incluso cuando están vacunados. Las evidencias sugieren que, además de la edad avanzada y de la elevada prevalencia de comorbilidades frecuentemente asociadas a un peor pronóstico, como diabetes, obesidad y enfermedades cardiovasculares, la inmunosupresión prolongada ejerce un efecto independiente sobre los resultados. De hecho, la respuesta inmune adaptativa celular y humoral, la cual está inhibida por la inmunosupresión, es un paso fundamental para la resolución de la infección por Sars-CoV-2. Por otro lado, la inhibición linfocitaria podría modular la producción aberrante de citoquinas proinflamatorias que resultan en el grave comprometimiento pulmonar, amenizando la gravedad del cuadro. Además de esto, algunos fármacos inmunosupresores poseen propiedades antivirales, potencialmente aplicables al coronavirus. Esta revisión narrativa tuvo como objetivo discutir las evidencias disponibles sobre el impacto de los fármacos inmunosupresores sobre los resultados del Covid-19 en transplantados renales
... As a result, patients treated with cyclosporine had significantly lower mortality. 40 Preliminary evidence in transplanted individuals also revealed that those on CNI had better outcomes. 41,42 The potential beneficial effect of CNIs on viral replication and modulation of the inflammatory response is countered by a potential negative effect on the humoral adaptive immune response, demonstrated by lower neutralizing antibody production after vaccination with the immunizers BNT162b2 (Pfizer-Biontech), mRNA-1273 (Moderna) and ChAdOx1-nCoV-19 (AstraZeneca). ...
Kidney transplant patients have a high case fatality rate following severe acute respiratory syndrome 2 (SARS-CoV-2) infection. In addition, the vaccine immune response is lower and less durable, which makes them more susceptible to severe forms, even when vaccinated. Evidence suggests that in addition to advanced age and the high prevalence of comorbidities often associated with worse prognosis, such as diabetes, obesity, and cardiovascular disease, prolonged immunosuppression exerts an independent effect on outcomes. In fact, the cellular and humoral adaptive immune response, which is inhibited by immunosuppression, is a key step in resolving SARS-CoV-2 infection. On the other hand, lymphocyte inhibition could modulate the aberrant production of proinflammatory cytokines that result in severe lung impairment, mitigating the severity of the condition. In addition, some immunosuppressive drugs have antiviral properties, potentially applicable to coronavirus. This narrative review aimed to discuss the available evidence on the impact of immunosuppressive drugs on COVID-19 outcomes in kidney transplant recipients
... Como resultado, os pacientes tratados com ciclosporina apresentaram significativa menor mortalidade. 40 Evidências preliminares em indivíduos transplantados também revelaram que aqueles em uso de ICN apresentaram melhores desfechos. 41,42 O potencial efeito benéfico dos ICN na replicação viral e modulação da resposta inflamatória é contraposto por um potencial efeito negativo na resposta imune adaptativa humoral, demonstrado por menor produção de anticorpos neutralizantes após a vacinação com os imunizantes BNT162b2 (Pfizer-Biontech), mRNA-1273 (Moderna) e ChAdOx1-nCoV-19 (AstraZeneca). ...
Os pacientes transplantados renais apresentam elevada taxa de letalidade após a infecção por síndrome respiratória aguda grave 2 (Sars-CoV-2). Além disso, a resposta imune vacinal é menor e menos duradoura, o que os torna mais susceptíveis a formas graves, mesmo quando vacinados. As evidências sugerem que, além da idade avançada e da elevada prevalência de comorbidades frequentemente associadas a pior prognóstico, como diabetes, obesidade e doenças cardiovasculares, a imunossupressão prolongada exerce um efeito independente sobre os desfechos. De fato, a resposta imune adaptativa celular e humoral, a qual está inibida pela imunossupressão, é passo fundamental para a resolução da infecção por Sars-CoV-2. Por outro lado, a inibição linfocitária poderia modular a produção aberrante de citocinas pró-inflamatórias que resultam no grave comprometimento pulmonar, amenizando a gravidade do quadro. Além disso, alguns fármacos imunossupressores possuem propriedades antivirais, potencialmente aplicáveis ao coronavírus. Essa revisão narrativa teve como objetivo discutir as evidências disponíveis sobre o impacto dos fármacos imunossupressores sobre os desfechos da Covid-19 em transplantados renais.
... An independent multicenter study with 40 kidney-transplanted patients also found that CsA significantly reduced mortality (Demir et al., 2020). Most strikingly, another observational single-center study (607 patients), where the impact of multiple prescribed therapies on clinical outcome after COVID-19 was assessed, identified CsA as the only therapy that was associated with a significant decrease in mortality (Guisado-Vasco et al., 2020). Likewise, in a study involving 243 liver transplant recipients, continuous use of FK506 was associated with improved patient survival (Belli et al., 2021;Yin et al., 2021). ...
Rationale
Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively.
Methods
Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication.
Results
Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model.
Conclusion
The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.
... For instance, the anti-inflammatory theophylline, which is used for the treatment of asthma and chronic obstructive pulmonary disease, has been associated with increased respiratory rate and oxygenation score in COVID-19 pneumonia patients (Wall et al., 2021), and its potential as a relevant candidate to treat COVID-19 patients was recently reviewed based on computational studies (Montaño et al., 2022). Cyclosporin A has been associated with decreased COVID-19 mortality (Guisado-Vasco et al., 2020) and it has been demonstrated to act as an antiviral against SARS-CoV-2 in preclinical infection models (Sauerhering et al., 2022). Fenofibrate has been suggested to enable faster recovery of COVID-19 patients compared to patients treated with standard care (Nahmias et al., 2021). ...
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading across the world despite vast global vaccination efforts. Consequently, many studies have looked for potential human host factors and immune mechanisms associated with the disease. However, most studies have focused on comparing COVID-19 patients to healthy controls, while fewer have elucidated the specific host factors distinguishing COVID-19 from other infections. To discover genes specifically related to COVID-19, we reanalyzed transcriptome data from nine independent cohort studies, covering multiple infections, including COVID-19, influenza, seasonal coronaviruses, and bacterial pneumonia. The identified COVID-19-specific signature consisted of 149 genes, involving many signals previously associated with the disease, such as induction of a strong immunoglobulin response and hemostasis, as well as dysregulation of cell cycle-related processes. Additionally, potential new gene candidates related to COVID-19 were discovered. To facilitate exploration of the signature with respect to disease severity, disease progression, and different cell types, we also offer an online tool for easy visualization of the selected genes across multiple datasets at both bulk and single-cell levels.
... Some CNI's are already being evaluated in clinical trials to determine their efficacy in COVID-19 patients [reviewed in (67)]. Interestingly, one study found a clear survival benefit for patients on CsA compared to other experimental antiinflammatory therapy for COVID-19 (68). In the current study we demonstrate that cyclophilin-dependent CNIs, VCS or CsA, inhibit SARS-CoV-2 replication in cell culture more potently than TAC. ...
Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI’s in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.
... A great amount of data has been generated mostly by analyzing samples from hospitalized patients (66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84) but in most of the cases,with a few exceptions, the effect of the different drugs administered immediately on admission (7,55) has not been considered. ...
Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.
